1Genomics 2001 Apr 73: 123-6
PMID11352574
TitleIdentification of genes from a schizophrenia-linked translocation breakpoint region.
AbstractThe translocation t(1:11)(q42.1,q14.3) has previously been found to be linked with schizophrenia. Genes present at the chromosome 1 breakpoint have been investigated in some detail but little was known about genes in the chromosome 11 breakpoint region. Here we report a BAC clone contig encompassing 2.51 MB around the chromosome 11 breakpoint, which was constructed computationally using draft genomic sequence data and existing mapping data for the region. The contig includes 26 clones and has led to the identification and relative ordering of 10 candidate genes in the region, including 2 novel transcripts. It constitutes a resource for polymorphic marker discovery and association studies to validate or reject candidate genes. Four candidate genes appear to be particularly promising based upon their proximity to the breakpoint and their likely functional roles. Three of these are involved in glutamatergic neurotransmission (the glutamate receptor GRM5, NAALADase II, and a close homolog), perturbation of which is one of the most widely held theories on the underlying biochemistry of schizophrenia. The 4th gene, tyrosinase, has been previously linked to schizophrenia through the cosegregation of oculocutaneous albinism with psychosis in several pedigrees.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
2Hum. Mol. Genet. 2001 Nov 10: 2645-50
PMID11726551
TitleMice deleted for the DiGeorge/velocardiofacial syndrome region show abnormal sensorimotor gating and learning and memory impairments.
AbstractDel22q11 syndrome is caused by heterozygous deletion of an approximately 3 MB segment of chromosome 22q11.2. Children diagnosed with del22q11 syndrome commonly have learning difficulties, deficits of motor development, cognitive defects and attention deficit disorder. They also have a higher than normal risk for developing psychiatric disorders, mainly schizophrenia, schizoaffective disorder and bipolar disorder. Here, we show that mice that are heterozygously deleted for a subset of the genes that are deleted in patients have deficits in sensorimotor gating and learning and memory. The finding of sensorimotor gating deficits is particularly significant because patients with schizophrenia and schizotypal personality disorder show similar deficits. Thus, our deletion mouse models at least two major features of the del22q11-associated behavioral phenotype, and as such, represents an animal model of this complex behavioral phenotype. These findings not only open the way to pharmacological analyses that may lead to improved treatments, but also to the identification of gene/s that modulate these specific behaviors in humans.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
3Hum. Mol. Genet. 2001 Nov 10: 2645-50
PMID11726551
TitleMice deleted for the DiGeorge/velocardiofacial syndrome region show abnormal sensorimotor gating and learning and memory impairments.
AbstractDel22q11 syndrome is caused by heterozygous deletion of an approximately 3 MB segment of chromosome 22q11.2. Children diagnosed with del22q11 syndrome commonly have learning difficulties, deficits of motor development, cognitive defects and attention deficit disorder. They also have a higher than normal risk for developing psychiatric disorders, mainly schizophrenia, schizoaffective disorder and bipolar disorder. Here, we show that mice that are heterozygously deleted for a subset of the genes that are deleted in patients have deficits in sensorimotor gating and learning and memory. The finding of sensorimotor gating deficits is particularly significant because patients with schizophrenia and schizotypal personality disorder show similar deficits. Thus, our deletion mouse models at least two major features of the del22q11-associated behavioral phenotype, and as such, represents an animal model of this complex behavioral phenotype. These findings not only open the way to pharmacological analyses that may lead to improved treatments, but also to the identification of gene/s that modulate these specific behaviors in humans.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
4Genomics 2002 May 79: 635-56
PMID11991713
TitleAn evaluation of the assembly of an approximately 15-Mb region on human chromosome 13q32-q33 linked to bipolar disorder and schizophrenia.
AbstractThe human 13q32-q33 region has been linked to both bipolar disorder and schizophrenia. Before completion of the draft sequences, we developed an approximately 15-MB comprehensive map for the region extending from D13S1300 to ATA35H12. This map was asseMBled using publicly available mapping data and sequence-tagged site (STS)-based PCR confirmation. We then compared this map with the NCBI, Celera Genomics, and UCSC Golden Path data in February, June, and SepteMBer 2001. All data sets showed gaps, misassignment of STSs, and errors in orientation and marker order. Surprisingly, the completed sequences of many bacterial artificial chromosomes (BACs) had been truncated. Of 21 gaps that were detected, 4 were present in both the NCBI and Celera databases. All gaps could be filled using 1-2 BAC clones. A total of 39 loci mapped to additional sites within the human genome, providing evidence of segmental duplications. Additionally, 61 unique cDNA clones were sequenced to increase available transcribed sequence, and 11,353 reference single-nucleotide polymorphisms (SNPs) with an average density of 1 SNP/3720 bases were identified. Overall, integration of the data from multiple sources is still needed for complete asseMBly of the 13q32-q33 region. (c)
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
5Hum. Hered. 2002 -1 54: 199-209
PMID12771552
TitleFine mapping of the schizophrenia susceptibility locus on chromosome 1q22.
Abstractschizophrenia is a serious neuropsychiatric illness estimated to affect approximately 1% of the general population. As part of a genome scan for schizophrenia susceptibility loci, we have previously reported a maximum heterogeneity four-point lod score of 6.50 on chromosome 1q21-22 in a group of 22 medium-sized Canadian families, selected for study because multiple relatives were clinically diagnosed with schizophrenia or schizoaffective disorder. We have now conducted fine mapping of this locus in the same set of individuals using 15 genetic markers spanning an approximately 15-cM interval. Parametric linkage analysis with GENEHUNTER v2.1 and VITESSE v2.0 produced a maximum multipoint heterogeneity lod score of 6.50, with a Zmax-1 support interval of <3 cM, corresponding to approximately 1 MB. Physical mapping and sequence analysis from this region confirmed the presence of an approximately 81-kb tandem duplication, containing low-affinity IgG receptor genes and heat shock protein genes. The sequences of the two copies of this duplication are approximately 97% identical, which has led to the collapse of the two copies into one in the June 2002 NCBI Build 30 of the Human Genome. This duplication may be involved in genomic instability, leading to gene deletion, and so presents an intriguing candidate locus for schizophrenia susceptibility.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
6Psychiatr. Genet. 2002 Dec 12: 231-5
PMID12454528
TitleA linkage disequilibrium study of bipolar disorder and microsatellite markers on 22q13.
AbstractBipolar disorder is a major psychiatric disorder characterized by extreme mood states that alternate between mania and depression. Family, twin, and adoption studies indicate a genetic component to the disease, but the etiology is suspected to be complex, with multiple genes contributing to an increased susceptibility to the disorder. We have previously reported a genome scan in which a genome-wide maximum LOD score indicated evidence of linkage at the marker D22S278 at 22q13. This area is of particular interest since it is also implicated in schizophrenia, and thus may harbor a susceptibility gene common to both disorders. In our further efforts to fine map this region, we examined 10 microsatellite markers spanning an interval of 2.3 MB in a set of 142 parent-proband triads. Linkage disequilibrium to illness was tested using the Transmission Disequilibrium Test. Haplotypes were determined and marker-to-marker linkage disequilibrium across the region was examined. D22S281 and D22S685 yielded suggestive evidence of linkage disequilibrium to bipolar disorder (empirical values of 0.023 and 0.036, respectively), but a marker-to-marker analysis indicates that a higher density screen is needed to adequately analyze this region.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
7Genomics 2002 Apr 79: 560-72
PMID11944989
TitleAn integrated, functionally annotated gene map of the DXS8026-ELK1 interval on human Xp11.3-Xp11.23: potential hotspot for neurogenetic disorders.
AbstractHuman chromosome Xp11.3-Xp11.23 encompasses the map location for a growing nuMBer of diseases with a genetic basis or genetic component. These include several eye disorders, syndromic and nonsyndromic forms of X-linked mental retardation (XLMR), X-linked neuromuscular diseases and susceptibility loci for schizophrenia, type 1 diabetes, and Graves' disease. We have constructed an approximately 2.7-MB high-resolution physical map extending from DXS8026 to ELK1, corresponding to a genetic distance of approximately 5.5 cM. A coMBination of chromosome walking and sequence-tagged site (STS)-content mapping resulted in an integrated framework and transcript map, precisely positioning 10 polymorphic microsatellites (one of which is novel), 16 ESTs, and 12 known genes (RP2, PCTK1, UHX1, UBE1, RBM10, ZNF157, SYN1, ARAF1, TIMP1, PFC, ELK1, UXT). The composite map is currently anchored with 89 STSs to give an average resolution of approximately 1 STS every 30 kb. By a coMBination of EST database searches and in silico detection of UniGene clusters within genomic sequence generated from this template map, we have mapped several novel genes within this interval: a Na+/H+ exchanger (SLC9A7), at least two zincfinger transcription factors (KIAA0215 and Hs.68318), carbohydrate sulfotransferase-7 (CHST7), regucalcin (RGN), inactivation-escape-1 (INE1), the human ortholog of mouse neuronal protein 15.6, and four putative novel genes. Further genomic analysis enabled annotation of the sequence interval with 20 predicted pseudogenes and 21 UniGene clusters of unknown function. The coMBined PAC/BAC transcript map and YAC scaffold presented here clarifies previously conflicting data for markers and genes within the Xp11.3-Xp11.23 interval and provides a powerful integrated resource for functional characterization of this clonally unstable, yet gene-rich and clinically significant region of proximal Xp.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
8Proc. Natl. Acad. Sci. U.S.A. 2002 Dec 99: 16859-64
PMID12477929
TitleGenetic variation in the 22q11 locus and susceptibility to schizophrenia.
AbstractAn increased prevalence of microdeletions at the 22q11 locus has been reported in samples of patients with schizophrenia. 22q11 microdeletions represent the highest known genetic risk factor for the development of schizophrenia, second only to that of the monozygotic cotwin of an affected individual or the offspring of two schizophrenic parents. It is therefore clear that a schizophrenia susceptibility locus maps to chromosome 22q11. In light of evidence for suggestive linkage for schizophrenia in this region, we hypothesized that, whereas deletions of chromosome 22q11 may account for only a small proportion of schizophrenia cases in the general population (up to approximately 2%), nondeletion variants of individual genes within the 22q11 region may make a larger contribution to susceptibility to schizophrenia in the wider population. By studying a dense collection of markers (average one single nucleotide polymorphism20 kb over 1.5 MB) in the vicinity of the 22q11 locus, in both family- and population-based samples, we present here results consistent with this assumption. Moreover, our results are consistent with contribution from more than one gene to the strikingly increased disease risk associated with this locus. Finer-scale haplotype mapping has identified two subregions within the 1.5-MB locus that are likely to harbor candidate schizophrenia susceptibility genes.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
9Proc. Natl. Acad. Sci. U.S.A. 2002 Dec 99: 16859-64
PMID12477929
TitleGenetic variation in the 22q11 locus and susceptibility to schizophrenia.
AbstractAn increased prevalence of microdeletions at the 22q11 locus has been reported in samples of patients with schizophrenia. 22q11 microdeletions represent the highest known genetic risk factor for the development of schizophrenia, second only to that of the monozygotic cotwin of an affected individual or the offspring of two schizophrenic parents. It is therefore clear that a schizophrenia susceptibility locus maps to chromosome 22q11. In light of evidence for suggestive linkage for schizophrenia in this region, we hypothesized that, whereas deletions of chromosome 22q11 may account for only a small proportion of schizophrenia cases in the general population (up to approximately 2%), nondeletion variants of individual genes within the 22q11 region may make a larger contribution to susceptibility to schizophrenia in the wider population. By studying a dense collection of markers (average one single nucleotide polymorphism20 kb over 1.5 MB) in the vicinity of the 22q11 locus, in both family- and population-based samples, we present here results consistent with this assumption. Moreover, our results are consistent with contribution from more than one gene to the strikingly increased disease risk associated with this locus. Finer-scale haplotype mapping has identified two subregions within the 1.5-MB locus that are likely to harbor candidate schizophrenia susceptibility genes.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
10Proc. Natl. Acad. Sci. U.S.A. 2002 Oct 99: 13675-80
PMID12364586
TitleGenetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia.
AbstractA map of 191 single-nucleotide polymorphism (SNPs) was built across a 5-MB segment from chromosome 13q34 that has been genetically linked to schizophrenia. DNA from 213 schizophrenic patients and 241 normal individuals from Canada were genotyped with this marker set. Two 1,400- and 65-kb regions contained markers associated with the disease. Two markers from the 65-kb region were also found to be associated to schizophrenia in a Russian sample. Two overlapping genes G72 and G30 transcribed in brain were experimentally annotated in this 65-kb region. Transfection experiments point to the existence of a 153-aa protein coded by the G72 gene. This protein is rapidly evolving in primates, is localized to endoplasmic reticulum/Golgi in transfected cells, is able to form multimers and specifically binds to carbohydrates. Yeast two-hybrid experiments with the G72 protein identified the enzyme d-amino acid oxidase (DAAO) as an interacting partner. DAAO is expressed in human brain where it oxidizes d-serine, a potent activator of N-methyl-D-aspartate type glutamate receptor. The interaction between G72 and DAAO was confirmed in vitro and resulted in activation of DAAO. Four SNP markers from DAAO were found to be associated with schizophrenia in the Canadian samples. Logistic regression revealed genetic interaction between associated SNPs in vicinity of two genes. The association of both DAAO and a new gene G72 from 13q34 with schizophrenia together with activation of DAAO activity by a G72 protein product points to the involvement of this N-methyl-d-aspartate receptor regulation pathway in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
11Proc. Natl. Acad. Sci. U.S.A. 2002 Oct 99: 13675-80
PMID12364586
TitleGenetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia.
AbstractA map of 191 single-nucleotide polymorphism (SNPs) was built across a 5-MB segment from chromosome 13q34 that has been genetically linked to schizophrenia. DNA from 213 schizophrenic patients and 241 normal individuals from Canada were genotyped with this marker set. Two 1,400- and 65-kb regions contained markers associated with the disease. Two markers from the 65-kb region were also found to be associated to schizophrenia in a Russian sample. Two overlapping genes G72 and G30 transcribed in brain were experimentally annotated in this 65-kb region. Transfection experiments point to the existence of a 153-aa protein coded by the G72 gene. This protein is rapidly evolving in primates, is localized to endoplasmic reticulum/Golgi in transfected cells, is able to form multimers and specifically binds to carbohydrates. Yeast two-hybrid experiments with the G72 protein identified the enzyme d-amino acid oxidase (DAAO) as an interacting partner. DAAO is expressed in human brain where it oxidizes d-serine, a potent activator of N-methyl-D-aspartate type glutamate receptor. The interaction between G72 and DAAO was confirmed in vitro and resulted in activation of DAAO. Four SNP markers from DAAO were found to be associated with schizophrenia in the Canadian samples. Logistic regression revealed genetic interaction between associated SNPs in vicinity of two genes. The association of both DAAO and a new gene G72 from 13q34 with schizophrenia together with activation of DAAO activity by a G72 protein product points to the involvement of this N-methyl-d-aspartate receptor regulation pathway in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
12Am. J. Hum. Genet. 2002 Aug 71: 337-48
PMID12098102
TitleGenetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia.
AbstractPrior evidence has supported the existence of multiple susceptibility genes for schizophrenia. Multipoint linkage analysis of the 270 Irish high-density pedigrees that we have studied, as well as results from several other samples, suggest that at least one such gene is located in region 6p24-21. In the present study, family-based association analysis of 36 simple sequence-length-polymorphism markers and of 17 SNP markers implicated two regions, separated by approximately 7 MB. The first region, and the focus of this report, is 6p22.3. In this region, single-nucleotide polymorphisms within the 140-kb gene DTNBP1 (dystrobrevin-binding protein 1, or dysbindin) are strongly associated with schizophrenia. Uncorrected, empirical P values produced by the program TRANSMIT were significant (P<.01) for a nuMBer of individual SNP markers, and most remained significant when the data were restricted to include only one affected offspring per nuclear family per extended pedigree; multiple three-marker haplotypes were highly significant (P=.008-.0001) under the restricted conditions. The pattern of linkage disequilibrium is consistent with the presence of more than one susceptibility allele, but this important issue is unresolved. The nuMBer of markers tested in the adjacent genes, all of which are negative, is not sufficient to rule out the possibility that the dysbindin gene is not the actual susceptibility gene, but this possibility appears to be very unlikely. We conclude that further investigation of dysbindin is warranted.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
13Proc. Natl. Acad. Sci. U.S.A. 2002 Mar 99: 3717-22
PMID11891283
TitleGenetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia.
AbstractThe location of a schizophrenia susceptibility locus at chromosome 22q11 has been suggested by genome-wide linkage studies. Additional support was provided by the observation of a higher-than-expected frequency of 22q11 microdeletions in patients with schizophrenia and the demonstration that approximately 20-30% of individuals with 22q11 microdeletions develop schizophrenia or schizoaffective disorder in adolescence and adulthood. Analysis of the extent of these microdeletions by using polymorphic markers afforded further refinement of this locus to a region of approximately 1.5 MB. Recently, a high rate of 22q11 microdeletions was also reported for a cohort of 47 patients with Childhood Onset schizophrenia, a rare and severe form of schizophrenia with onset by age 13. It is therefore likely that this 1.5-MB region contains one or more genes that predispose to schizophrenia. In three independent samples, we provide evidence for a contribution of the PRODH2/DGCR6 locus in 22q11-associated schizophrenia. We also uncover an unusual pattern of PRODH2 gene variation that mimics the sequence of a linked pseudogene. Several of the pseudogene-like variants we identified result in missense changes at conserved residues and may prevent synthesis of a fully functional enzyme. Our results have implications for understanding the genetic basis of the 22q11-associated psychiatric phenotypes and provide further insights into the genomic instability of this region.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
14Proc. Natl. Acad. Sci. U.S.A. 2003 Nov 100: 14433-8
PMID14614146
TitleA comprehensive analysis of 22q11 gene expression in the developing and adult brain.
AbstractDeletions at 22q11.2 are linked to DiGeorge or velocardiofacial syndrome (VCFS), whose hallmarks include heart, liMB, and craniofacial anomalies, as well as learning disabilities and increased incidence of schizophrenia. To assess the potential contribution of 22q11 genes to cognitive and psychiatric phenotypes, we determined the CNS expression of 32 mouse orthologs of 22q11 genes, primarily in the 1.5-MB minimal critical region consistently deleted in VCFS. None are uniquely expressed in the developing or adult mouse brain. Instead, 27 are localized in the eMBryonic forebrain as well as aortic arches, branchial arches, and liMB buds. Each continues to be expressed at apparently constant levels in the fetal, postnatal, and adult brain, except for Tbx1, ProDH2, and T10, which increase in adolescence and decline in maturity. At least six 22q11 proteins are seen primarily in subsets of neurons, including some in forebrain regions thought to be altered in schizophrenia. Thus, 22q11 deletion may disrupt expression of multiple genes during development and maturation of neurons and circuits compromised by cognitive and psychiatric disorders associated with VCFS.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
15Genomics 2003 May 81: 510-8
PMID12706109
TitleHigh-resolution SNP scan of chromosome 6p21 in pooled samples from patients with complex diseases.
AbstractWe apply a high-throughput protocol of chip-based mass spectrometry (matrix-assisted laser desorption/ionization time-of-flight; MALDI-TOF) as a method of screening for differences in single-nucleotide polymorphism (SNP) allele frequencies. Using pooled DNA from individuals with asthma, Crohn's disease (CD), schizophrenia, type 1 diabetes (T1D), and controls, we selected 534 SNPs from an initial set of 1435 SNPs spanning a 25-MB region on chromosome 6p21. The standard deviations of measurements of time of flight at different dots, from different PCRs, and from different pools indicate reliable results on each analysis step. In 90% of the disease-control comparisons we found allelic differences of <10%. Of the T1D samples, which served as a positive control, 10 SNPs with significant differences were observed after taking into account multiple testing. Of these 10 SNPs, 5 are located between DQB1 and DRB1, confirming the known association with the DR3 and DR4 haplotypes whereas two additional SNPs also reproduced known associations of T1D with DOB and LTA. In the CD pool also, two earlier described associations were found with SNPs close to DRB1 and MICA. Additional associations were found in the schizophrenia and asthma pools. They should be confirmed in individual samples or can be used to develop further quality criteria for accepting true differences between pools. The determination of SNP allele frequencies in pooled DNA appears to be of value in assigning further genotyping priorities also in large linkage regions.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
16Am. J. Hum. Genet. 2003 Sep 73: 601-11
PMID12929083
TitleGenomewide linkage scan for schizophrenia susceptibility loci among Ashkenazi Jewish families shows evidence of linkage on chromosome 10q22.
AbstractPrevious linkage studies in schizophrenia have been discouraging due to inconsistent findings and weak signals. Genetic heterogeneity has been cited as one of the primary culprits for such inconsistencies. We have performed a 10-cM autosomal genomewide linkage scan for schizophrenia susceptibility regions, using 29 multiplex families of Ashkenazi Jewish descent. Although there is no evidence that the rate of schizophrenia among the Ashkenazim differs from that in other populations, we have focused on this population in hopes of reducing genetic heterogeneity among families and increasing the detectable effects of any particular locus. We pursued both allele-sharing and parametric linkage analyses as implemented in Genehunter, version 2.0. Our strongest signal was achieved at chromosome 10q22.3 (D10S1686), with a nonparametric linkage score (NPL) of 3.35 (genomewide empirical P=.035) and a dominant heterogeneity LOD score (HLOD) of 3.14. Six other regions gave NPL scores >2.00 (on chromosomes 1p32.2, 4q34.3, 6p21.31, 7p15.2, 15q11.2, and 21q21.2). Upon follow-up with an additional 23 markers in the chromosome 10q region, our peak NPL score increased to 4.27 (D10S1774; empirical P=.00002), with a 95% confidence interval of 12.2 MB for the location of the trait locus (D10S1677 to D10S1753). We find these results encouraging for the study of schizophrenia among Ashkenazi families and suggest further linkage and association studies in this chromosome 10q region.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
17Nat. Genet. 2004 Jul 36: 725-31
PMID15184899
TitleEvidence that the gene encoding ZDHHC8 contributes to the risk of schizophrenia.
AbstractUsing a relatively dense genetic map of 72 single-nucleotide polymorphisms (SNPs) distributed across the entire 1.5-MB locus on chromosome 22q11 associated with susceptibilit to schizophrenia, we previously identified two subregions that were consistently associated with the disease. In the distal subregion, we detected an association signal with five neighboring SNPs distributed over a haplotypic block of 80 kb encompassing six known genes. One of these five SNPs, rs175174, had the strongest association of all 72 SNPs that we tested. Here we show that rs175174 regulates the level of the fully functional transcript by modulating the retention of intron 4 of the gene ZDHHC8, which encodes a putative transmeMBrane palmitoyltransferase. Zdhhc8-knockout mice had a sexually dimorphic deficit in prepulse inhibition, a gene dosage-dependent decrease in exploratory activity in a new environment and a decreased sensitivity to the locomotor stimulatory effects of the psychomimetic drug dizocilpine (MK801). SNP rs175174 shows differences in transmission distortion between sexes in individuals with schizophrenia. Our results indicate that there is an unexpected connection between impaired palmitate modification of neuronal proteins and the psychiatric phenotypes associated with microdeletions of chromosome 22q11.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
18Am. J. Hum. Genet. 2004 May 74: 1057-63
PMID15065015
TitleLinkage disequilibrium mapping of schizophrenia susceptibility to the CAPON region of chromosome 1q22.
AbstractPreviously, we have reported linkage of markers from chromosome 1q22 to schizophrenia, a finding supported by several independent studies. We have now examined the region of strongest linkage for evidence of linkage disequilibrium (LD) in a sample of 24 Canadian familial-schizophrenia pedigrees. Analysis of 14 microsatellites and 15 single-nucleotide polymorphisms (SNPs) from the 5.4-MB region between D1S1653 and D1S1677 produced significant evidence (nominal P<.05) of LD between schizophrenia and 2 microsatellites and 6 SNPs. All of the markers exhibiting significant LD to schizophrenia fall within the genomic extent of the gene for carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase (CAPON), making it a prime positional candidate for the schizophrenia-susceptibility locus on 1q22, although initial mutation analysis of this gene has not identified any schizophrenia-associated changes within exons. Consistent with several recently identified candidate genes for schizophrenia, CAPON is involved in signal transduction in the NMDA receptor system, highlighting the potential importance of this pathway in the etiology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
19Nature 2004 Apr 428: 522-8
PMID15057823
TitleThe DNA sequence and analysis of human chromosome 13.
AbstractChromosome 13 is the largest acrocentric human chromosome. It carries genes involved in cancer including the breast cancer type 2 (BRCA2) and retinoblastoma (RB1) genes, is frequently rearranged in B-cell chronic lymphocytic leukaemia, and contains the DAOA locus associated with bipolar disorder and schizophrenia. We describe completion and analysis of 95.5 megabases (MB) of sequence from chromosome 13, which contains 633 genes and 296 pseudogenes. We estimate that more than 95.4% of the protein-coding genes of this chromosome have been identified, on the basis of comparison with other vertebrate genome sequences. Additionally, 105 putative non-coding RNA genes were found. Chromosome 13 has one of the lowest gene densities (6.5 genes per MB) among human chromosomes, and contains a central region of 38 MB where the gene density drops to only 3.1 genes per MB.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
20Brain Res. Mol. Brain Res. 2004 Dec 132: 95-104
PMID15582150
TitleThe molecular genetics of the 22q11-associated schizophrenia.
Abstractschizophrenia has a strong genetic component but the mode of inheritance of the disease is complex and in all likelihood involves interaction among multiple genes and also possibly environmental or stochastic factors. A nuMBer of studies have shown that the 22q11 deletion syndrome (22q11DS) is a true genetic subtype of schizophrenia and as such may play an extremely important role in deciphering the genetic basis of schizophrenia. Microdeletions of the 22q11 locus are associated with a staggering increased risk to develop schizophrenia. The same locus has also been implicated by some linkage studies. Systematic examination of individual genes from the 1.5 MB critical region has identified so far the PRODH and ZDHHC8 as strong candidate schizophrenia susceptibility genes from this locus. Discovery of these genes implicates neuromodulatory aminoacids and protein palmitoylation as important for disease development. Other genes, including the gene encoding for COMT, have been implicated by candidate gene approaches. It therefore appears that the 22q11-associated schizophrenia may have the characteristics of a contiguous gene syndrome, where deficiency in more than one gene contributes to the strikingly increased disease risk. Mouse models for individual candidate genes will provide the investigators with the opportunity to start understanding the function of these genes and how they may impact on schizophrenia. Mouse models that carry long-range deletions will likely capture the interactions among the culprit genes and help explain the genetic contribution of this locus to the high risk for schizophrenia. In-depth human and animal model studies of 22q11DS promise to answer critical questions relating to the devastating illness of schizophrenia, whose causes remain largely unknown.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
21Mol. Psychiatry 2004 Jul 9: 698-704
PMID15007393
TitleIdentification of a novel neuregulin 1 at-risk haplotype in Han schizophrenia Chinese patients, but no association with the Icelandic/Scottish risk haplotype.
AbstractTo determine if neuregulin 1 (NRG1) is associated with schizophrenia in Asian populations, we investigated a Han Chinese population using both a family trio design and a case-control design. A total of 25 microsatellite markers and single nucleotide polymorphisms (SNPs) were genotyped spanning the 1.1 MB NRG1 gene including markers of a seven-marker haplotype at the 5' end of the gene found to be in excess in Icelandic and Scottish schizophrenia patients. The alleles of the individual markers forming the seven marker at-risk haplotype are not likely to be causative as they are not in excess in patients in the Chinese population studied here. However using unrelated patients, we find a novel haplotype (HAP(China 1)), immediately upstream of the Icelandic haplotype, in excess in patients (11.9% in patients vs 4.2% in controls; P=0.0000065, risk ratio (rr) 3.1), which was not significant when parental controls were used. Another haplotype (HAP(China 2)) overlapping the Icelandic risk haplotype was found in excess in the Chinese (8.5% of patients vs 4.0% of unrelated controls; P=0.003, rr 2.2) and was also significant using parental controls only (P=0.0047, rr 2.1). A four-marker haplotype at the 3' end of the NRG1 gene, HAP(China 3), was found at a frequency of 23.8% in patients and 13.7% in nontransmitted parental haplotypes (P=0.000042, rr=2.0) but was not significant in the case-control comparison. We conclude that different haplotypes within the boundaries of the NRG1 gene may be associated with schizophrenia in the Han Chinese.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
22Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 Jul 128B: 50-3
PMID15211631
TitleMECP2 structural and 3'-UTR variants in schizophrenia, autism and other psychiatric diseases: a possible association with autism.
AbstractMutations in the gene coding for methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome (RTT) and have also been reported in a nuMBer of X-linked mental retardation syndromes. Furthermore, putative mutations recently have been described in a few autistic patients and a boy with language disorder and schizophrenia. In this study, DNA samples from individuals with schizophrenia and other psychiatric diseases were scanned in order to explore whether the phenotypic spectrum of mutations in the MECP2 gene can extend beyond the traditional diagnoses of RTT in females and severe neonatal encephalopathy in males. The coding regions, adjacent splicing junctions, and highly conserved segments of the 3'-untranslated region (3'-UTR) were examined in 214 patients, including 106 with schizophrenia, 24 with autism, and 84 patients with other psychiatric diseases by detection of virtually all mutations-single strand conformation polymorphism (SSCP) (DOVAM-S). To our knowledge, this is the first analysis of variants in conserved regions of the 3'-UTR of this gene. A total of 5.2 kb per haploid gene was analyzed (1.5 MB for 214 patients). A higher frequency of missense and 3'-UTR variants was found in autism. One missense and two 3'-UTR variants were found in 24 patients with autism versus one patient with a missense change in 144 ethnically similar individuals without autism (P = 0.009). These mutations suggest that a possible association between MECP2 mutations and autism may warrant further study.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
23Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004 May 127B: 30-4
PMID15108176
TitleGenome-wide scan in Portuguese Island families implicates multiple loci in bipolar disorder: fine mapping adds support on chromosomes 6 and 11.
AbstractAs part of an extensive study in the Portuguese Island population of families with multiple patients suffering from bipolar disorder and schizophrenia, we performed an initial genome-wide scan of 16 extended families with bipolar disorder that identified three regions on chromosomes 2, 11, and 19 with genome-wide suggestive linkage and several other regions, including chromosome 6q, also approached suggestive levels of significance. Dick et al. [2003: Am J Hum Genet 73:107-114] recently reported in a study of 250 families with bipolar disorder a maxLOD score of 3.61 near marker D6S1021 on chromosome 6q. This study replicates this finding having detected a peak NPL = 2.02 (P = 0.025) with the same marker D6S1021(104.7 MB). Higher-density mapping provided additional support for loci on chromosome 6 including marker D6S1021 with an NPL = 2.59 (P = 0.0068) and peaking at marker D6S1639 (125 MB) with an NPL = 3.06 (P = 0.0019). A similar pattern was detected with higher-density mapping of chromosome 11 with an NPL = 3.15 (P = 0.0014) at marker D11S1883 (63.1 MB). Simulations at the density of our fine mapping data indicate that less than 1 scan out of 10 would find two such scores genome-wide in the same scan by chance. Our findings provide additional support for a susceptibility locus for bipolar disorder on 6q, as well as, suggesting the importance of denser scans. Published 2004 Wiley-Liss, Inc.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
24Psychiatr. Genet. 2005 Sep 15: 205-10
PMID16094256
TitleFine mapping of the 5p13 locus linked to schizophrenia and schizotypal personality disorder in a Puerto Rican family.
AbstractA locus involved in schizophrenia and related disorders in a Puerto Rican family has previously been mapped to chromosome 5p. The maximum two-point log of the odds (LOD) score of 3.72 was obtained for marker D5S111, and increased to 4.37 by multipoint analysis, assuming autosomal dominant inheritance with 90% penetrance. Additional genotyping and haplotype analysis placed the novel locus on 5p13.2-p13.3 within the interval between markers D5S1993 and D5S631. In the current study, we saturated the interval between markers D5S1993 and D5S631 with densely spaced polymorphic markers, genotyped these markers in the most informative branch of the family, and narrowed the critical region to 2.8 MB. G-protein-coupled receptor gene [somatostatin and angiotensin-like peptide receptor (SALPR)] is one of the candidate genes within the critical interval. Sequence analysis of the coding region and the putative promoter of somatostatin and angiotensin-like peptide receptor did not reveal functionally significant variants in affected family meMBers, although several polymorphisms were detected.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
25Psychiatr. Genet. 2005 Sep 15: 205-10
PMID16094256
TitleFine mapping of the 5p13 locus linked to schizophrenia and schizotypal personality disorder in a Puerto Rican family.
AbstractA locus involved in schizophrenia and related disorders in a Puerto Rican family has previously been mapped to chromosome 5p. The maximum two-point log of the odds (LOD) score of 3.72 was obtained for marker D5S111, and increased to 4.37 by multipoint analysis, assuming autosomal dominant inheritance with 90% penetrance. Additional genotyping and haplotype analysis placed the novel locus on 5p13.2-p13.3 within the interval between markers D5S1993 and D5S631. In the current study, we saturated the interval between markers D5S1993 and D5S631 with densely spaced polymorphic markers, genotyped these markers in the most informative branch of the family, and narrowed the critical region to 2.8 MB. G-protein-coupled receptor gene [somatostatin and angiotensin-like peptide receptor (SALPR)] is one of the candidate genes within the critical interval. Sequence analysis of the coding region and the putative promoter of somatostatin and angiotensin-like peptide receptor did not reveal functionally significant variants in affected family meMBers, although several polymorphisms were detected.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
26BMC Genomics 2005 -1 6: 157
PMID16280085
TitleGenetic mapping of putative Chrna7 and Luzp2 neuronal transcriptional enhancers due to impact of a transgene-insertion and 6.8 Mb deletion in a mouse model of Prader-Willi and Angelman syndromes.
AbstractPrader-Willi and Angelman syndrome (PWS and AS) patients typically have an approximately 5 MB deletion of human chromosome 15q11-q13, of opposite parental origin. A mouse model of PWS and AS has a transgenic insertion-deletion (TgPWS/TgAS) of chromosome 7B/C subsequent to paternal or maternal inheritance, respectively. In this study, we define the deletion endpoints and examine the impact on expression of flanking genes.
Using molecular and cytological methods we demonstrate that 13 imprinted and 11 non-imprinted genes are included in the TgPWS/TgAS deletion. Normal expression levels were found in TgPWS brain for genes extending 9.1- or 5.6-MB centromeric or telomeric of the deletion, respectively. Our molecular cytological studies map the proximal deletion breakpoint between the Luzp2 and Siglec-H loci, and we show that overall mRNA levels of Luzp2 in TgPWS and TgAS brain are significantly reduced by 17%. Intriguingly, 5' Chrna7 shows 1.7-fold decreased levels in TgPWS and TgAS brain whereas there is a > or =15-fold increase in expression in neonatal liver and spleen of these mouse models. By isolating a Chrna7-Tg fusion transcript from TgAS mice, we mapped the telomeric deletion breakpoint in Chrna7 intron 4.
Based on the extent of the deletion, TgPWS/TgAS mice are models for PWS/AS class I deletions. Other than for the first gene promoters immediately outside the deletion, since genes extending 5.6-9.1 MB away from each end of the deletion show normal expression levels in TgPWS brain, this indicates that the transgene array does not induce silencing and there are no additional linked rearrangements. Using gene expression, non-coding conserved sequence (NCCS) and synteny data, we have genetically mapped a putative Luzp2 neuronal enhancer responsible for approximately 33% of allelic transcriptional activity. The Chrna7 results are explained by hypothesizing loss of an essential neuronal transcriptional enhancer required for approximately 80% of allelic Chrna7 promoter activity, while the Chrna7 promoter is upregulated in B lymphocytes by the transgene immunoglobulin enhancer. The mapping of a putative Chrna7 neuronal enhancer inside the deletion has significant implications for understanding the transcriptional regulation of this schizophrenia-susceptibility candidate gene.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
27Am. J. Med. Genet. B Neuropsychiatr. Genet. 2005 Feb 133B: 37-42
PMID15635661
TitleSite-specific cytosine methylation in S-COMT promoter in 31 brain regions with implications for studies involving schizophrenia.
AbstractThe catechol-o-methyltransferase (COMT) gene on chromosome 22q11 has been considered a strong candidate gene for schizophrenia (SZ) susceptibility. A functional Val/Met polymorphism in exon 4, with potential to affect COMT activity has been implicated in SZ, but the results remain inconclusive. We hypothesized that the association of COMT gene with SZ is not strictly a genetic alteration but could involve DNA methylation, as an epigenetic alteration. Thus, we chose to examine the cytosine DNA methylation profile of the human COMT promoter regions, which partially overlaps with the MB-COMT coding region and covers a total of 56 cytosines. Our analysis of 31 brain regions and 51 individual blood samples suggests that the cytosine methylation in his region is restricted to the CpG dinucleotides only. Also, the methylation pattern is nearly identical in the brain and blood with few exceptions. One cytosine (#27) is partially methylated in 5 brain regions and another cytosine (#23) is partially methylated in 81 of 82 samples studied. The exception being the blood DNA from a single SZ patient with prominent extreme negative symptoms, which was completely methylated. Interestingly, there was no difference in methylation at these sites in the blood DNA from three pairs of monozygotic twins discordant for SZ. The results support the use of blood DNA in methylation studies and rule out S-COMT promoter methylation as a common cause of SZ. The unique observation of a completely methylated cytosine 23 in one patient with SZ may have the potential to affect COMT mRNA transcription and gene activity, but remains to be evaluated.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
28Curr. Top. Dev. Biol. 2005 -1 69: 101-38
PMID16243598
TitleClassical embryological studies and modern genetic analysis of midbrain and cerebellum development.
AbstractThe brain is a remarkably complex anatomical structure that contains a diverse array of subdivisions, cell types, and synaptic connections. It is equally extraordinary in its physiological properties, as it constantly evaluates and integrates external stimuli as well as controls a complicated internal environment. The brain can be divided into three primary broad regions: the forebrain, midbrain (MB), and hindbrain (Hb), each of which contain further subdivisions. The regions considered in this chapter are the MB and most-anterior Hb (MB/aHb), which are derived from the mesencephalon (mes) and rhoMBomere 1 (r1), respectively. The dorsal MB consists of the laminated superior colliculus and the globular inferior colliculus (Fig. 1A and B), which modulate visual and auditory stimuli, respectively. The dorsal component of the aHb is the highly foliated cerebellum (Cb), which is primarily attributed to controlling motor skills (Fig. 1A and B). In contrast, the ventral MB/aHb (Fig. 1B) consists of distinct clusters of neurons that together comprise a network of nuclei and projections-notably, the MB dopaminergic and Hb serotonergic and MB/aHb cholinergic neurons (Fig. 1G and H), which modulate a collection of behaviors, including movement, arousal, feeding, wakefulness, and emotion. Historically, the dorsal MB and Cb have been studied using the chick as a model system because of the ease of performing both cell labeling and tissue transplants in the eMBryo in ovo; currently DNA electroporation techniques are also used. More recently the mouse has emerged as a powerful genetic system with numerous advantages to study events underpinning MB/aHb development. There is a diverse array of spontaneous mutants with both MB- and Cb-related phenotypes. In addition, numerous gene functions have been enumerated in mouse, gene expression is similar across vertebrates, and powerful genetic tools have been developed. Finally, additional insight into MB/aHb function has been gained from studies of genetic diseases, such as Parkinson's disease, schizophrenia, cancer, and Dandy Walker syndrome, that afflict the MB/aHb in humans and have genetic counterparts in mouse. Accordingly, this chapter discusses a spectrum of experiments, including classic eMBryology, in vitro assays, sophisticated genetic methods, and human diseases. We begin with an overview of MB and aHb anatomy and physiology and mes/r1 gene expression patterns. We then provide a summary of fate-mapping studies that collectively demonstrate the complex cell behaviors that occur while the MB and aHb primordia are established during eMBryogenesis and discuss the integration of both anterior-posterior (A-P) and dorsal-ventral (D-V) patterning. Finally, we describe some aspects of postnatal development and some of the insights gained from human diseases.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
29Am. J. Med. Genet. A 2006 Jun 140: 1208-13
PMID16642507
TitleSchizophrenia in an adult with 6p25 deletion syndrome.
AbstractChromosomal deletions at 6p25-p24 are rare findings in patients with developmental delay. There is limited information about the adult phenotype. We present a 36-year-old patient with schizophrenia, mild mental retardation, progressive hearing deficits, and characteristic facial features. Ocular (Axenfeld-Rieger anomaly) abnormalities were diagnosed in infancy; vision, however, has remained unimpaired. There were no other major congenital anomalies. Brain imaging showed only minor changes. There was no family history of intellectual deficits or psychosis. Karyotyping revealed a 6p25 deletion, and detailed fluorescence in situ hybridization (FISH) analyses using 23 probes confirmed a 6.7 MB 6p25-pter deletion. The breakpoint is near a possible 6p25-p24 locus for schizophrenia. Psychotic illness may be part of the neurodevelopmental abnormalities and long-term outcome of patients with 6p terminal deletions. Other similarly affected patients likely remain to be diagnosed in adult populations of schizophrenia and/or mental retardation.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
30Hum. Genet. 2006 Jun 119: 558-70
PMID16604350
TitleGenome scans and gene expression microarrays converge to identify gene regulatory loci relevant in schizophrenia.
AbstractMultiple linkage regions have been reported in schizophrenia, and some appear to harbor susceptibility genes that are differentially expressed in postmortem brain tissue derived from unrelated individuals. We coMBined traditional genome-wide linkage analysis in a multiplex family with lymphocytic genome-wide expression analysis. A genome scan suggested linkage to a chromosome 4q marker (D4S1530, LOD 2.17, theta = 0) using a dominant model. Haplotype analysis using flanking microsatellite markers delineated a 14 MB region that cosegregated with all those affected. Subsequent genome-wide scan with SNP genotypes supported the evidence of linkage to 4q33-35.1 (LOD = 2.39) using a dominant model. Genome-wide microarray analysis of five affected and five unaffected family meMBers identified two differentially expressed genes within the haplotype AGA and GALNT7 (aspartylglucosaminidase and UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 7) with nominal significance; however, these genes did not remain significant following analysis of covariance. We carried out genome-wide linkage analyses between the quantitative expression phenotype and genetic markers. AGA expression levels showed suggestive linkage to multiple markers in the haplotype (maximum LOD = 2.37) but to no other genomic region. GALNT7 expression levels showed linkage to regulatory loci at 4q28.1 (maximum LOD = 3.15) and in the haplotype region at 4q33-35.1 (maximum LOD = 2.37). ADH1B (alcohol dehydrogenase IB) was linked to loci at 4q21-q23 (maximum LOD = 3.08) and haplotype region at 4q33-35.1 (maximum LOD = 2.27). Seven differentially expressed genes were validated with RT-PCR. Three genes in the 4q33-35.1 haplotype region were also differentially expressed in schizophrenia in postmortem dorsolateral prefrontal cortex: AGA, HMGB2, and SCRG1. These results indicate that coMBining differential gene expression with linkage analysis may help in identifying candidate genes and potential regulatory sites. Moreover, they also replicate recent findings of complex trans- and cis- regulation of genes.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
31Schizophr. Res. 2006 Dec 88: 251-9
PMID17008057
TitleAltered expression of hippocampal dentate granule neuron genes in a mouse model of human 22q11 deletion syndrome.
AbstractHemizygous deletion of a 3 MB region of 22q11.2 is found in 1/4000 humans and produces 22q11 deletion syndrome (22q11DS). Up to 35% of 22q11DS patients develop schizophrenia, making it the second highest risk factor for schizophrenia. A mouse model for 22q11DS, the Df1/+ mouse, carries a hemizygous deletion in a region syntenic with the human deletion. Df1/+ mice are mostly viable but display deficits in prepulse inhibition and learning and memory, two common traits of schizophrenia thought to result, at least in part, from defects in hippocampal neurons. We used oligonucleotide microarrays and QRT-PCR to evaluate gene expression changes in hippocampal dentate granule neurons of Df1/+ mice versus wild-type littermates (n=12/group). The expression of only 287 genes changed with p value significance below 0.05 by microarray, yet 12 of the 21 Df1 region genes represented on the array showed highly significantly reduced expression compared to wild-type controls (33% on average, p values from 10(-3) to 10(-7)). Variants in two of these genes, COMT and PRODH, have been linked with schizophrenia. Overlap of the 287 genes with the reportedly reduced expression of mitochondrial, ubiquitin/proteasome, and synaptic plasticity genes in schizophrenia dentate granule neurons, was not significant. However, modest increases in expression of mitochondrial electron transport genes were observed in the Df1/+ mice. This perhaps indicates a compensation for mitochondrial dysfunction caused by the strongly reduced expression of the Df1 region-encoded mitochondrial enzymes proline dehydrogenase (Prodh) and thioredoxin reductase 2 (Txnrd2).
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
32Hum. Mol. Genet. 2006 Nov 15: 3132-45
PMID16984965
TitleHypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder.
AbstractThe variability in phenotypic presentations and the lack of consistency of genetic associations in mental illnesses remain a major challenge in molecular psychiatry. Recently, it has become increasingly clear that altered promoter DNA methylation could play a critical role in mediating differential regulation of genes and in facilitating short-term adaptation in response to the environment. Here, we report the investigation of the differential activity of meMBrane-bound catechol-O-methyltransferase (MB-COMT) due to altered promoter methylation and the nature of the contribution of COMT Val158Met polymorphism as risk factors for schizophrenia and bipolar disorder by analyzing 115 post-mortem brain samples from the frontal lobe. These studies are the first to reveal that the MB-COMT promoter DNA is frequently hypomethylated in schizophrenia and bipolar disorder patients, compared with the controls (methylation rate: 26 and 29 versus 60%; P=0.004 and 0.008, respectively), particularly in the left frontal lobes (methylation rate: 29 and 30 versus 81%; P=0.003 and 0.002, respectively). Quantitative gene-expression analyses showed a corresponding increase in transcript levels of MB-COMT in schizophrenia and bipolar disorder patients compared with the controls (P=0.02) with an accompanying inverse correlation between MB-COMT and DRD1 expression. Furthermore, there was a tendency for the enrichment of the Val allele of the COMT Val158Met polymorphism with MB-COMT hypomethylation in the patients. These findings suggest that MB-COMT over-expression due to promoter hypomethylation and/or hyperactive allele of COMT may increase dopamine degradation in the frontal lobe providing a molecular basis for the shared symptoms of schizophrenia and bipolar disorder.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
33Hum. Genet. 2006 Sep 120: 160-70
PMID16783572
TitleA complete genetic association scan of the 22q11 deletion region and functional evidence reveal an association between DGCR2 and schizophrenia.
AbstractSeveral lines of evidence have established the presence of an association between a 3-MB deletion in chromosome 22q11 and schizophrenia. In this paper we present a complete high-density SNP scan of this segment using DNA pools, and demonstrate significant association between two distinct regions and schizophrenia in an Ashkenazi Jewish population. One of these regions contains the previously identified COMT gene. The pattern of association and linkage disequilibrium (LD) in the second region suggest that DGCR2, which encodes a putative adhesion receptor protein, is the susceptibility gene. We confirmed the association between DGCR2 and schizophrenia through individual genotyping of 1,400 subjects. In a gene expression analysis the risk allele of a coding SNP associated with schizophrenia was found to be associated with a reduced expression of DGCR2. Interestingly, the expression of DGCR2 was also found to be elevated in the dorsolateral prefrontal cortex of schizophrenic patients relative to matched controls. This increase is likely to be explained by exposure to antipsychotic drugs. To test that hypothesis, we looked at rats exposed to antipsychotic medication and found significantly elevated levels of DGCR2 transcripts. The genetic and functional evidences here reported suggest a possible role of the DGCR2 gene in the pathology of schizophrenia and also in the therapeutic effects of antipsychotic drugs.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
34Hum. Genet. 2006 Sep 120: 160-70
PMID16783572
TitleA complete genetic association scan of the 22q11 deletion region and functional evidence reveal an association between DGCR2 and schizophrenia.
AbstractSeveral lines of evidence have established the presence of an association between a 3-MB deletion in chromosome 22q11 and schizophrenia. In this paper we present a complete high-density SNP scan of this segment using DNA pools, and demonstrate significant association between two distinct regions and schizophrenia in an Ashkenazi Jewish population. One of these regions contains the previously identified COMT gene. The pattern of association and linkage disequilibrium (LD) in the second region suggest that DGCR2, which encodes a putative adhesion receptor protein, is the susceptibility gene. We confirmed the association between DGCR2 and schizophrenia through individual genotyping of 1,400 subjects. In a gene expression analysis the risk allele of a coding SNP associated with schizophrenia was found to be associated with a reduced expression of DGCR2. Interestingly, the expression of DGCR2 was also found to be elevated in the dorsolateral prefrontal cortex of schizophrenic patients relative to matched controls. This increase is likely to be explained by exposure to antipsychotic drugs. To test that hypothesis, we looked at rats exposed to antipsychotic medication and found significantly elevated levels of DGCR2 transcripts. The genetic and functional evidences here reported suggest a possible role of the DGCR2 gene in the pathology of schizophrenia and also in the therapeutic effects of antipsychotic drugs.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
35Mol. Psychiatry 2006 Jan 11: 66-75
PMID16189508
TitleExtreme population differences across Neuregulin 1 gene, with implications for association studies.
AbstractNeuregulin 1 (NRG1) is one of the most exciting candidate genes for schizophrenia in recent years since its first association with the disease in an Icelandic population. Since then, many association studies have analysed allele and haplotype frequencies in distinct populations yielding varying results: some have replicated the association, although with different alleles or haplotypes being associated, whereas others have failed to replicate the association. These contradictory results might be attributed to population differences in allele and haplotype frequencies. In order to approach this issue, we have typed 13 SNPs across this large 1.4 MB gene, including two of the SNPs originally found associated with schizophrenia in the Icelandic population, the objective being to discover if the underlying cause of the association discrepancies to date may be due to population-specific genetic variation. The analyses have been performed in a total of 1088 individuals from 39 populations, covering most of the genetic diversity in the human species. Most of the SNPs analysed displayed differing frequencies according to geographical region. These allele differences are especially relevant in two SNPs located in a large intron of the gene, as shown by the extreme F(ST) values, which reveal genetic stratification correlated to broad continental areas. This finding may be indicative of the influence of some local selective forces on this gene. Furthermore, haplotype analysis reveals a clear clustering according to geographical areas. In summary, our findings suggest that NRG1 presents extreme population differences in allele and haplotype frequencies. We have given recommendations for taking this into account in future association studies since this diversity could give rise to erroneous results.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
36Biol. Psychiatry 2006 Sep 60: 554-62
PMID16997000
TitleA single nucleotide polymorphism fine mapping study of chromosome 1q42.1 reveals the vulnerability genes for schizophrenia, GNPAT and DISC1: Association with impairment of sustained attention.
AbstractThe marker D1S251 of chromosome 1q42.1 showed significant association with schizophrenia in a Taiwanese sample. We used single nucleotide polymorphism (SNP) fine mapping to search for the vulnerability genes of schizophrenia.
We selected 120 SNPs covering 1 MB around D1S251 from the public database. These selected SNPs were initially validated if allele frequency was >10%. Forty-seven validated SNPs were genotyped in 102 families with at least 2 siblings affected with schizophrenia.
Two SNP blocks showed significant association with schizophrenia. Block 1 (five-SNP), located between intron 2 and intron 13 of the glyceronephosphate O-acyltransferase (GNPAT) gene, showed the most significant associations using single-locus TDT (z = -2.07, p = .038, df = 1) and haplotype association analyses (z = -1.99, p = .046, df = 1). Block 2 (two-SNP), located between intron 4 and intron 5 of the disrupted-in-schizophrenia 1 (DISC1) gene, also showed the most significant results in both the single-locus (z = -3.22, p = .0013, df = 1) and haplotype association analyses (z = 3.35, p = .0008, df = 1). The association of the DISC1 gene with schizophrenia was mainly in the patient group with sustained attention deficits as assessed by the Continuous Performance Test.
Chromosome 1q42.1 harbors GNPAT and DISC1 as candidate genes for schizophrenia, and DISC1 is associated with sustained attention deficits.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
37Neurogenetics 2006 Nov 7: 247-57
PMID16900388
TitleBehavior of mice with mutations in the conserved region deleted in velocardiofacial/DiGeorge syndrome.
AbstractVelocardiofacial/DiGeorge syndrome (VCFS/DGS) is a developmental disorder caused by a 1.5 to 3-MB hemizygous 22q11.2 deletion. VCFS/DGS patients display malformations in multiple systems, as well as an increased frequency of neuropsychiatric defects including schizophrenia. Haploinsufficiency of TBX1 appears to be responsible for these physical malformations in humans and mice, but the genes responsible for the neuropsychiatric defects are unknown. In this study, two mouse models of VCFS/DGS, a deletion mouse model (Lgdel/+) and a single gene model (Tbx1 +/-), as well as a third mouse mutant (Gscl -/-) for a gene within the Lgdel deletion, were tested in a large behavioral battery designed to assess gross physical features, sensorimotor reflexes, motor activity nociception, acoustic startle, sensorimotor gating, and learning and memory. Lgdel/+ mice contain a 1.5-MB hemizygous deletion of 27 genes in the orthologous region on MMU 16 and present with impairment in sensorimotor gating, grip strength, and nociception. Tbx1 +/- mice were impaired in grip strength similar to Lgdel/+ mice and movement initiation. Gscl -/- mice were not impaired in any of the administered tests, suggesting that redundant function of other Gsc family meMBers may compensate for the loss of Gscl. Thus, although deletion of the genes in the Lgdel region in mice may recapitulate some of the behavioral phenotypes seen in humans with VCFS/DGS, these phenotypes are not found in mice with complete loss of Gscl or in mice with heterozygous loss of Tbx1, suggesting that the neuropsychiatric and physical malformations of VCFS/DGS may act by different genetic mechanisms.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
38Eur. J. Hum. Genet. 2006 Oct 14: 1111-9
PMID16773125
TitleAHI1, a pivotal neurodevelopmental gene, and C6orf217 are associated with susceptibility to schizophrenia.
Abstractschizophrenia, a severe neuropsychiatric disorder, is believed to involve multiple genetic factors. A significant body of evidence supports a pivotal role for abnormalities of brain development in the disorder. Linkage signals for schizophrenia map to human chromosome 6q. To obtain a finer localization, we genotyped 180 single nucleotide polymorphisms (SNPs) in a young, inbred Arab-Israeli family sample with a limited nuMBer of founders. The SNPs were mostly within a approximately 7 MB region around the strong linkage peak at 136.2 MB that we had previously mapped. The most significant genetic association with schizophrenia for single SNPs and haplotypes was within a 500 kb genomic region of high linkage disequilibrium (LD) at 135.85 MB. In a different, outbred, nuclear family sample that was not appropriate for linkage analysis, under-transmitted haplotypes incorporating the same SNPs (but not the individual SNPs) were significantly associated with schizophrenia. The implicated genomic region harbors the Abelson Helper Integration Site 1 (AHI1) gene, which showed the strongest association signal, and an adjacent, primate-specific gene, C6orf217. Mutations in human AHI1 underlie the autosomal recessive Joubert Syndrome with brain malformation and mental retardation. Previous comparative genomic analysis has suggested accelerated evolution of AHI1 in the human lineage. C6orf217 has multiple splice isoforms and is expressed in brain but does not seem to encode a functional protein. The two genes appear in opposite orientations and their regulatory upstream regions overlap, which might affect their expression. Both, AHI1 and C6orf217 appear to be highly relevant candidate genes for schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
39BMC Med. Genet. 2006 -1 7: 18
PMID16512914
TitleBreakpoint Associated with a novel 2.3 Mb deletion in the VCFS region of 22q11 and the role of Alu (SINE) in recurring microdeletions.
AbstractChromosome 22q11.2 region is highly susceptible to rearrangement, specifically deletions that give rise to a variety of genomic disorders including velocardiofacial or DiGeorge syndrome. Individuals with this 22q11 microdeletion syndrome are at a greatly increased risk to develop schizophrenia.
Genotype analysis was carried out on the DNA from a patient with the 22q11 microdeletion using genetic markers and custom primer sets to define the deletion. Bioinformatic analysis was performed for molecular characterization of the deletion breakpoint sequences in this patient.
This 22q11 deletion patient was established to have a novel 2.3 MB deletion with a proximal breakpoint located between genetic markers RH48663 and RH48348 and a distal breakpoint between markers D22S1138 and SHGC-145314. Molecular characterization of the sequences at the breakpoints revealed a 270 bp shared sequence of the breakpoint regions (SSBR) common to both ends that share >90% sequence similarity to each other and also to short interspersed nuclear elements/Alu elements.
This Alu sequence like SSBR is commonly in the proximity of all known deletion breakpoints of 22q11 region and also in the low copy repeat regions (LCRs). This sequence may represent a preferred sequence in the breakpoint regions or LCRs for intra-chromosomal homologous recoMBination mechanisms resulting in common 22q11 deletion.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
40Am. J. Med. Genet. B Neuropsychiatr. Genet. 2006 Jan 141B: 84-90
PMID16342280
TitleHuman QKI, a new candidate gene for schizophrenia involved in myelination.
AbstractWe have previously shown that chromosome 6q25-6q27 includes a susceptibility locus for schizophrenia in a large pedigree from northern Sweden. In this study, we fine-mapped a 10.7 MB region, included in this locus, using 42 microsatellites or SNP markers. We found a 0.5 MB haplotype, likely to be inherited identical by decent, within the large family that is shared among the majority of the patients (69%). A gamete competition test of this haplotype in 176 unrelated nuclear families from the same geographical area as the large family showed association to schizophrenia (empirical P-value 0.041). The only gene located in the region, the quaking homolog, KH domain RNA binding (mouse) (QKI), was investigated in human brain autopsies from 55 cases and 55 controls using a high-resolution mRNA expression analysis. Relative mRNA expression levels of two QKI splice variants were clearly downregulated in schizophrenic patients (P-value 0.0004 and 0.03, respectively). The function of QKI has not been studied in humans, but the mouse homolog is involved in neural development and myelination. In conclusion, we present evidence from three unrelated sample-sets that propose the involvement of the QKI gene in schizophrenia. The two family based studies suggest that there may be functional variants of the QKI gene that increase the susceptibility of schizophrenia in northern Sweden, whereas the case-control study suggest that splicing of the gene may be disturbed in schizophrenic patients from other geographical origins. Taken together, we propose QKI as a possible target for functional studies related to the role of myelination in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
41Am. J. Med. Genet. B Neuropsychiatr. Genet. 2006 Jan 141B: 84-90
PMID16342280
TitleHuman QKI, a new candidate gene for schizophrenia involved in myelination.
AbstractWe have previously shown that chromosome 6q25-6q27 includes a susceptibility locus for schizophrenia in a large pedigree from northern Sweden. In this study, we fine-mapped a 10.7 MB region, included in this locus, using 42 microsatellites or SNP markers. We found a 0.5 MB haplotype, likely to be inherited identical by decent, within the large family that is shared among the majority of the patients (69%). A gamete competition test of this haplotype in 176 unrelated nuclear families from the same geographical area as the large family showed association to schizophrenia (empirical P-value 0.041). The only gene located in the region, the quaking homolog, KH domain RNA binding (mouse) (QKI), was investigated in human brain autopsies from 55 cases and 55 controls using a high-resolution mRNA expression analysis. Relative mRNA expression levels of two QKI splice variants were clearly downregulated in schizophrenic patients (P-value 0.0004 and 0.03, respectively). The function of QKI has not been studied in humans, but the mouse homolog is involved in neural development and myelination. In conclusion, we present evidence from three unrelated sample-sets that propose the involvement of the QKI gene in schizophrenia. The two family based studies suggest that there may be functional variants of the QKI gene that increase the susceptibility of schizophrenia in northern Sweden, whereas the case-control study suggest that splicing of the gene may be disturbed in schizophrenic patients from other geographical origins. Taken together, we propose QKI as a possible target for functional studies related to the role of myelination in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
42BMC Psychiatry 2007 -1 7: 21
PMID17519028
TitleThe NRG1 exon 11 missense variant is not associated with autism in the Central Valley of Costa Rica.
AbstractWe are conducting a genetic study of autism in the isolated population of the Central Valley of Costa Rica (CVCR). A novel Neuregulin 1 (NRG1) missense variant (exon 11 G>T) was recently associated with psychosis and schizophrenia (SCZ) in the same population isolate.
We genotyped the NRG1 exon 11 missense variant in 146 cases with autism, or autism spectrum disorder, with CVCR ancestry, and both parents when available (N = 267 parents) from 143 independent families. Additional microsatellites were genotyped to examine haplotypes bearing the exon 11 variant.
The NRG1 exon 11 G>T variant was found in 4/146 cases including one de novo occurrence. The frequency of the variant in case chromosomes was 0.014 and 0.045 in the parental non-transmitted chromosomes. At least 6 haplotypes extending 0.229 MB were associated with the T allele. Three independent individuals, with no personal or family history of psychiatric disorder, shared at least a 1 megabase haplotype 5' to the T allele.
The NRG1 exon 11 missense variant is not associated with autism in the CVCR.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
43Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Oct 144B: 954-7
PMID17503451
TitleFamily-based association study of neuregulin-1 gene and psychosis in a Spanish sample.
AbstractNeuregulin 1 (NRG1) is one of the most exciting candidate genes for schizophrenia since its first association with the disorder in an Icelandic population. Since then, many studies have analyzed allele and haplotype frequencies in European and Asian populations in cases and controls yielding varying results. We investigated the association of NRG1 with psychosis in a total sample set of 575 individuals from 151 Spanish nuclear families. We tested eight SNPs across 1.2 MB along NRG1 including regions previously associated to schizophrenia in association studies. After correction for multiple testing, the TDT analysis for each marker did not show a significant over-transmission of alleles from the parents to the affected offspring for any of the markers (P > 0.05). The haplotypic analysis with TRANSMIT and PDT did not show preferential transmission for any of the haplotypes analyzed in our sample. These results do not seem to suggest that the investigated NRG1 markers play a role in schizophrenia in the Spanish population, although the finding of a trend for association with one SNP in the 3'of the gene warrants further investigation.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
44Neurosci. Lett. 2007 Jun 421: 47-51
PMID17548156
TitleHigh dopamine turnover in the brains of Sandy mice.
Abstractschizophrenia is a chronic mental disorder and patients with this disease show positive and negative symptoms, cognitive dysfunction, and deficits in the processing of emotion. From previous studies, dopaminergic neurons are believed to be related to schizophrenic symptoms. Dysbindin (DTNBP1: dystrobrevin binding protein 1) gene is a susceptibility gene for schizophrenia, but the involvement of this gene in the dopaminergic tone remains unknown. In this paper, we studied regional contents of dopamine and its metabolite in the Sandy (Sdy) mouse which expresses no dysbindin protein. The brains of Sdy and wild-type (WT) mice were dissected into ten regions and dopamine (DA) and homovanillic acid (HVA) in each region were determined. DA contents were significantly lower in the cortex, hippocampus, and hypothalamus of Sdy mice than WT mice, while HVA contents showed no differences between the strains. Western blot analysis revealed there were no differences in the amount of tyrosine hydroxylase (TH) in the midbrain (MB) of both strains. The ratios of DA to HVA, which is an index of DA turnover, were higher in the cortex and the hippocampus, but not in the hypothalamus. These data demonstrate that DA turnover in the specific regions of the brain of the Sdy mouse was increased, and the Sdy mouse is a possible useful candidate animal for studying the pathogenic mechanism of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
45Neurosci. Lett. 2007 Jun 421: 47-51
PMID17548156
TitleHigh dopamine turnover in the brains of Sandy mice.
Abstractschizophrenia is a chronic mental disorder and patients with this disease show positive and negative symptoms, cognitive dysfunction, and deficits in the processing of emotion. From previous studies, dopaminergic neurons are believed to be related to schizophrenic symptoms. Dysbindin (DTNBP1: dystrobrevin binding protein 1) gene is a susceptibility gene for schizophrenia, but the involvement of this gene in the dopaminergic tone remains unknown. In this paper, we studied regional contents of dopamine and its metabolite in the Sandy (Sdy) mouse which expresses no dysbindin protein. The brains of Sdy and wild-type (WT) mice were dissected into ten regions and dopamine (DA) and homovanillic acid (HVA) in each region were determined. DA contents were significantly lower in the cortex, hippocampus, and hypothalamus of Sdy mice than WT mice, while HVA contents showed no differences between the strains. Western blot analysis revealed there were no differences in the amount of tyrosine hydroxylase (TH) in the midbrain (MB) of both strains. The ratios of DA to HVA, which is an index of DA turnover, were higher in the cortex and the hippocampus, but not in the hypothalamus. These data demonstrate that DA turnover in the specific regions of the brain of the Sdy mouse was increased, and the Sdy mouse is a possible useful candidate animal for studying the pathogenic mechanism of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
46Mol. Psychiatry 2007 Nov 12: 1011-25
PMID17457313
TitleAssociation analysis of the chromosome 4p15-p16 candidate region for bipolar disorder and schizophrenia.
AbstractSeveral independent linkage studies have identified chromosome 4p15-p16 as a putative region of susceptibility for bipolar disorder (BP), schizophrenia (SCZ) and related phenotypes. Previously, we identified two subregions (B and D) of the 4p15-p16 region that are shared by three of four 4p-linked families examined. Here, we describe a large-scale association analysis of regions B and D (3.8 and 4.5 MB, respectively). We selected 408 haplotype-tagging single nucleotide polymorphisms (SNPs) on a block-by-block basis from the International HapMap project and tested them in 368 BP, 386 SCZ and 458 control individuals. Nominal significance thresholds were determined using principal component analysis as implemented in the program SNPSpD. In region B, overlapping SNPs and haplotypes met the region-wide threshold (P
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
47Hum. Genet. 2007 Feb 120: 837-45
PMID17028864
TitleMolecular characterization of deletion breakpoints in adults with 22q11 deletion syndrome.
Abstract22q11 Deletion syndrome (22q11DS) is a common microdeletion syndrome with variable expression, including congenital and later onset conditions such as schizophrenia. Most studies indicate that expression does not appear to be related to length of the deletion but there is limited information on the endpoints of even the common deletion breakpoint regions in adults. We used a real-time quantitative PCR (qPCR) approach to fine map 22q11.2 deletions in 44 adults with 22q11DS, 22 with schizophrenia (SZ; 12 M, 10 F; mean age 35.7 SD 8.0 years) and 22 with no history of psychosis (NP; 8 M, 14 F; mean age 27.1 SD 8.6 years). QPCR data were consistent with clinical FISH results using the TUPLE1 or N25 probes. Two subjects (one SZ, one NP) negative for clinical FISH had atypical 22q11.2 deletions confirmed by FISH using the RP11-138C22 probe. Most (n = 34; 18 SZ, 16 NP) subjects shared a common 3 MB hemizygous 22q11.2 deletion. However, eight subjects showed breakpoint variability: a more telomeric proximal breakpoint (n = 2), or more centromeric (n = 3) or more telomeric distal breakpoint (n = 3). One NP subject had a proximal nested 1.4 MB deletion. COMT and TBX1 were deleted in all 44 subjects, and PRODH in 40 subjects (19 SZ, 21 NP). The results delineate proximal and distal breakpoint variants in 22q11DS. Neither deletion extent nor PRODH haploinsufficiency appeared to explain the clinical expression of schizophrenia in the present study. Further studies are needed to elucidate the molecular basis of schizophrenia and clinical heterogeneity in 22q11DS.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
48Proc. Natl. Acad. Sci. U.S.A. 2007 Dec 104: 19942-7
PMID18077426
TitleRuns of homozygosity reveal highly penetrant recessive loci in schizophrenia.
AbstractEvolutionarily significant selective sweeps may result in long stretches of homozygous polymorphisms in individuals from outbred populations. We developed whole-genome homozygosity association (WGHA) methodology to characterize this phenomenon in healthy individuals and to use this genomic feature to identify genetic risk loci for schizophrenia (SCZ). Applying WGHA to 178 SCZ cases and 144 healthy controls genotyped at 500,000 markers, we found that runs of homozygosity (ROHs), ranging in size from 200 kb to 15 MB, were common in unrelated Caucasians. Properties of common ROHs in healthy subjects, including chromosomal location and presence of nonancestral haplotypes, converged with prior reports identifying regions under selective pressure. This interpretation was further supported by analysis of multiethnic HapMap samples genotyped with the same markers. ROHs were significantly more common in SCZ cases, and a set of nine ROHs significantly differentiated cases from controls. Four of these 9 "risk ROHs" contained or neighbored genes associated with SCZ (NOS1AP, ATF2, NSF, and PIK3C3). Several of these risk ROHs were very rare in healthy subjects, suggesting that recessive effects of relatively high penetrance may explain a proportion of the genetic liability for SCZ. Other risk ROHs feature haplotypes that are also common in healthy individuals, possibly indicating a source of balancing selection.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
49Twin Res Hum Genet 2007 Dec 10: 861-70
PMID18179399
TitlePrioritization of positional candidate genes using multiple web-based software tools.
AbstractThe prioritization of genes within a candidate genomic region is an important step in the identification of causal gene variants affecting complex traits. Surprisingly, there have been very few reports of bioinformatics tools to perform such prioritization. The purpose of this article is to investigate the performance of 3 positional candidate gene software tools available, PosMed, GeneSniffer and SUSPECTS. The comparison was made for 40, 20 and 10 MB regions in the human genome centred around known susceptibility genes for the common diseases breast cancer, Crohn's disease, age-related macular degeneration and schizophrenia. The known susceptibility gene was not always ranked highly, or not ranked at all, by 1 or more of the software tools. There was a large variation between the 3 tools regarding which genes were prioritized, and their rank order. PosMed and GeneSniffer were most similar in their prioritization gene list, whereas SUSPECTS identified the same candidate genes only for the narrowest (10 MB) regions. CoMBining 2 or all of the candidate gene finding tools was superior in terms of ranking positional candidates. It is possible to reduce the nuMBer of candidate genes from a starting set in a region of interest by coMBining a variety of candidate gene finding tools. Conversely, we recommend caution in relying solely on single positional candidate gene prioritization tools. Our results confirm the obvious, that is, that starting with a narrower positional region gives a higher likelihood that the true susceptibility gene is selected, and that it is ranked highly. A narrow confidence interval for the mapping of complex trait genes by linkage can be achieved by maximizing marker informativeness and by having large samples. Our results suggest that the best approach to classify a minimum set of candidate genes is to take those genes that are prioritized by multiple prioritization tools.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
50Am. J. Med. Genet. B Neuropsychiatr. Genet. 2007 Dec 144B: 1094-6
PMID17525977
TitleCandidate gene analysis of 21q22: support for S100B as a susceptibility gene for bipolar affective disorder with psychosis.
AbstractA genome-wide scan in 60 bipolar affective disorder (BPAD) affected sib-pairs (ASPs) identified linkage on chromosome 21 at 21q22 (D21S1446, NPL = 1.42, P = 0.08), a BPAD susceptibility locus supported by multiple studies. Although this linkage only approaches significance, the peak marker is located 12 Kb upstream of S100B, a neurotrophic factor implicated in the pathology of psychiatric disorders, including BPAD and schizophrenia. We hypothesized that the linkage signal at 21q22 may result from pathogenic disease variants within S100B and performed an association analysis of this gene in a collection of 125 BPAD type I trios. S100B single nucleotide polymorphisms (SNPs) rs2839350 (P = 0.022) and rs3788266 (P = 0.031) were significantly associated with BPAD. Since variants within S100B have also been associated with schizophrenia susceptibility, we reanalyzed the data in trios with a history of psychosis, a phenotype in common between the two disorders. SNPs rs2339350 (P = 0.016) and rs3788266 (P = 0.009) were more significantly associated in the psychotic subset. Increased significance was also obtained at the haplotype level. Interestingly, SNP rs3788266 is located within a consensus-binding site for Six-family transcription factors suggesting that this variant may directly affect S100B gene expression. Fine-mapping analyses of 21q22 have previously identified transient receptor potential gene melastatin 2 (TRPM2), which is 2 MB upstream of S100B, as a possible BPAD susceptibility gene at 21q22. We also performed a family-based association analysis of TRPM2 which did not reveal any evidence for association of this gene with BPAD. Overall, our findings suggest that variants within the S100B gene predispose to a psychotic subtype of BPAD, possibly via alteration of gene expression.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
51Ann. N. Y. Acad. Sci. 2007 Jan 1096: 120-7
PMID17405923
TitleStrongly reduced number of parvalbumin-immunoreactive projection neurons in the mammillary bodies in schizophrenia: further evidence for limbic neuropathology.
AbstractThe mammillary bodies (MB) are important relay nuclei within liMBic and extraliMBic connections. They are known to play important roles in memory formation and are affected in alcoholism and vitamin B1 deficiency. Their strategic position linking temporo-liMBic to cortico-thalamic brain structures make the MB a candidate brain structure for alterations in schizophrenia. We studied 15 postmortem brains of schizophrenics and 15 matched control brains. Brain sections were stained either with Heidenhain-Woelcke, glutamic acid decarboxylase (GAD), calretinin, or parvalbumin. We determined the volumes of the MB and performed cell countings using stereological principles and a computerized image analysis system. The volumes of MB do not differ between schizophrenics and controls. However, in schizophrenia the nuMBer of neurons as well as the resulting neuronal densities was significantly reduced on both sides (on left side by 38.9%, on right side by 22%). No changes were seen in the nuMBer of GAD-expressing or calretinin-containing neurons, whereas the nuMBer of parvalbumin-immunoreactive MB neurons was reduced by more than 50% in schizophrenia. This cell loss (as a result of developmental malformation and/or neurodegeneration) points to a prominent involvement of the MB in the pathomorphology of schizophrenia. Parvalbumin-immunoreactive GABAergic interneurons have been reported to be diminished in schizophrenia. However, in the MB parvalbumin labels a subpopulation of glutamate/aspartate-containing neurons projecting mainly to the anterior thalamus. Thus, our data provide new evidence for impaired liMBic circuits in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
52Ann. N. Y. Acad. Sci. 2007 Jan 1096: 120-7
PMID17405923
TitleStrongly reduced number of parvalbumin-immunoreactive projection neurons in the mammillary bodies in schizophrenia: further evidence for limbic neuropathology.
AbstractThe mammillary bodies (MB) are important relay nuclei within liMBic and extraliMBic connections. They are known to play important roles in memory formation and are affected in alcoholism and vitamin B1 deficiency. Their strategic position linking temporo-liMBic to cortico-thalamic brain structures make the MB a candidate brain structure for alterations in schizophrenia. We studied 15 postmortem brains of schizophrenics and 15 matched control brains. Brain sections were stained either with Heidenhain-Woelcke, glutamic acid decarboxylase (GAD), calretinin, or parvalbumin. We determined the volumes of the MB and performed cell countings using stereological principles and a computerized image analysis system. The volumes of MB do not differ between schizophrenics and controls. However, in schizophrenia the nuMBer of neurons as well as the resulting neuronal densities was significantly reduced on both sides (on left side by 38.9%, on right side by 22%). No changes were seen in the nuMBer of GAD-expressing or calretinin-containing neurons, whereas the nuMBer of parvalbumin-immunoreactive MB neurons was reduced by more than 50% in schizophrenia. This cell loss (as a result of developmental malformation and/or neurodegeneration) points to a prominent involvement of the MB in the pathomorphology of schizophrenia. Parvalbumin-immunoreactive GABAergic interneurons have been reported to be diminished in schizophrenia. However, in the MB parvalbumin labels a subpopulation of glutamate/aspartate-containing neurons projecting mainly to the anterior thalamus. Thus, our data provide new evidence for impaired liMBic circuits in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
53Brain Res. 2007 Mar 1139: 48-59
PMID17292336
TitleDifferential gene expression in the hippocampus of the Df1/+ mice: a model for 22q11.2 deletion syndrome and schizophrenia.
AbstractGenes and a 3-MB deletion mapping to human chromosome 22q11.2 have been implicated in 22q11.2 deletion syndrome (22q11.2DS) and schizophrenia. The Df1 heterozygous (Df1/+) mice, a model for 22q11.2DS, display specific deficits in hippocampus-dependent learning and memory and impaired sensorimotor gating, abnormalities observed in patients with schizophrenia and 22q11.2DS. In light of the analogous behavioral abnormalities observed between the Df1/+ mice and 22q11.2DS and schizophrenia respectively, particularly in association with the 22q11.2 deletion, the Df1/+ mice are suitable for investigating the molecular changes that may underlie the cognitive deficits and behavioral abnormalities arising as a result of this deletion. Hence we applied microarray technology to identify such molecular changes in the hippocampus at the transcript level. Twelve genes mapping to the deleted region were reliably identified as expressed in the hippocampus by microarray analysis. 159 other differentially expressed genes/ESTs were also identified. Thus far differential expression of fifteen of these genes involved in signal transduction, synaptic plasticity, neuronal differentiation, microtubule asseMBly and ubiquitin pathway relevant to hippocampus mediated function have been confirmed by real-time PCR. Of particular interest is the decreased expression (32%) of calmodulin 1, encoding a calcium-dependent protein involved in the calmodulin-calcineurin regulated pathway implicated in learning and memory.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
54Biol. Psychiatry 2007 Mar 61: 797-805
PMID16996484
TitleHaplotype analysis and a novel allele-sharing method refines a chromosome 4p locus linked to bipolar affective disorder.
AbstractBipolar affective disorder (BPAD) and schizophrenia (SCZ) are common conditions. Their causes are unknown, but they include a substantial genetic component. Previously, we described significant linkage of BPAD to a chromosome 4p locus within a large pedigree (F22). Others subsequently have found evidence for linkage of BPAD and SCZ to this region.
We constructed high-resolution haplotypes for four linked families, calculated logarithm of the odds (LOD) scores, and developed a novel method to assess the extent of allele sharing within genes between the families.
We describe an increase in the F22 LOD score for this region. Definition and comparison of the linked haplotypes allowed us to prioritize two subregions of 3.8 and 4.4 MB. Analysis of the extent of allele sharing within these subregions identified 200 kb that shows increased allele sharing between families.
Linkage of BPAD to chromosome 4p has been strengthened. Haplotype analysis in the additional linked families refined the 20-MB linkage region. Development of a novel allele-sharing method allowed us to bridge the gap between conventional linkage and association studies. Description of a 200-kb region of increased allele sharing prioritizes this region, which contains two functional candidate genes for BPAD, SLC2A9, and WDR1, for subsequent studies.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
55J. Hum. Genet. 2008 -1 53: 914-9
PMID18685808
TitleMicroarray comparative genomic hybridization analysis of 59 patients with schizophrenia.
Abstractschizophrenia is a common psychiatric disorder with a strong genetic contribution. Disease-associated chromosomal abnormalities in this condition may provide important clues, such as DISC1. In this study, 59 schizophrenia patients were analyzed by microarray comparative genomic hybridization (CGH) using custom bacterial artificial chromosome (BAC) microarray (4,219 BACs with 0.7-MB resolution). Chromosomal abnormalities were found in six patients (10%): 46,XY,der(13)t(12;13)(p12.1; p11).ish del(5)(p11p12); 46,XY, ish del(17)(p12p12); 46,XX.ish dup(11)(p13p13); and 46,X,idic(Y)(q11.2); and in two cases, mos 45,X/46XX. Autosomal abnormalities in three cases are likely to be pathogenic, and sex chromosome abnormalities in three follow previous findings. It is noteworthy that 10% of patients with schizophrenia have (sub)microscopic chromosomal abnormalities, indicating that genome-wide copy nuMBer survey should be considered in genetic studies of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
56Methods Mol. Biol. 2008 -1 448: 187-212
PMID18370235
TitleEpigenetic alterations of the dopaminergic system in major psychiatric disorders.
AbstractAlthough there is evidence to link schizophrenia (SCZ) and bipolar disorder (BD) to genetic and environmental factors, specific individual or groups of genes/factors causative of the disease have been elusive to the research community. An understanding of the molecular aberrations that cause these mental illnesses requires comprehensive approaches that examine both genetic and epigenetic factors. Because of the overwhelming evidence for the role of environmental factors in the disease presentation, our initial approach involved deciphering how epigenetic changes resulting from promoter DNA methylation affect gene expression in SCZ and BD. Apparently, the central reversible but covalent epigenetic modification to DNA is derived from methylation of the cytosine residues that is potentially heritable and can affect gene expression and downstream activities. Environmental factors can influence DNA methylation patterns and hence alter gene expression. Such changes can be especially problematic in individuals with genetic susceptibilities to specific diseases. Recent reports from our laboratory provided compelling evidence that both hyper- and hypo-DNA methylation changes of the regulatory regions play critical roles in defining the altered functionality of genes in major psychiatric disorders such as SCZ and BD. In this chapter, we outline the technical details of the methods that could help to expand this line of research to assist with compiling the differential methylation-mediated epigenetic alterations that are responsible for the pathogenesis of SCZ, BD, and other mental diseases. We use the genes of the extended dopaminergic (DAergic) system such as meMBrane-bound catechol-O-methyltransferase (MB-COMT), monoamine oxidase A (MAOA), dopamine transporter 1 (DAT1), tyrosine hydroxylase (TH), dopamine (DA) receptors1 and 2 (DRD1/2), and related genes (e.g., reelin [RELN] and brain-derived neurotrophic factor [BDNF]) to illustrate the associations between differential promoter DNA methylations and disease phenotype. It is our hope that comprehensive analyses of the DAergic system as the prototype could provide the impetus and molecular basis to uncover early markers for diagnosis, help in the understanding of differences in disease severity in individuals with similar or identical genetic makeup, and assist with the identification of novel targets for therapeutic applications.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
57Biol. Psychiatry 2008 Nov 64: 789-96
PMID18571626
TitleRASD2, MYH9, and CACNG2 genes at chromosome 22q12 associated with the subgroup of schizophrenia with non-deficit in sustained attention and executive function.
AbstractIn a previous linkage study of schizophrenia that included Taiwanese samples, the marker D22S278 (22q12.3) was significantly linked to schizophrenia (p = .001).
We conducted fine mapping of the implicated genomic region, with 47 validated single nucleotide polymorphism (SNP) markers around 1 MB of D22S278, in a Taiwanese sample of 218 pedigrees with at least 2 siblings affected with schizophrenia. We examined the association of these SNPs and their haplotypes with schizophrenia and with subgroups defined by the presence and absence of deficits in sustained attention as assessed by undegraded and degraded continuous performance tests (CPTs). We also examined subgroups defined by deficits in categories achieved in the Wisconsin Card Sort Test (WCST).
Three of five candidate vulnerability genes (RASD2, APOL5, MYH9, EIF3S7, and CACNG2), which had marginally significant associations with schizophrenia, had significant associations with schizophrenic patients who did not have deficits in sustained attention on the undegraded CPT (RASD2 gene SNP rs736212; p = .0008 with single locus analysis) and the degraded CPT (MYH9 gene haplotype 1-1-1-1 of SNP rs3752463 - rs1557540 - rs713839 - rs739097; p = .0059 with haplotype analysis). We also found a significant association for patients who showed no deficits in executive function as measured by categories achieved in the WCST (CACNG2 gene haplotype 2-1-1-1 of SNP rs2267360 - rs140526 - rs1883987 - rs916269; p = .0163 with haplotype analysis).
The genes RASD2, MYH9, and CACNG2 might be vulnerability genes for neuropsychologically defined subgroups of schizophrenic patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
58Biol. Psychiatry 2008 Nov 64: 789-96
PMID18571626
TitleRASD2, MYH9, and CACNG2 genes at chromosome 22q12 associated with the subgroup of schizophrenia with non-deficit in sustained attention and executive function.
AbstractIn a previous linkage study of schizophrenia that included Taiwanese samples, the marker D22S278 (22q12.3) was significantly linked to schizophrenia (p = .001).
We conducted fine mapping of the implicated genomic region, with 47 validated single nucleotide polymorphism (SNP) markers around 1 MB of D22S278, in a Taiwanese sample of 218 pedigrees with at least 2 siblings affected with schizophrenia. We examined the association of these SNPs and their haplotypes with schizophrenia and with subgroups defined by the presence and absence of deficits in sustained attention as assessed by undegraded and degraded continuous performance tests (CPTs). We also examined subgroups defined by deficits in categories achieved in the Wisconsin Card Sort Test (WCST).
Three of five candidate vulnerability genes (RASD2, APOL5, MYH9, EIF3S7, and CACNG2), which had marginally significant associations with schizophrenia, had significant associations with schizophrenic patients who did not have deficits in sustained attention on the undegraded CPT (RASD2 gene SNP rs736212; p = .0008 with single locus analysis) and the degraded CPT (MYH9 gene haplotype 1-1-1-1 of SNP rs3752463 - rs1557540 - rs713839 - rs739097; p = .0059 with haplotype analysis). We also found a significant association for patients who showed no deficits in executive function as measured by categories achieved in the WCST (CACNG2 gene haplotype 2-1-1-1 of SNP rs2267360 - rs140526 - rs1883987 - rs916269; p = .0163 with haplotype analysis).
The genes RASD2, MYH9, and CACNG2 might be vulnerability genes for neuropsychologically defined subgroups of schizophrenic patients.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
59Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Mar 147B: 209-15
PMID17823922
TitleGenome-wide linkage scan, fine mapping, and haplotype analysis in a large, inbred, Arab Israeli pedigree suggest a schizophrenia susceptibility locus on chromosome 20p13.
AbstractLinkage and association studies in schizophrenia have repeatedly drawn attention to several chromosomal regions and to genes within them. Conflicting patterns of association and the lack of a clear functional significance of the associated variants limit the interpretation of these results. The use of rare pedigrees, where genes with a major effect cause the disorder, has been proven beneficial in studies of other complex disorders. Our objective was to use this advantage by performing a genome wide linkage analysis for schizophrenia in a large, multiplex Israeli Arab pedigree. We genotyped 346 microsatellite markers in 24 pedigree meMBers affected with schizophrenia spectrum disorders and 32 unaffected relatives. Two-point linkage analysis with SUPERLINK demonstrated a LOD score of 2.47 for D20S116 on chromosome 20p13 under an autosomal dominant mode of inheritance. Further fine mapping yielded a two-point LOD score of 2.56 for the adjacent marker D20S193 and narrowed down the linked region to 2-5 cM. A haplotype containing the markers D20S193, D20S889, and D20S116, 0.7 MB in length, was found to be shared by most affected pedigree meMBers. Genotyping of 43 SNPs in the interval supported these results with a multipoint LOD score of 2.7 around D20S193. We were also able to better define the boundaries of the shared haplotype which contains strong candidate genes for schizophrenia. Our study exemplifies the power of rare and unique pedigrees in drawing attention to novel regions for genetic studies of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
60Am. J. Med. Genet. B Neuropsychiatr. Genet. 2008 Jan 147B: 59-67
PMID17671966
TitleGene-based SNP mapping of a psychotic bipolar affective disorder linkage region on 22q12.3: association with HMG2L1 and TOM1.
AbstractGenetic linkage studies in both bipolar affective disorder (BPAD) and schizophrenia have implicated overlapping regions of chromosome 22q. We previously reported that BPAD pedigrees containing multiple meMBers with psychotic symptoms showed suggestive linkage to chromosome 22q12.3. Now we have tested 189 single nucleotide polymorphisms (SNPs) spanning a 3 MB region around the linkage peak for association with BPAD in 305 families, unrelated cases, and controls. SNPs were selected in or near genes, resulting in coverage at a density of 1 SNP per 6.7 kb across the 22 annotated genes in the region. The strongest signal emerged from family-based association analysis of an 11-SNP, 54 kb haplotype straddling the gene HMG2L1 and part of TOM1. A 3-marker haplotype of SNPs within TOM1 was associated with BPAD (allele-wise P = 0.0011) and with psychotic BPAD (allele-wise P = 0.00049). As hypothesized, the mean odds ratio for the risk alleles across the region was 1.39 in the psychotic but only 0.96 in the non-psychotic subset. Genotype-wise analyses yielded similar results, but the psychotic/non-psychotic distinction was more pronounced with mean odds ratios of 1.91 versus 0.8. Permutation of genotype-wise results for rs2413338 in HMG2L1 showed an empirical P = 0.037 for the difference between subsets. HMG2L1 is a negative regulator of Wnt signaling, a pathway of interest in psychotic BPAD as it is activated by both mood stabilizer and anti-psychotic medications. Further work is needed to confirm these results and uncover the functional variation underlying the association signal.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
61Eur. J. Hum. Genet. 2009 May 17: 687-92
PMID19050728
TitleA 15q13.3 microdeletion segregating with autism.
AbstractAutism and mental retardation (MR) show high rates of comorbidity and potentially share genetic risk factors. In this study, a rare approximately 2 MB microdeletion involving chromosome band 15q13.3 was detected in a multiplex autism family. This genomic loss lies between distal break points of the Prader-Willi/Angelman syndrome locus and was first described in association with MR and epilepsy. Together with recent studies that have also implicated this genomic iMBalance in schizophrenia, our data indicate that this CNV shows considerable phenotypic variability. Further studies should aim to characterise the precise phenotypic range of this CNV and may lead to the discovery of genetic or environmental modifiers.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
62BMC Med. Genet. 2009 -1 10: 144
PMID20030804
TitleBAC array CGH in patients with Velocardiofacial syndrome-like features reveals genomic aberrations on chromosome region 1q21.1.
AbstractMicrodeletion of the chromosome 22q11.2 region is the most common genetic aberration among patients with velocardiofacial syndrome (VCFS) but a subset of subjects do not show alterations of this chromosome region.
We analyzed 18 patients with VCFS-like features by comparative genomic hybridisation (aCGH) array and performed a face-to-face slide hybridization with two different arrays: a whole genome and a chromosome 22-specific BAC array. Putative rearrangements were confirmed by FISH and MLPA assays.
One patient carried a coMBination of rearrangements on 1q21.1, consisting in a microduplication of 212 kb and a close microdeletion of 1.15 MB, previously reported in patients with variable phenotypes, including mental retardation, congenital heart defects (CHD) and schizophrenia. While 326 control samples were negative for both 1q21.1 rearrangements, one of 73 patients carried the same 212-kb microduplication, reciprocal to TAR microdeletion syndrome. Also, we detected four copy nuMBer variants (CNVs) inherited from one parent (a 744-kb duplication on 10q11.22; a 160 kb duplication and deletion on 22q11.21 in two cases; and a gain of 140 kb on 22q13.2), not present in control subjects, raising the potential role of these CNVs in the VCFS-like phenotype.
Our results confirmed aCGH as a successful strategy in order to characterize additional submicroscopic aberrations in patients with VCF-like features that fail to show alterations in 22q11.2 region. We report a 212-kb microduplication on 1q21.1, detected in two patients, which may contribute to CHD.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
63Genes Brain Behav. 2009 Nov 8: 806-16
PMID19694817
TitleGenomic survey of prepulse inhibition in mouse chromosome substitution strains.
AbstractPrepulse inhibition (PPI) is a measure of sensorimotor gating, a pre-attentional inhibitory brain mechanism that filters extraneous stimuli. Prepulse inhibition is correlated with measures of cognition and executive functioning, and is considered an endophenotype of schizophrenia and other psychiatric illnesses in which patients show PPI impairments. As a first step toward identifying genes that regulate PPI, we performed a quantitative trait locus (QTL) screen of PPI phenotypes in a panel of mouse chromosome substitution strains (CSSs). We identified five CSSs with altered PPI compared with the host C57BL/6J strain: CSS-4 exhibited decreased PPI, whereas CSS-10, -11, -16 and -Y exhibited higher PPI compared with C57BL/6J. These data indicate that A/J chromosomes 4, 10, 11, 16 and Y harbor at least one QTL region that modulates PPI in these CSSs. Quantitative trait loci for the acoustic startle response were identified on seven chromosomes. Like PPI, habituation of the startle response is also disrupted in schizophrenia, and in the present study CSS-7 and -8 exhibited deficits in startle habituation. Linkage analysis of an F(2) intercross identified a highly significant QTL for PPI on chromosome 11 between positions 101.5 and 114.4 MB (peak LOD = 4.54). Future studies will map the specific genes contributing to these QTLs using congenic strains and other genomic approaches. Identification of genes that modulate PPI will provide insight into the neural mechanisms underlying sensorimotor gating, as well as the psychopathology of disorders characterized by gating deficits.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
64Mol. Psychiatry 2009 Aug 14: 774-85
PMID19349958
TitleMeta-analysis of 32 genome-wide linkage studies of schizophrenia.
AbstractA genome scan meta-analysis (GSMA) was carried out on 32 independent genome-wide linkage scan analyses that included 3255 pedigrees with 7413 genotyped cases affected with schizophrenia (SCZ) or related disorders. The primary GSMA divided the autosomes into 120 bins, rank-ordered the bins within each study according to the most positive linkage result in each bin, summed these ranks (weighted for study size) for each bin across studies and determined the empirical probability of a given summed rank (P(SR)) by simulation. Suggestive evidence for linkage was observed in two single bins, on chromosomes 5q (142-168 MB) and 2q (103-134 MB). Genome-wide evidence for linkage was detected on chromosome 2q (119-152 MB) when bin boundaries were shifted to the middle of the previous bins. The primary analysis met empirical criteria for 'aggregate' genome-wide significance, indicating that some or all of 10 bins are likely to contain loci linked to SCZ, including regions of chromosomes 1, 2q, 3q, 4q, 5q, 8p and 10q. In a secondary analysis of 22 studies of European-ancestry samples, suggestive evidence for linkage was observed on chromosome 8p (16-33 MB). Although the newer genome-wide association methodology has greater power to detect weak associations to single common DNA sequence variants, linkage analysis can detect diverse genetic effects that segregate in families, including multiple rare variants within one locus or several weakly associated loci in the same region. Therefore, the regions supported by this meta-analysis deserve close attention in future studies.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
65PLoS Genet. 2009 Feb 5: e1000373
PMID19197363
TitleA genome-wide investigation of SNPs and CNVs in schizophrenia.
AbstractWe report a genome-wide assessment of single nucleotide polymorphisms (SNPs) and copy nuMBer variants (CNVs) in schizophrenia. We investigated SNPs using 871 patients and 863 controls, following up the top hits in four independent cohorts comprising 1,460 patients and 12,995 controls, all of European origin. We found no genome-wide significant associations, nor could we provide support for any previously reported candidate gene or genome-wide associations. We went on to examine CNVs using a subset of 1,013 cases and 1,084 controls of European ancestry, and a further set of 60 cases and 64 controls of African ancestry. We found that eight cases and zero controls carried deletions greater than 2 MB, of which two, at 8p22 and 16p13.11-p12.4, are newly reported here. A further evaluation of 1,378 controls identified no deletions greater than 2 MB, suggesting a high prior probability of disease involvement when such deletions are observed in cases. We also provide further evidence for some smaller, previously reported, schizophrenia-associated CNVs, such as those in NRXN1 and APBA2. We could not provide strong support for the hypothesis that schizophrenia patients have a significantly greater "load" of large (>100 kb), rare CNVs, nor could we find common CNVs that associate with schizophrenia. Finally, we did not provide support for the suggestion that schizophrenia-associated CNVs may preferentially disrupt genes in neurodevelopmental pathways. Collectively, these analyses provide the first integrated study of SNPs and CNVs in schizophrenia and support the emerging view that rare deleterious variants may be more important in schizophrenia predisposition than common polymorphisms. While our analyses do not suggest that implicated CNVs impinge on particular key pathways, we do support the contribution of specific genomic regions in schizophrenia, presumably due to recurrent mutation. On balance, these data suggest that very few schizophrenia patients share identical genomic causation, potentially complicating efforts to personalize treatment regimens.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
66Am. J. Hum. Genet. 2009 Jan 84: 21-34
PMID19118813
TitleFine mapping on chromosome 10q22-q23 implicates Neuregulin 3 in schizophrenia.
AbstractLinkage studies have implicated 10q22-q23 as a schizophrenia (SZ) susceptibility locus in Ashkenazi Jewish (AJ) and Han Chinese from Taiwan populations. To further explore our previous linkage signal in the AJ population (NPL score: 4.27, empirical p = 2 x 10(-5)), we performed a peakwide association fine mapping study by using 1414 SNPs across approximately 12.5 MB in 10q22-q23. We genotyped 1515 AJ individuals, including 285 parent-child trios, 173 unrelated cases, and 487 unrelated controls. We analyzed the binary diagnostic phenotype of SZ and 9 heritable quantitative traits derived from a principal components factor analysis of 73 items from our consensus diagnostic ratings and direct assessment interviews. Although no marker withstood multiple test correction for association with the binary SZ phenotype, we found strong evidence of association by using the "delusion" factor as the quantitative trait at three SNPs (rs10883866, rs10748842, and rs6584400) located in a 13 kb interval in intron 1 of Neuregulin 3 (NRG3). Our best p value from family-based association analysis was 7.26 x 10(-7). We replicated this association in the collection of 173 unrelated AJ cases (p = 1.55 x 10(-2)), with a coMBined p value of 2.30 x 10(-7). After performing 10,000 permutations of each of the phenotypes, we estimated the empirical study-wide significance across all 9 factors (90,000 permutations) to be p = 2.7 x 10(-3). NRG3 is primarily expressed in the central nervous system and is one of three paralogs of NRG1, a gene strongly implicated in SZ. These biological properties together with our linkage and association results strongly support NRG3 as a gene involved in SZ.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
67Hum. Mol. Genet. 2009 Apr 18: 1497-503
PMID19181681
TitleSupport for the involvement of large copy number variants in the pathogenesis of schizophrenia.
AbstractWe investigated the involvement of rare (<1%) copy nuMBer variants (CNVs) in 471 cases of schizophrenia and 2792 controls that had been genotyped using the Affymetrix GeneChip 500K Mapping Array. Large CNVs >1 MB were 2.26 times more common in cases (P = 0.00027), with the effect coming mostly from deletions (odds ratio, OR = 4.53, P = 0.00013) although duplications were also more common (OR = 1.71, P = 0.04). Two large deletions were found in two cases each, but in no controls: a deletion at 22q11.2 known to be a susceptibility factor for schizophrenia and a deletion on 17p12, at 14.0-15.4 MB. The latter is known to cause hereditary neuropathy with liability to pressure palsies. The same deletion was found in 6 of 4618 (0.13%) cases and 6 of 36 092 (0.017%) controls in the re-analysed data of two recent large CNV studies of schizophrenia (OR = 7.82, P = 0.001), with the coMBined significance level for all three studies achieving P = 5 x 10(-5). One large duplication on 16p13.1, which has been previously implicated as a susceptibility factor for autism, was found in three cases and six controls (0.6% versus 0.2%, OR = 2.98, P = 0.13). We also provide the first support for a recently reported association between deletions at 15q11.2 and schizophrenia (P = 0.026). This study confirms the involvement of rare CNVs in the pathogenesis of schizophrenia and contributes to the growing list of specific CNVs that are implicated.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
68Eur. J. Hum. Genet. 2009 Aug 17: 1034-42
PMID19172987
TitleChromosome 13q13-q14 locus overlaps mood and psychotic disorders: the relevance for redefining phenotype.
AbstractThe nosology of major psychoses is challenged by the findings that schizophrenia (SZ) and bipolar disorder (BP) share several neurobiological, neuropsychological and clinical phenotypic characteristics. Moreover, several vulnerability loci or genes may be common to the two DSM disorders. We previously reported, in a sample of 21 kindreds (sample 1), a genome-wide suggestive linkage in 13q13-q14 with a common locus (CL) phenotype that crossed the diagnostic boundaries by coMBining SZ, BP and schizoaffective disorders. Our objectives were to test phenotype specificity in a separate sample (sample 2) of 27 kindreds from Eastern Quebec and to also analyze the coMBined sample of 48 kindreds (1274 family meMBers). We performed nonparametric and parametric analyses and tested as phenotypes: SZ alone, BP alone, and a CL phenotype. We replicated in sample 2 our initial finding with CL with a maximum NPL(pair) score of 3.36 at D13S1272 (44 MB), only 2.1 MB telomeric to our previous maximum result. In the coMBined sample, the peak with CL was at marker D13S1297 (42.1 MB) with a NPL(pair) score reaching 5.21, exceeding that obtained in each sample and indicating consistency across the two samples. Our data suggest a susceptibility locus in 13q13-q14 that is shared by schizophrenia and mood disorder. That locus would be additional to another well documented and more distal 13q locus where the G72/G30 gene is mapped.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
69Am. J. Med. Genet. B Neuropsychiatr. Genet. 2009 Oct 150B: 914-25
PMID19152384
TitleEvidence for an interaction of schizophrenia susceptibility loci on chromosome 6q23.3 and 10q24.33-q26.13 in Arab Israeli families.
AbstractA genome scan for schizophrenia related loci in Arab Israeli families by Lerer et al. [Lerer et al. (2003); Mol Psychiatry 8:488-498] detected significant evidence for linkage at chromosome 6q23. Subsequent fine mapping [Levi et al. (2005); Eur J Hum Genet 13:763-771], association [Amann-Zalcenstein et al. (2006); Eur J Hum Genet 14:1111-1119] and replication studies [Ingason et al. (2007); Eur J Hum Genet 15:988-991] identified AHI1 as a putative susceptibility gene. The same genome scan revealed suggestive evidence for a schizophrenia susceptibility locus in the 10q23-26 region. Genes at these two loci may act independently in the pathogenesis of the disease in our homogeneous sample of Arab Israeli families or may interact with each other and with other factors in a common biological pathway. The purpose of our current study was to test the hypothesis of genetic interaction between these two loci and to identify the type of interaction between them. The initial stage of our study focused on the 10q23-q26 region which has not been explored further in our sample. The second stage of the study included a test for possible genetic interaction between the 6q23.3 locus and the refined 10q24.33-q26.13 locus. A final candidate region of 19.9 MB between markers D10S222 (105.3 MB) and D10S587 (125.2 MB) was found on chromosome 10 by non-parametric and parametric linkage analyses. These linkage findings are consistent with previous reports in the same chromosomal region. Two-locus multipoint linkage analysis under three complex disease inheritance models (heterogeneity, multiplicative, and additive models) yielded a best maximum LOD score of 7.45 under the multiplicative model suggesting overlapping function of the 6q23.3 and 10q24.33-q26.13 loci.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
70Am. J. Hum. Genet. 2010 Aug 87: 229-36
PMID20691406
TitleMicrodeletions of 3q29 confer high risk for schizophrenia.
Abstractschizophrenia (SZ) is a severe psychiatric illness that affects approximately 1% of the population and has a strong genetic underpinning. Recently, genome-wide analysis of copy-nuMBer variation (CNV) has implicated rare and de novo events as important in SZ. Here, we report a genome-wide analysis of 245 SZ cases and 490 controls, all of Ashkenazi Jewish descent. Because many studies have found an excess burden of large, rare deletions in cases, we limited our analysis to deletions over 500 kb in size. We observed seven large, rare deletions in cases, with 57% of these being de novo. We focused on one 836 kb de novo deletion at chromosome 3q29 that falls within a 1.3-1.6 MB deletion previously identified in children with intellectual disability (ID) and autism, because increasing evidence suggests an overlap of specific rare copy-nuMBer variants (CNVs) between autism and SZ. By coMBining our data with prior CNV studies of SZ and analysis of the data of the Genetic Association Information Network (GAIN), we identified six 3q29 deletions among 7545 schizophrenic subjects and one among 39,748 controls, resulting in a statistically significant association with SZ (p = 0.02) and an odds ratio estimate of 17 (95% confidence interval: 1.36-1198.4). Moreover, this 3q29 deletion region contains two linkage peaks from prior SZ family studies, and the minimal deletion interval implicates 20 annotated genes, including PAK2 and DLG1, both paralogous to X-linked ID genes and now strong candidates for SZ susceptibility.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
71Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Jan 153B: 103-13
PMID19367581
TitleIdentification of neuroglycan C and interacting partners as potential susceptibility genes for schizophrenia in a Southern Chinese population.
AbstractChromosome 3p was reported by previous studies as one of the regions showing strong evidence of linkage with schizophrenia. We performed a fine-mapping association study of a 6-MB high-LD and gene-rich region on 3p in a Southern Chinese sample of 489 schizophrenia patients and 519 controls to search for susceptibility genes. In the initial screen, 4 SNPs out of the 144 tag SNPs genotyped were nominally significant (P < 0.05). One of the most significant SNPs (rs3732530, P = 0.0048) was a non-synonymous SNP in the neuroglycan C (NGC, also known as CSPG5) gene, which belongs to the neuregulin family. The gene prioritization program Endeavor ranked NGC 8th out of the 129 genes in the 6-MB region and the highest among the genes within the same LD block. Further genotyping of NGC revealed 3 more SNPs to be nominally associated with schizophrenia. Three other genes (NRG1, ErbB3, ErbB4) involved in the neuregulin pathways were subsequently genotyped. Interaction analysis by multifactor dimensionality reduction (MDR) revealed a significant two-SNP interaction between NGC and NRG1 (P = 0.015) and three-SNP interactions between NRG1 and ErbB4 (P = 0.009). The gene NGC is exclusively expressed in the brain. It is implicated in neurodevelopment in rats and was previously shown to promote neurite outgrowth. Methamphetamine, a drug that may induce psychotic symptoms, was reported to alter the expression of NGC. Taken together, these results suggest that NGC may be a novel candidate gene, and neuregulin signaling pathways may play an important role in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
72Clin. Genet. 2010 Apr 77: 389-94
PMID20002455
TitleDISC1 duplication in two brothers with autism and mild mental retardation.
AbstractWe describe the identification and delineation of an inherited 2.07 MB microduplication in 1q42.2 in two brothers with autism and mild mental retardation. Since this duplication was not present in 1577 Belgian persons, we consider this as an extremely rare variant which has the potential to provide further insight into the genetics of autism. The duplication contains seven genes including the DISC1 gene, an interesting candidate gene that has been associated to schizophrenia, bipolar disorder, autism and Asperger syndrome. In this report we describe additional analyses undertaken to investigate the causal relationship of the duplication to the autism phenotype. We conclude that the 1q42.2 microduplication probably confers susceptibility to autism in the current family. This study is a typical illustration of the difficult interpretation of causality of a very rare variant in neuropsychiatric disease and the challenge of genetic counselling in a particular family.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
73Mol. Psychiatry 2010 Oct 15: 1023-33
PMID19528963
TitleAssociation of common copy number variants at the glutathione S-transferase genes and rare novel genomic changes with schizophrenia.
AbstractCopy nuMBer variants (CNVs) are a substantial source of human genetic diversity, influencing the variable susceptibility to multifactorial disorders. schizophrenia is a complex illness thought to be caused by a nuMBer of genetic and environmental effects, few of which have been clearly defined. Recent reports have found several low prevalent CNVs associated with the disease. We have used a multiplex ligation-dependent probe amplification-based (MLPA) method to target 140 previously reported and putatively relevant gene-containing CNV regions in 654 schizophrenic patients and 604 controls for association studies. Most genotyped CNVs (95%) showed very low (<1%) population frequency. A few novel rare variants were only present in patients suggesting a possible pathogenic involvement, including 1.39?MB overlapping duplications at 22q11.23 found in two unrelated patients, and duplications of the somatostatin receptor 5 gene (SSTR5) at 16p13.3 in three unrelated patients. Furthermore, among the few relatively common CNVs observed in patients and controls, the coMBined analysis of gene copy nuMBer genotypes at two glutathione S-transferase (GST) genes, GSTM1 (glutathione S-transferase mu 1) (1p13.3) and GSTT2 (glutathione S-transferase theta 2) (22q11.23), showed a statistically significant association of non-null genotypes at both loci with an additive effect for increased vulnerability to schizophrenia (odds ratio of 1.92; P=0.0008). Our data provide complementary evidences for low prevalent, but highly penetrant chromosomal variants associated with schizophrenia, as well as for common CNVs that may act as susceptibility factors by disturbing glutathione metabolism.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
74Am. J. Hum. Genet. 2010 Nov 87: 618-30
PMID21055719
TitleDeletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia.
AbstractAutism spectrum disorders (ASD) and schizophrenia are neurodevelopmental disorders for which recent evidence indicates an important etiologic role for rare copy nuMBer variants (CNVs) and suggests common genetic mechanisms. We performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing. We detected a recurrent 1.4 MB deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls. We identified additional shared phenotypic features among nine patients available for clinical assessment, including macrocephaly, characteristic facial features, renal anomalies, and neurocognitive impairments. In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 10??). These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function. In addition, the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD, which is caused by HNF1B mutations only.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
75Genet. Med. 2010 Oct 12: 641-7
PMID20808231
TitleRecurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity.
AbstractThe short arm of chromosome 16 is rich in segmental duplications, predisposing this region of the genome to a nuMBer of recurrent rearrangements. Genomic iMBalances of an approximately 600-kb region in 16p11.2 (29.5-30.1 MB) have been associated with autism, intellectual disability, congenital anomalies, and schizophrenia. However, a separate, distal 200-kb region in 16p11.2 (28.7-28.9 MB) that includes the SH2B1 gene has been recently associated with isolated obesity. The purpose of this study was to better define the phenotype of this recurrent SH2B1-containing microdeletion in a cohort of phenotypically abnormal patients not selected for obesity.
Array comparative hybridization was performed on a total of 23,084 patients in a clinical setting for a variety of indications, most commonly developmental delay.
Deletions of the SH2B1-containing region were identified in 31 patients. The deletion is enriched in the patient population when compared with controls (P = 0.003), with both inherited and de novo events. Detailed clinical information was available for six patients, who all had developmental delays of varying severity. Body mass index was ?95th percentile in four of six patients, supporting the previously described association with obesity. The reciprocal duplication, found in 17 patients, does not seem to be significantly enriched in our patient population compared with controls.
Deletions of the 16p11.2 SH2B1-containing region are pathogenic and are associated with developmental delay in addition to obesity.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
76Am. J. Hum. Genet. 2010 Sep 87: 316-24
PMID20797689
TitleDirect measure of the de novo mutation rate in autism and schizophrenia cohorts.
AbstractThe role of de novo mutations (DNMs) in common diseases remains largely unknown. Nonetheless, the rate of de novo deleterious mutations and the strength of selection against de novo mutations are critical to understanding the genetic architecture of a disease. Discovery of high-impact DNMs requires substantial high-resolution interrogation of partial or complete genomes of families via resequencing. We hypothesized that deleterious DNMs may play a role in cases of autism spectrum disorders (ASD) and schizophrenia (SCZ), two etiologically heterogeneous disorders with significantly reduced reproductive fitness. We present a direct measure of the de novo mutation rate (?) and selective constraints from DNMs estimated from a deep resequencing data set generated from a large cohort of ASD and SCZ cases (n = 285) and population control individuals (n = 285) with available parental DNA. A survey of ?430 MB of DNA from 401 synapse-expressed genes across all cases and 25 MB of DNA in controls found 28 candidate DNMs, 13 of which were cell line artifacts. Our calculated direct neutral mutation rate (1.36 10(-8)) is similar to previous indirect estimates, but we observed a significant excess of potentially deleterious DNMs in ASD and SCZ individuals. Our results emphasize the importance of DNMs as genetic mechanisms in ASD and SCZ and the limitations of using DNA from archived cell lines to identify functional variants.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
77Psychiatr. Genet. 2010 Jun 20: 93-101
PMID20410851
TitleSupport for a bipolar affective disorder susceptibility locus on chromosome 12q24.3.
AbstractLinkage and association studies of bipolar affective disorder (BAD) point out chromosome 12q24 as a region of interest.
To investigate this region further, we conducted an association study of 22 DNA markers within a 1.14 MB region in a Danish sample of 166 patients with BAD and 311 control individuals. Two-hundred and four Danish patients with schizophrenia were also included in the study.
We observed highly significant allelic and genotypic association between BAD and two highly correlated markers. The risk allele of both markers considered separately conferred an odds ratio of 2 to an individual carrying one risk allele and an odds ratio of 4 for individuals carrying both risk alleles assuming an additive genetic model. These findings were supported by the haplotype analysis. In addition, we obtained a replication of four markers associated with BAD in an earlier UK study. The most significantly associated marker was also analyzed in a Scottish case-control sample and was earlier associated with BAD in the UK cohort. The association of that particular marker was strongly associated with BAD in a meta-analysis of the Danish, Scottish and UK sample (P=0.0003). The chromosome region confined by our most distant markers is gene-poor and harbours only a few predicted genes. This study implicates the Slynar locus. We confirmed one annotated Slynar transcript and identified a novel transcript in human brain cDNA.
This study confirms 12q24.3 as a region of functional importance in the pathogenesis of BAD and highlights the importance of focused genotyping.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
78Am. J. Hum. Genet. 2010 May 86: 707-18
PMID20398883
TitleRare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes.
AbstractDeletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy nuMBer variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls. Large deletions (> 100 kb) at 16p13.11 were observed in 23 patients, whereas no control had a deletion greater than 16 kb. Patients, even those with identically sized 16p13.11 deletions, presented with highly variable epilepsy phenotypes. For a subset of patients with a 16p13.11 deletion, we show a consistent reduction of expression for included genes, suggesting that haploinsufficiency might contribute to pathogenicity. We also investigated another possible mechanism of pathogenicity by using hybridization-based capture and next-generation sequencing of the homologous chromosome for ten 16p13.11-deletion patients to look for unmasked recessive mutations. Follow-up genotyping of suggestive polymorphisms failed to identify any convincing recessive-acting mutations in the homologous interval corresponding to the deletion. The observation that two of the 16p13.11 deletions were larger than 2 MB in size led us to screen for other large deletions. We found 12 additional genomic regions harboring deletions > 2 MB in epilepsy patients, and none in controls. Additional evaluation is needed to characterize the role of these exceedingly large, non-locus-specific deletions in epilepsy. Collectively, these data implicate 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders, and they appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
79PLoS ONE 2010 -1 5: e9401
PMID20195527
TitleHotspots of large rare deletions in the human genome.
AbstractWe have examined the genomic distribution of large rare autosomal deletions in a sample of 440 parent-parent-child trios from the Quebec founder population (QFP) which was recruited for a study of Attention Deficit Hyperactivity Disorder.
DNA isolated from blood was genotyped on Illumina Hap300 arrays. PennCNV coMBined with visual evaluation of images generated by the Beadstudio program was used to determine deletion boundary definition of sufficient precision to discern independent events, with near-perfect concordance between parent and child in about 98% of the 399 events detected in the offspring; the remaining 7 deletions were considered de novo. We defined several genomic regions of very high deletion frequency ('hotspots'), usually of 0.4-0.6 MB in length where independent rare deletions were found at frequencies of up to 100 fold higher than the average for the genome as a whole. Five of the 7 de novo deletions were in these hotspots. The same hotspots were also observed in three other studies on meMBers of the QFP, those with schizophrenia, with endometriosis and those from a longevity cohort.
Nine of the 13 hotspots carry one gene (7 of which are very long), while the rest contain no known genes. All nine genes have been implicated in disease. The patterns of exon deletions support the proposed roles for some of these genes in human disease, such as NRXN1 and PARKIN, and suggest limited roles or no role at all, for others, including MACROD2 and CTNNA3. Our results also offer an alternative interpretation for the observations of deletions in tumors which have been proposed as reflecting tumor-suppressive activity of genes in these hotspots.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
80Mol. Psychiatry 2010 Nov 15: 1101-11
PMID19786960
TitleEvidence for rare and common genetic risk variants for schizophrenia at protein kinase C, alpha.
AbstractWe earlier reported a genome-wide significant linkage to schizophrenia at chromosome 17 that was identified in a single pedigree (C702) consisting of six affected, male siblings with DSM-IV schizophrenia and prominent mood symptoms. In this study, we adopted several approaches in an attempt to map the putative disease locus. First, mapping the source of linkage to chromosome 17 in pedigree C702. We refined the linkage region in family C702 to a 21-marker segment spanning 11.7?MB at 17q23-q24 by genotyping a total of 50 microsatellites across chromosome 17 in the pedigree. Analysis of data from 1028 single nucleotide polymorphisms (SNPs) across the refined linkage region identified a single region of homozygosity present in pedigree C702 but not in 2938 UK controls. This spanned ~432?kb of the gene encoding protein kinase C, alpha (PRKCA), the encoded protein of which has been implicated in the pathogenesis of psychiatric disorders. Analysis of pedigree C702 by oligonucleotide-array comparative genome hybridization excluded the possibility that this region of homozygosity was because of a deletion. Mutation screening of PRKCA identified a rare, four-marker haplotype (C-HAP) in the 3' untranslated region of the gene, which was present in the homozygous state in all six affected meMBers of pedigree C702. No other homozygotes were observed in genotype data for a total of 6597 unrelated Europeans (case N=1755, control N=3580 and parents of probands N=1262). Second, association analysis of C702 alleles at PRKCA. The low-frequency haplotype (C-HAP) showed a trend for association in a study of unrelated schizophrenia cases and controls from the UK (661 cases, 2824 controls, P=0.078 and odd ratio (OR)=1.9) and significant evidence for association when the sample was expanded to include cases with bipolar (N=710) and schizoaffective disorder (N=50) (psychosis sample: 1421 cases, 2824 controls, P=0.037 and OR=1.9). Given that all the affected meMBers of C702 are male, we also undertook sex-specific analyses. This revealed that the association was strongest in males for both schizophrenia (446 male cases, 1421 male controls, P=0.008 and OR=3.9) and in the broader psychosis group (730 male cases, 1421 male controls, P=0.008 and OR=3.6). Analysis of C-HAP in follow-up samples from Ireland and Bulgaria revealed no evidence for association in either the whole sample or in males alone, and meta-analysis of all male psychosis samples yielded no significant evidence of association (969 male cases, 1939 male controls, 311 male probands P=0.304 and OR=1.4). Third, association mapping of the pedigree C702 linkage region. Independent of pedigree C702, genotype data from the Affymetrix 500k GeneChip set were available for 476 patients with schizophrenia and 2938 controls from the United Kingdom. SNPs in PRKCA showed evidence for association with schizophrenia that achieved gene-wide significance (P=0.027). Moreover, the same SNP was the most significantly associated marker out of the 1028 SNPs genotyped across the linkage region (rs873417, allelic P=0.0004). Follow-up genotyping in samples from Ireland, Bulgaria and Germany did not show consistent replication, but meta-analysis of all samples (4116 cases and 6491 controls) remained nominally significant (meta-analysis P=0.026, OR=1.1). We conclude that, although we have obtained convergent lines of evidence implicating both rare and common schizophrenia risk variants at PRKCA, none of these is individually compelling. However, the evidence across all approaches suggests that further study of this locus is warranted.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
81Am. J. Hum. Genet. 2010 Aug 87: 229-36
PMID20691406
TitleMicrodeletions of 3q29 confer high risk for schizophrenia.
Abstractschizophrenia (SZ) is a severe psychiatric illness that affects approximately 1% of the population and has a strong genetic underpinning. Recently, genome-wide analysis of copy-nuMBer variation (CNV) has implicated rare and de novo events as important in SZ. Here, we report a genome-wide analysis of 245 SZ cases and 490 controls, all of Ashkenazi Jewish descent. Because many studies have found an excess burden of large, rare deletions in cases, we limited our analysis to deletions over 500 kb in size. We observed seven large, rare deletions in cases, with 57% of these being de novo. We focused on one 836 kb de novo deletion at chromosome 3q29 that falls within a 1.3-1.6 MB deletion previously identified in children with intellectual disability (ID) and autism, because increasing evidence suggests an overlap of specific rare copy-nuMBer variants (CNVs) between autism and SZ. By coMBining our data with prior CNV studies of SZ and analysis of the data of the Genetic Association Information Network (GAIN), we identified six 3q29 deletions among 7545 schizophrenic subjects and one among 39,748 controls, resulting in a statistically significant association with SZ (p = 0.02) and an odds ratio estimate of 17 (95% confidence interval: 1.36-1198.4). Moreover, this 3q29 deletion region contains two linkage peaks from prior SZ family studies, and the minimal deletion interval implicates 20 annotated genes, including PAK2 and DLG1, both paralogous to X-linked ID genes and now strong candidates for SZ susceptibility.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
82Mol. Psychiatry 2010 Oct 15: 1023-33
PMID19528963
TitleAssociation of common copy number variants at the glutathione S-transferase genes and rare novel genomic changes with schizophrenia.
AbstractCopy nuMBer variants (CNVs) are a substantial source of human genetic diversity, influencing the variable susceptibility to multifactorial disorders. schizophrenia is a complex illness thought to be caused by a nuMBer of genetic and environmental effects, few of which have been clearly defined. Recent reports have found several low prevalent CNVs associated with the disease. We have used a multiplex ligation-dependent probe amplification-based (MLPA) method to target 140 previously reported and putatively relevant gene-containing CNV regions in 654 schizophrenic patients and 604 controls for association studies. Most genotyped CNVs (95%) showed very low (<1%) population frequency. A few novel rare variants were only present in patients suggesting a possible pathogenic involvement, including 1.39?MB overlapping duplications at 22q11.23 found in two unrelated patients, and duplications of the somatostatin receptor 5 gene (SSTR5) at 16p13.3 in three unrelated patients. Furthermore, among the few relatively common CNVs observed in patients and controls, the coMBined analysis of gene copy nuMBer genotypes at two glutathione S-transferase (GST) genes, GSTM1 (glutathione S-transferase mu 1) (1p13.3) and GSTT2 (glutathione S-transferase theta 2) (22q11.23), showed a statistically significant association of non-null genotypes at both loci with an additive effect for increased vulnerability to schizophrenia (odds ratio of 1.92; P=0.0008). Our data provide complementary evidences for low prevalent, but highly penetrant chromosomal variants associated with schizophrenia, as well as for common CNVs that may act as susceptibility factors by disturbing glutathione metabolism.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
83Am. J. Med. Genet. B Neuropsychiatr. Genet. 2011 Mar 156: 188-97
PMID21302347
TitleLinkage and association on 8p21.2-p21.1 in schizophrenia.
AbstractIn the past decade, we and others have consistently reported linkage to a schizophrenia (SZ) susceptibility region on chromosome 8p21. Most recently, in the largest SZ linkage sample to date, a multi-site international collaboration performed a SNP-based linkage scan (~6,000 SNPs; 831 pedigrees; 121 from Johns Hopkins (JHU)), that showed the strongest evidence for linkage in a 1?MB region of chr 8p21 from rs1561817 to rs9797 (Z(max)?=?3.22, P?=?0.0004) [Holmans et al. 2009. Mol Psychiatry]. We have investigated this 8p21 peak region further in two ways: first by linkage and family-based association in 106 8p-linked European-Caucasian (EUC) JHU pedigrees using 1,402 SNPs across a 4.4?MB region surrounding the peak; second, by an independent case-control association study in the genetically more homogeneous Ashkenazim (AJ) (709 cases, 1,547 controls) using 970 SNPs in a further narrowed 2.8?MB region. Family-based association analyses in EUC pedigrees and case-control analyses in AJ samples reveal significant associations for SNPs in and around DPYSL2 and ADRA1A, candidate genes previously associated with SZ in our work and others. Further, several independent gene expression studies have shown that DPYSL2 is differentially expressed in SZ brains [Beasley et al. 2006. Proteomics 6(11):3414?3425; Edgar et al. 2000. Mol Psychiatry 5(1):85?90; Johnston-Wilson et al. 2000. Mol Psychiatry 5(2):142?149] or in response to psychosis-inducing pharmaceuticals [Iwazaki et al. 2007. Proteomics 7(7):1131?1139; Paulson et al. 2004. Proteomics 4(3):819?825]. Taken together, this work further supports DPYSL2 and the surrounding genomic region as a susceptibility locus for SZ.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
84Am J Psychiatry 2011 Mar 168: 302-16
PMID21285140
TitleCopy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications.
AbstractTo evaluate previously reported associations of copy nuMBer variants (CNVs) with schizophrenia and to identify additional associations, the authors analyzed CNVs in the Molecular Genetics of schizophrenia study (MGS) and additional available data.
After quality control, MGS data for 3,945 subjects with schizophrenia or schizoaffective disorder and 3,611 screened comparison subjects were available for analysis of rare CNVs (<1% frequency). CNV detection thresholds were chosen that maximized concordance in 151 duplicate assays. Pointwise and genewise analyses were carried out, as well as analyses of previously reported regions. Selected regions were visually inspected and confirmed with quantitative polymerase chain reaction.
In analyses of MGS data coMBined with other available data sets, odds ratios of 7.5 or greater were observed for previously reported deletions in chromosomes 1q21.1, 15q13.3, and 22q11.21, duplications in 16p11.2, and exon-disrupting deletions in NRXN1. The most consistently supported candidate associations across data sets included a 1.6-MB deletion in chromosome 3q29 (21 genes, TFRC to BDH1) that was previously described in a mild-moderate mental retardation syndrome, exonic duplications in the gene for vasoactive intestinal peptide receptor 2 (VIPR2), and exonic duplications in C16orf72. The case subjects had a modestly higher genome-wide nuMBer of gene-containing deletions (>100 kb and >1 MB) but not duplications.
The data strongly confirm the association of schizophrenia with 1q21.1, 15q13.3, and 22q11.21 deletions, 16p11.2 duplications, and exonic NRXN1 deletions. These CNVs, as well as 3q29 deletions, are also associated with mental retardation, autism spectrum disorders, and epilepsy. Additional candidate genes and regions, including VIPR2, were identified. Study of the mechanisms underlying these associations should shed light on the pathophysiology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
85J Psychiatr Res 2011 Nov 45: 1432-8
PMID21820670
TitleDNA hypomethylation of MB-COMT promoter in the DNA derived from saliva in schizophrenia and bipolar disorder.
AbstractThe failure in the discovery of etiology of psychiatric diseases, despite extensive genetic studies, has directed the attention of neuroscientists to the contribution of epigenetic modulations, which play important roles in fine-tuning of gene expression in response to environmental factors. Previously, we analyzed 115 human post-mortem brain samples from the frontal lobe and reported DNA hypo methylation of the meMBrane-bound catechol-O-methyltransferase (MB-COMT) gene promoter, associated with an increased gene expression, as a risk factor for schizophrenia (SCZ) and bipolar disorder (BD). Since most epigenetic modifications are tissue specific and the availability of brain tissue to identify epigenetic aberrations in living subjects is limited, detection of epigenetic abnormalities in other tissues that represent the brain epigenetic marks is one of the critical steps to develop diagnostic and therapeutic biomarkers for mental diseases. Here, hypothesizing that; those factors that lead to the brain MB-COMT promoter DNA hypo-methylation may also cause concurrent epigenetic aberrations in peripheral tissues, we analyzed MB-COMT promoter methylation in DNA derived from the saliva in SCZ, BD and their first-degree relatives (20 cases each) as well as 25 control subjects. Using bisulfite DNA sequencing and quantitative methylation specific PCR (qMSP), we found that similar to the brain, MB-COMT promoter was hypo-methylated (?50%) in DNA derived from the saliva in SCZ and BD compared to the control subjects (p=0.02 and 0.037, respectively). These studies suggest that DNA methylation analysis of MB-COMT promoter in saliva can potentially be used as an available epigenetic biomarker for disease state in SCZ and BD.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
86Hum. Genet. 2011 Jan 129: 1-15
PMID21104274
TitleRegions of homozygosity and their impact on complex diseases and traits.
AbstractRegions of homozygosity (ROHs) are more abundant in the human genome than previously thought. These regions are without heterozygosity, i.e. all the genetic variations within the regions have two identical alleles. At present there are no standardized criteria for defining the ROHs resulting in the different studies using their own criteria in the analysis of homozygosity. Compared to the era of genotyping microsatellite markers, the advent of high-density single nucleotide polymorphism genotyping arrays has provided an unparalleled opportunity to comprehensively detect these regions in the whole genome in different populations. Several studies have identified ROHs which were associated with complex phenotypes such as schizophrenia, late-onset of Alzheimer's disease and height. Collectively, these studies have conclusively shown the abundance of ROHs larger than 1 MB in outbred populations. The homozygosity association approach holds great promise in identifying genetic susceptibility loci harboring recessive variants for complex diseases and traits.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
87Am. J. Med. Genet. A 2011 Nov 155A: 2739-45
PMID21990140
TitleMYT1L is a candidate gene for intellectual disability in patients with 2p25.3 (2pter) deletions.
AbstractA partial deletion of chromosome band 2p25.3 (2pter) is a rarely described cytogenetic aberration in patients with intellectual disability (ID). Using microarrays we identified deletions of 2p25.3, sized 0.37-3.13 MB, in three adult siblings and three unrelated patients. All patients had ID, obesity or overweight and/or a square-shaped stature without overt facial dysmorphic features. CoMBining our data with phenotypic and genotypic data of three patients from the literature we defined the minimal region of overlap which contained one gene, i.e., MYT1L. MYT1L is highly transcribed in the mouse eMBryonic brain where its expression is restricted to postmitotic differentiating neurons. In mouse-induced pluripotent stem cell (iPS) models, MYT1L is essential for inducing functional mature neurons. These reseMBle excitatory cortical neurons of the forebrain, suggesting a role for MYT1L in development of cognitive functions. Furthermore, MYT1L can directly convert human fibroblasts into functional neurons in conjunction with other transcription factors. MYT1L duplication was previously reported in schizophrenia, indicating that the gene is dosage-sensitive and that shared neurodevelopmental pathways may be affected in ID and schizophrenia. Finally, deletion of MYT1, another meMBer of the Myelin Transcription Factor family involved in neurogenesis and highly similar to MYT1L, was recently described in ID as well. The identification of MYT1L as candidate gene for ID justifies further molecular studies aimed at detecting mutations and for mechanistic studies on its role in neuron development and on neuropathogenic effects of haploinsufficiency.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
88PLoS ONE 2011 -1 6: e18612
PMID21572526
TitleIdentifying human disease genes through cross-species gene mapping of evolutionary conserved processes.
AbstractUnderstanding complex networks that modulate development in humans is hampered by genetic and phenotypic heterogeneity within and between populations. Here we present a method that exploits natural variation in highly diverse mouse genetic reference panels in which genetic and environmental factors can be tightly controlled. The aim of our study is to test a cross-species genetic mapping strategy, which compares data of gene mapping in human patients with functional data obtained by QTL mapping in recoMBinant inbred mouse strains in order to prioritize human disease candidate genes.
We exploit evolutionary conservation of developmental phenotypes to discover gene variants that influence brain development in humans. We studied corpus callosum volume in a recoMBinant inbred mouse panel (C57BL/6JDBA/2J, BXD strains) using high-field strength MRI technology. We aligned mouse mapping results for this neuro-anatomical phenotype with genetic data from patients with abnormal corpus callosum (ACC) development.
From the 61 syndromes which involve an ACC, 51 human candidate genes have been identified. Through interval mapping, we identified a single significant QTL on mouse chromosome 7 for corpus callosum volume with a QTL peak located between 25.5 and 26.7 MB. Comparing the genes in this mouse QTL region with those associated with human syndromes (involving ACC) and those covered by copy nuMBer variations (CNV) yielded a single overlap, namely HNRPU in humans and Hnrpul1 in mice. Further analysis of corpus callosum volume in BXD strains revealed that the corpus callosum was significantly larger in BXD mice with a B genotype at the Hnrpul1 locus than in BXD mice with a D genotype at Hnrpul1 (F?=?22.48, p<9.87*10(-5)).
This approach that exploits highly diverse mouse strains provides an efficient and effective translational bridge to study the etiology of human developmental disorders, such as autism and schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
89Autism Res 2011 Jun 4: 221-7
PMID21360829
TitleA de novo 1.5?Mb microdeletion on chromosome 14q23.2-23.3 in a patient with autism and spherocytosis.
AbstractAutism is a neuro-developmental disorder characterized by deficits in social interaction and communication as well as restricted interests or repetitive behaviors. Cytogenetic studies have implicated large chromosomal aberrations in the etiology of approximately 5-7% of autism patients, and the recent advent of array-based techniques allows the exploration of submicroscopic copy nuMBer variations (CNVs). We genotyped a 14-year-old boy with autism, spherocytosis and other physical dysmorphia, his parents, and two non-autistic siblings with the Illumina Human 1M Beadchip as part of a study of the molecular genetics of autism and determined copy nuMBer variants using the PennCNV algorithm. We identified and validated a de novo 1.5?MB microdeletion of 14q23.2-23.3 in our autistic patient. This region contains 15 genes, including spectrin beta (SPTB), encoding a cytoskeletal protein previously associated with spherocytosis, methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), a folate metabolizing enzyme previously associated with bipoloar disorder and schizophrenia, pleckstrin homology domain-containing family G meMBer 3 (PLEKHG3), a guanide nucleotide exchange enriched in the brain, and churchill domain containing protein 1 (CHURC1), homologs of which regulate neuronal development in model organisms. While a similar deletion has previously been reported in a family with spherocytosis, severe learning disabilities, and mild mental retardation, this is the first implication of chr14q23.2-23.3 in the etiology of autism and points to MTHFD1, PLEKHG3, and CHURC1 as potential candidate genes contributing to autism risk.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
90J. Nerv. Ment. Dis. 2012 Nov 200: 941-5
PMID23124177
TitlePsychosocial functioning and cognitive deficits are not associated with membrane-bound catechol-O-methyltransferase deoxyribonucleic acid methylation in siblings of patients with schizophrenia.
AbstractIn this study, we investigated whether the siblings of patients with schizophrenia have deficits in cognition and psychosocial functioning and whether the psychosocial functioning and cognitive deficits correlate with the methylation status of the meMBrane-bound catechol-O-methyltransferase (MB-COMT) gene in peripheral leukocytes. Cognitive abilities were evaluated using the attention/vigilance Continuous Performance Test, delayed/immediate recall scores, the Wisconsin Card Sorting Test, and the Semantic Verbal Fluency Test. Psychosocial functioning was evaluated using the Scale for the Assessment of Negative Symptoms, the Global Assessment of Functioning scale, and the Social Adjustment Scale. A bisulfate-based sequencing was adopted to analyze the methylation status of the MB-COMT promoter in peripheral leukocytes. Significant impairments in attention/vigilance and verbal memory and significant decreases in immediate and delayed recall scores were observed in the siblings of patients with schizophrenia compared with the healthy subjects. In addition, significant deficits in global social functioning and in social interaction were found in the siblings. The tested region of the MB-COMT promoter was generally unmethylated in peripheral leukocytes, without significant correlation with behavioral deficits in the siblings.Our study demonstrated that the siblings have significant deficits in cognition and psychosocial functioning, which may not be associated with MB-COMT methylation in peripheral leukocytes.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
91ACS Chem Neurosci 2012 Feb 3: 129-40
PMID22860182
TitleCharacterization of non-nitrocatechol pan and isoform specific catechol-O-methyltransferase inhibitors and substrates.
AbstractReduced dopamine neurotransmission in the prefrontal cortex has been implicated as causal for the negative symptoms and cognitive deficit associated with schizophrenia; thus, a compound which selectively enhances dopamine neurotransmission in the prefrontal cortex may have therapeutic potential. Inhibition of catechol-O-methyltransferase (COMT, EC 2.1.1.6) offers a unique advantage, since this enzyme is the primary mechanism for the elimination of dopamine in cortical areas. Since meMBrane bound COMT (MB-COMT) is the predominant isoform in human brain, a high throughput screen (HTS) to identify novel MB-COMT specific inhibitors was completed. Subsequent optimization led to the identification of novel, non-nitrocatechol COMT inhibitors, some of which interact specifically with MB-COMT. Compounds were characterized for in vitro efficacy versus human and rat MB and soluble (S)-COMT. Select compounds were administered to male Wistar rats, and ex vivo COMT activity, compound levels in plasma and cerebrospinal fluid (CSF), and CSF dopamine metabolite levels were determined as measures of preclinical efficacy. Finally, novel non-nitrocatechol COMT inhibitors displayed less potent uncoupling of the mitochondrial meMBrane potential (MMP) compared to tolcapone as well as nonhepatotoxic entacapone, thus mitigating the risk of hepatotoxicity.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
92Prog. Neuropsychopharmacol. Biol. Psychiatry 2012 Oct 39: 163-9
PMID22705295
TitleAssociation of MB-COMT polymorphisms with schizophrenia-susceptibility and symptom severity in an African cohort.
AbstractThe catechol-O-methyltransferase (COMT) gene is an attractive schizophrenia candidate gene, encoding a catabolic dopamine enzyme. The enzyme exists as two distinct isoforms, with the meMBrane bound enzyme (i.e. MB-COMT) being predominantly expressed in the brain. Since African populations remain underrepresented in genetic/genomic research, we performed an association study to determine whether MB-COMT genetic variants are associated with schizophrenia-susceptibility and symptom severity in the South African Xhosa population. Fourteen candidate polymorphisms were selected by means of a literature search and in silico analyses and were subsequently genotyped in a cohort of 238 Xhosa schizophrenia patients and 240 healthy Xhosa controls. Genetic association was tested with schizophrenia-susceptibility as well as symptom severity within the patient group. Polymorphisms of interest were also analysed using functional assays. Two SNPs, rs2020917 (OR=0.54, 95% CI 0.37-0.79; P=0.0011) and rs737865 (OR=0.52, 95% CI 0.36-0.74; P=0.0002), in the P2 promoter region were significantly associated with schizophrenia as well as an increase (increase=11.2%, 95% CI 3.7%-19.2%; P=0.0031) in reporter gene expression. The minor alleles of these SNPs were underrepresented in the schizophrenia cohort, indicating a possible protective effect. The P2 region also formed part of a haplotype found to be associated with the severity of the negative symptoms of the disorder. The data generated by this study indicate that genetic variation of MB-COMT could be associated with schizophrenia and negative symptom severity in the Xhosa population and may therefore be one of the genomic loci contributing towards the disorder in the South African community. Future large-scale studies in other African schizophrenia populations are required to further elucidate the significance of these findings.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
93Front Genet 2012 -1 3: 291
PMID23248646
TitlemiRNA-mediated risk for schizophrenia in 22q11.2 deletion syndrome.
AbstractIn humans, the most common genomic disorder is a hemizygous deletion of a 1.5-3 MB region of chromosome 22q11.2. The resultant 22q11.2 deletion syndrome (22q11.2DS) can affect multiple organ systems, and most notably includes cardiac, craniofacial, and neurodevelopmental defects. Individuals with 22q11.2DS have a 20-25-fold risk of developing schizophrenia compared to individuals from the general population, making 22q11.2DS the strongest known molecular genetic risk factor for schizophrenia. Although the deleted region includes DGCR8, a gene coding for a miRNA processing protein, the exact mechanism by which this deletion increases risk is unknown. Importantly, several lines of evidence suggest that miRNAs may modulate risk for schizophrenia in other, non-22q11.2DS populations. Here we present a theory which mechanistically explains the link between 22q11.2DS, miRNAs, and schizophrenia risk. We outline the testable predictions generated by this theory and present preliminary data in support of our model. Further experimental validation of this model could provide important insights into the etiology of both 22q11.2DS and more common forms of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
94J. Neurosci. 2012 Oct 32: 14132-44
PMID23055483
TitleAge-dependent microRNA control of synaptic plasticity in 22q11 deletion syndrome and schizophrenia.
AbstractThe 22q11 deletion syndrome (22q11DS) is characterized by multiple physical and psychiatric abnormalities and is caused by the hemizygous deletion of a 1.5-3 MB region of chromosome 22. It constitutes one of the strongest known genetic risks for schizophrenia; schizophrenia arises in as many as 30% of patients with 22q11DS during adolescence or early adulthood. A mouse model of 22q11DS displays an age-dependent increase in hippocampal long-term potentiation (LTP), a form of synaptic plasticity underlying learning and memory. The sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA2), which is responsible for loading Ca(2+) into the endoplasmic reticulum (ER), is elevated in this mouse model. The resulting increase in ER Ca(2+) load leads to enhanced neurotransmitter release and increased LTP. However, the mechanism by which the 22q11 microdeletion leads to SERCA2 overexpression and LTP increase has not been determined. Screening of multiple mutant mouse lines revealed that haploinsufficiency of Dgcr8, a microRNA (miRNA) biogenesis gene in the 22q11DS disease-critical region, causes age-dependent, synaptic SERCA2 overexpression and increased LTP. We found that miR-25 and miR-185, regulators of SERCA2, are depleted in mouse models of 22q11DS. Restoration of these miRNAs to presynaptic neurons rescues LTP in Dgcr8(+/-) mice. Finally, we show that SERCA2 is elevated in the brains of patients with schizophrenia, providing a link between mouse model findings and the human disease. We conclude that miRNA-dependent SERCA2 dysregulation is a pathogenic event in 22q11DS and schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
95J Psychiatr Res 2012 Nov 46: 1414-20
PMID22944046
TitleThe chromosome 15q14 locus for bipolar disorder and schizophrenia: is C15orf53 a major candidate gene?
AbstractBipolar disorder (BD) and schizophrenia are complexly inherited and highly heritable disorders with currently unknown etiologies. Recently, two independent genome-wide association studies for BD identified a small region on chromosome 15q14-15.1, pointing to a locus close to the gene C15orf53. Previously, this genomic region was also found to co-segregate with periodic catatonia (SCZD10, OMIM %605419), an unsystematic schizophrenia according to Leonhard's classification, in several multiplex families, thus pointing to overlapping etiologies of both conditions. A susceptibility locus on chromosome 15q14-15.1 was narrowed down to a 4.38 MB region in these affected families followed by mutation and segregation analyses of C15orf53. Association analysis of individuals affected by BD and/or SCZD10 (n = 274) and controls (n = 230) and expression analyses in distinct post-mortem human liMBic brain tissues were conducted. C15orf53 revealed no mutations in our SCZD10 family meMBers, but segregation of two common haplotypes was found. No association of identified haplotypes was found in our case-control samples. Gene expression could be demonstrated for immune-system-derived cells but not for the post-mortem human liMBic brain tissue. Our results indicate that C15orf53 is probably neither causative for the etiology of BD nor for SCZD10 in our samples.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
96J. Formos. Med. Assoc. 2012 May 111: 265-74
PMID22656397
TitleMedium-term course and outcome of schizophrenia depicted by the sixth-month subtype after an acute episode.
AbstractThe intermediate course of schizophrenia is a complex intertwined with the heterogeneity of the illness. This article attempts to simplify this complexity using a hypothetical tripartite based on the profile of symptoms at 6 months after acute treatment.
This is a prospective 5-year follow-up study including 163 schizophrenic inpatients in northern Taiwan comparing patients' demographic data at index admission, scores on the Positive and Negative Syndrome Scale (PANSS) for schizophrenia and social function scale measured at admission, 6-month follow-up, and annually, and scores on a neuropsychologic test battery measured approximately 5 years after recruitment.
Patients were grouped into three subtypes based on their sixth-month symptomatology by Generalized Association Plots, designated as remitted (RM), persistent delusion/hallucination (PDH), and markedly blunting (MB) groups. These three subtypes presented with similar positive symptom profiles at recruitment, yet during follow-up, the PDH group tended to maintain the highest risk of having worse clinical symptomatology, social functioning, and neuropsychologic functioning, and the RM was the best outcome group.
This three-subtype model provides a practical reference to predict medium-term outcomes by the subject's response to acute treatment and serves as a model to sort out part of the heterogeneous nature of schizophrenia that still should be examined by further psychopharmacological, neurobiological, and genetic studies.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
97Am. J. Med. Genet. B Neuropsychiatr. Genet. 2012 Jun 159B: 383-91
PMID22461138
TitleGenetic overlap of schizophrenia and bipolar disorder in a high-density linkage survey in the Portuguese Island population.
AbstractRecent family and genome-wide association studies strongly suggest shared genetic risk factors for schizophrenia (SZ) and bipolar disorder (BP). However, linkage studies have not been used to test for statistically significant genome-wide overlap between them. Forty-seven Portuguese families with sibpairs concordant for SZ, BP, or psychosis (PSY, which includes either SZ or psychotic BP) were genotyped for over 57,000 markers using the Affymetrix 50K Xba SNP array. NPL and Kong and Cox LOD scores were calculated in Merlin for all three phenotypes. Empirical significance was determined using 1,000 gene-dropping simulations. Significance of genome-wide genetic overlap between SZ and BP was determined by the nuMBer of simulated BP scans having the same nuMBer of loci jointly linked with the real SZ scan, and vice versa. For all three phenotypes, a nuMBer of regions previously linked in this sample remained so. For BP, chromosome 1p36 achieved significance (11.54-15.71 MB, LOD = 3.51), whereas it was not even suggestively linked at lower marker densities, as did chromosome 11q14.1 (89.32-90.15 MB, NPL = 4.15). Four chromosomes had loci at which both SZ and BP had NPL ? 1.98, which was more than would be expected by chance (empirical P = 0.01 using simulated SZ scans; 0.07 using simulated BP scans), although they did not necessarily meet criteria for suggestive linkage individually. These results suggest that high-density marker maps may provide greater power and precision in linkage studies than lower density maps. They also further support the hypothesis that SZ and BP share at least some risk alleles.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
98Am. J. Med. Genet. B Neuropsychiatr. Genet. 2012 Jan 159B: 61-71
PMID22095694
TitleEvidence for involvement of GNB1L in autism.
AbstractStructural variations in the chromosome 22q11.2 region mediated by nonallelic homologous recoMBination result in 22q11.2 deletion (del22q11.2) and 22q11.2 duplication (dup22q11.2) syndromes. The majority of del22q11.2 cases have facial and cardiac malformations, immunologic impairments, specific cognitive profile and increased risk for schizophrenia and autism spectrum disorders (ASDs). The phenotype of dup22q11.2 is frequently without physical features but includes the spectrum of neurocognitive abnormalities. Although there is substantial evidence that haploinsufficiency for TBX1 plays a role in the physical features of del22q11.2, it is not known which gene(s) in the critical 1.5?MB region are responsible for the observed spectrum of behavioral phenotypes. We identified an individual with a balanced translocation 46,XY,t(1;22)(p36.1;q11.2) and a behavioral phenotype characterized by cognitive impairment, autism, and schizophrenia in the absence of congenital malformations. Using somatic cell hybrids and comparative genomic hybridization (CGH) we mapped the chromosome-22 breakpoint within intron 7 of the GNB1L gene. Copy nuMBer evaluations and direct DNA sequencing of GNB1L in 271 schizophrenia and 513 autism cases revealed dup22q11.2 in two families with autism and private GNB1L missense variants in conserved residues in three families (P?=?0.036). The identified missense variants affect residues in the WD40 repeat domains and are predicted to have deleterious effects on the protein. Prior studies provided evidence that GNB1L may have a role in schizophrenia. Our findings support involvement of GNB1L in ASDs as well.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
99Mol. Psychiatry 2012 Dec 17: 1328-39
PMID21968932
TitlePromoter polymorphisms in two overlapping 6p25 genes implicate mitochondrial proteins in cognitive deficit in schizophrenia.
AbstractIn a previous study, we detected a 6p25-p24 region linked to schizophrenia in families with high composite cognitive deficit (CD) scores, a quantitative trait integrating multiple cognitive measures. Association mapping of a 10 MB interval identified a 260 kb region with a cluster of single-nucleotide polymorphisms (SNPs) significantly associated with CD scores and memory performance. The region contains two colocalising genes, LYRM4 and FARS2, both encoding mitochondrial proteins. The two tagging SNPs with strongest evidence of association were located around the overlapping putative promoters, with rs2224391 predicted to alter a transcription factor binding site (TFBS). Sequencing the promoter region identified 22 SNPs, many predicted to affect TFBSs, in a tight linkage disequilibrium block. Luciferase reporter assays confirmed promoter activity in the predicted promoter region, and demonstrated marked downregulation of expression in the LYRM4 direction under the haplotype comprising the minor alleles of promoter SNPs, which however is not driven by rs2224391. Experimental evidence from LYRM4 expression in lymphoblasts, gel-shift assays and modelling of DNA breathing dynamics pointed to two adjacent promoter SNPs, rs7752203-rs4141761, as the functional variants affecting expression. Their C-G alleles were associated with higher transcriptional activity and preferential binding of nuclear proteins, whereas the G-A coMBination had opposite effects and was associated with poor memory and high CD scores. LYRM4 is a eukaryote-specific component of the mitochondrial biogenesis of Fe-S clusters, essential cofactors in multiple processes, including oxidative phosphorylation. LYRM4 downregulation may be one of the mechanisms involved in inefficient oxidative phosphorylation and oxidative stress, increasingly recognised as contributors to schizophrenia pathogenesis.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
100Hum. Genet. 2012 Mar 131: 373-91
PMID21866342
TitleIon channels and schizophrenia: a gene set-based analytic approach to GWAS data for biological hypothesis testing.
Abstractschizophrenia is a complex genetic disorder. Gene set-based analytic (GSA) methods have been widely applied for exploratory analyses of large, high-throughput datasets, but less commonly employed for biological hypothesis testing. Our primary hypothesis is that variation in ion channel genes contribute to the genetic susceptibility to schizophrenia. We applied Exploratory Visual Analysis (EVA), one GSA application, to analyze European-American (EA) and African-American (AA) schizophrenia genome-wide association study datasets for statistical enrichment of ion channel gene sets, comparing GSA results derived under three SNP-to-gene mapping strategies: (1) GENIC; (2) 500-Kb; (3) 2.5-MB and three complimentary SNP-to-gene statistical reduction methods: (1) minimum p value (pMIN); (2) a novel method, proportion of SNPs per Gene with p values below a pre-defined ?-threshold (PROP); and (3) the truncated product method (TPM). In the EA analyses, ion channel gene set(s) were enriched under all mapping and statistical approaches. In the AA analysis, ion channel gene set(s) were significantly enriched under pMIN for all mapping strategies and under PROP for broader mapping strategies. Less extensive enrichment in the AA sample may reflect true ethnic differences in susceptibility, sampling or case ascertainment differences, or higher dimensionality relative to sample size of the AA data. More consistent findings under broader mapping strategies may reflect enhanced power due to increased SNP inclusion, enhanced capture of effects over extended haplotypes or significant contributions from regulatory regions. While extensive pMIN findings may reflect gene size bias, the extent and significance of PROP and TPM findings suggest that common variation at ion channel genes may capture some of the heritability of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
101Am. J. Med. Genet. B Neuropsychiatr. Genet. 2012 Jan 159B: 77-86
PMID22162401
TitleEvaluation of conserved and ultra-conserved non-genic sequences in chromosome 15q15-linked periodic catatonia.
AbstractConserved and ultra-conserved non-genic sequence elements (CNGs, UCEs) between human and other mammalian genomes seem to constitute a heterogeneous group of functional sequences which likely have important biological function. To determine whether variation in CNGs and UCEs contributes to risk for the schizophrenic subphenotype of periodic catatonia (according to K. Leonhard; OMIM 605419), we evaluated non-coding elements at a critical 7.35?MB interval on chromosome 15q15 in 8 unrelated cases with periodic catatonia (derived from pedigrees compatible with linkage to chromosome 15q15) and 8 controls, followed by association studies in a cohort of 510 cases and controls. Among 65 CNGs (?100?bp, 100% identity; human-mouse comparison), 7 CNGs matched criteria for UCE (?200? bp, 100% identity). A hot spot of 62/65 CNGs (95%) appeared at the MEIS2 locus, which implicates functional importance of associated (ultra-)conserved elements to this early developmental gene, which is present in the human fetal neocortex and associated with metabolic side effects to antipsychotic drugs. Further CNGs were identified at the PLCB2 and DLL4 locus or located intergenic between TYRO3 and MAPKBP1. Automated sequencing revealed genetic variation in 12.3% of CNGs, but frequencies were low (MAF: 0.06-0.4) in cases. Three variants located inside CNGs/UCEs were found in cases only. In a case-control association study we could not confirm a significant association of these three CNG-variants with periodic catatonia. Our results suggest genetic variation in (ultra-)conserved non-genic sequence elements which might alter functional properties. The identified variants are genetically not associated with the phenotype of periodic catatonia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
102J. Formos. Med. Assoc. 2012 May 111: 265-74
PMID22656397
TitleMedium-term course and outcome of schizophrenia depicted by the sixth-month subtype after an acute episode.
AbstractThe intermediate course of schizophrenia is a complex intertwined with the heterogeneity of the illness. This article attempts to simplify this complexity using a hypothetical tripartite based on the profile of symptoms at 6 months after acute treatment.
This is a prospective 5-year follow-up study including 163 schizophrenic inpatients in northern Taiwan comparing patients' demographic data at index admission, scores on the Positive and Negative Syndrome Scale (PANSS) for schizophrenia and social function scale measured at admission, 6-month follow-up, and annually, and scores on a neuropsychologic test battery measured approximately 5 years after recruitment.
Patients were grouped into three subtypes based on their sixth-month symptomatology by Generalized Association Plots, designated as remitted (RM), persistent delusion/hallucination (PDH), and markedly blunting (MB) groups. These three subtypes presented with similar positive symptom profiles at recruitment, yet during follow-up, the PDH group tended to maintain the highest risk of having worse clinical symptomatology, social functioning, and neuropsychologic functioning, and the RM was the best outcome group.
This three-subtype model provides a practical reference to predict medium-term outcomes by the subject's response to acute treatment and serves as a model to sort out part of the heterogeneous nature of schizophrenia that still should be examined by further psychopharmacological, neurobiological, and genetic studies.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
103Hum. Mol. Genet. 2013 Feb 22: 816-24
PMID23148125
TitleA genome-wide study shows a limited contribution of rare copy number variants to Alzheimer's disease risk.
AbstractWe assessed the role of rare copy nuMBer variants (CNVs) in Alzheimer's disease (AD) using intensity data from 3260 AD cases and 1290 age-matched controls from the genome-wide association study (GWAS) conducted by the Genetic and Environmental Risk for Alzheimer's disease Consortium (GERAD). We did not observe a significant excess of rare CNVs in cases, although we did identify duplications overlapping APP and CR1 which may be pathogenic. We looked for an excess of CNVs in loci which have been highlighted in previous AD CNV studies, but did not replicate previous findings. Through pathway analyses, we observed suggestive evidence for biological overlap between single nucleotide polymorphisms and CNVs in AD susceptibility. We also identified that our sample of elderly controls harbours significantly fewer deletions >1 MB than younger control sets in previous CNV studies on schizophrenia and bipolar disorder (P = 8.9 10(-4) and 0.024, respectively), raising the possibility that healthy elderly individuals have a reduced rate of large deletions. Thus, in contrast to diseases such as schizophrenia, autism and attention deficit/hyperactivity disorder, CNVs do not appear to make a significant contribution to the development of AD.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
104PLoS ONE 2013 -1 8: e61365
PMID23637818
TitleMale-biased autosomal effect of 16p13.11 copy number variation in neurodevelopmental disorders.
AbstractCopy nuMBer variants (CNVs) at chromosome 16p13.11 have been associated with a range of neurodevelopmental disorders including autism, ADHD, intellectual disability and schizophrenia. Significant sex differences in prevalence, course and severity have been described for a nuMBer of these conditions but the biological and environmental factors underlying such sex-specific features remain unclear. We tested the burden and the possible sex-biased effect of CNVs at 16p13.11 in a sample of 10,397 individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridisation (aCGH); cases were compared with 11,277 controls. In order to identify candidate phenotype-associated genes, we performed an interval-based analysis and investigated the presence of ohnologs at 16p13.11; finally, we searched the DECIPHER database for previously identified 16p13.11 copy nuMBer variants. In the clinical referral series, we identified 46 cases with CNVs of variable size at 16p13.11, including 28 duplications and 18 deletions. Patients were referred for various phenotypes, including developmental delay, autism, speech delay, learning difficulties, behavioural problems, epilepsy, microcephaly and physical dysmorphisms. CNVs at 16p13.11 were also present in 17 controls. Association analysis revealed an excess of CNVs in cases compared with controls (OR?=?2.59; p?=?0.0005), and a sex-biased effect, with a significant enrichment of CNVs only in the male subgroup of cases (OR?=?5.62; p?=?0.0002), but not in females (OR?=?1.19, p?=?0.673). The same pattern of results was also observed in the DECIPHER sample. Interval-based analysis showed a significant enrichment of case CNVs containing interval II (OR?=?2.59; p?=?0.0005), located in the 0.83 MB genomic region between 15.49-16.32 MB, and encompassing the four ohnologs NDE1, MYH11, ABCC1 and ABCC6. Our data confirm that duplications and deletions at 16p13.11 represent incompletely penetrant pathogenic mutations that predispose to a range of neurodevelopmental disorders, and suggest a sex-limited effect on the penetrance of the pathological phenotypes at the 16p13.11 locus.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
105Eur. J. Hum. Genet. 2013 Sep 21: 1007-11
PMID23321615
TitleMosaic copy number variation in schizophrenia.
AbstractRecent reports suggest that somatic structural changes occur in the human genome, but how these genomic alterations might contribute to disease is unknown. Using samples collected as part of the International schizophrenia Consortium (schizophrenia, n=3518; control, n=4238) recruited across multiple university research centers, we assessed single-nucleotide polymorphism genotyping arrays for evidence of chromosomal anomalies. Data from genotyping arrays on each individual were processed using Birdsuite and analyzed with PLINK. We validated potential chromosomal anomalies using custom nanostring probes and quantitative PCR. We estimate chromosomal alterations in the schizophrenia population to be 0.42%, which is not significantly different from controls (0.26%). We identified and validated a set of four extremely large (>10?MB) chromosomal anomalies in subjects with schizophrenia, including a chromosome 8 trisomy and deletion of the q arm of chromosome 7. These data demonstrate that chromosomal anomalies are present at low frequency in blood cells of both control and schizophrenia subjects.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
106Bipolar Disord 2013 Dec 15: 893-8
PMID24127788
TitleReduced burden of very large and rare CNVs in bipolar affective disorder.
AbstractLarge, rare chromosomal copy nuMBer variants (CNVs) have been shown to increase the risk for schizophrenia and other neuropsychiatric disorders including autism, attention-deficit hyperactivity disorder, learning difficulties, and epilepsy. Their role in bipolar disorder (BD) is less clear. There are no reports of an increase in large, rare CNVs in BD in general, but some have reported an increase in early-onset cases. We previously found that the rate of such CNVs in individuals with BD was not increased, even in early-onset cases. Our aim here was to examine the rate of large rare CNVs in BD in comparison with a new large independent reference sample from the same country.
We studied the CNVs in a case-control sample consisting of 1,650 BD cases (reported previously) and 10,259 reference individuals without a known psychiatric disorder who took part in the original Wellcome Trust Case Control Consortium (WTCCC) study. The 10,259 reference individuals were affected with six non-psychiatric disorders (coronary artery disease, types 1 and 2 diabetes, hypertension, Crohn's disease, and rheumatoid arthritis). Affymetrix 500K array genotyping data were used to call the CNVs.
The rate of CNVs > 100 kb was not statistically different between cases and controls. The rate of very large (defined as > 1 MB) and rare (< 1%) CNVs was significantly lower in patients with BD compared with the reference group. CNV loci associated with schizophrenia were not enriched in BD and, in fact, cases of BD had the lowest nuMBer of such CNVs compared with any of the WTCCC cohorts; this finding held even for the early-onset BD cases.
schizophrenia and BD differ with respect to CNV burden and association with specific CNVs. Our findings support the hypothesis that BD is etiologically distinct from schizophrenia with respect to large, rare CNVs and the accompanying associated neurodevelopmental abnormalities.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
107Am. J. Med. Genet. B Neuropsychiatr. Genet. 2013 Dec 162B: 847-54
PMID24115684
TitleA genome wide survey supports the involvement of large copy number variants in schizophrenia with and without intellectual disability.
AbstractCopy nuMBer variants (CNVs) have been shown to play a role in schizophrenia and intellectual disability.
We compared the CNV burden in 66 patients with intellectual disability and no symptoms of psychosis (ID-only) with the burden in 64 patients with intellectual disability and schizophrenia (ID?+?SCZ). Samples were genotyped on three plates by the Broad Institute using the Affymetrix 6.0 array.
For CNVs larger than 100?kb, there was no difference in the CNV burden of ID-only and ID?+?SCZ. In contrast, the nuMBer of duplications larger than 1?MB was increased in ID?+?SCZ compared to ID-only. We detected seven large duplications and two large deletions at chromosome 15q11.2 (18.5-20.1?MB) which were all present in patients with ID?+?SCZ. The involvement of this region in schizophrenia was confirmed in Scottish samples from the ISC study (N?=?2,114; 1,130 cases and 984 controls). Finally, one of the patients with schizophrenia and low IQ carrying a duplication at 15q11.2, is a meMBer of a previously described pedigree with multiple cases of mild intellectual disability, schizophrenia, hearing impairment, retinitis pigmentosa and cataracts. DNA samples were available for 11 meMBers of this family and the duplication was present in all 10 affected individuals and was absent in an unaffected individual.
Duplications at 15q11.2 (18.5-20.1?MB) are highly prevalent in a severe group of patients characterized by intellectual disability and comorbid schizophrenia. It is also associated with a phenotype that includes schizophrenia, low IQ, hearing and visual impairments reseMBling the spectrum of symptoms described in "ciliopathies."
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
108Hum. Mol. Genet. 2013 Nov 22: 4485-501
PMID23813976
TitlePathogenic rare copy number variants in community-based schizophrenia suggest a potential role for clinical microarrays.
AbstractIndividually rare, large copy nuMBer variants (CNVs) contribute to genetic vulnerability for schizophrenia. Unresolved questions remain, however, regarding the anticipated yield of clinical microarray testing in schizophrenia. Using high-resolution genome-wide microarrays and rigorous methods, we investigated rare CNVs in a prospectively recruited community-based cohort of 459 unrelated adults with schizophrenia and estimated the minimum prevalence of clinically significant CNVs that would be detectable on a clinical microarray. A blinded review by two independent clinical cytogenetic laboratory directors of all large (>500 kb) rare CNVs in cases and well-matched controls showed that those deemed to be clinically significant were highly enriched in schizophrenia (16.4-fold increase, P < 0.0001). In a single community catchment area, the prevalence of individuals with these CNVs was 8.1%. Rare 1.7 MB CNVs at 2q13 were found to be significantly associated with schizophrenia for the first time, compared with the prevalence in 23 838 population-based controls (42.9-fold increase, P = 0.0002). Additional novel findings that will facilitate the future clinical interpretation of smaller CNVs in schizophrenia include: (i) a greater proportion of individuals with two or more rare exonic CNVs >10 kb in size (1.5-fold increase, P = 0.0109) in schizophrenia; (ii) the systematic discovery of new candidate genes for schizophrenia; and, (iii) functional gene enrichment mapping highlighting a differential impact in schizophrenia of rare exonic deletions involving diverse functions, including neurodevelopmental and synaptic processes (4.7-fold increase, P = 0.0060). These findings suggest consideration of a potential role for clinical microarray testing in schizophrenia, as is now the suggested standard of care for related developmental disorders like autism.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
109Prog. Neuropsychopharmacol. Biol. Psychiatry 2013 Jun 43: 197-202
PMID23306218
TitleAssociation study of NRXN3 polymorphisms with schizophrenia and risperidone-induced bodyweight gain in Chinese Han population.
AbstractRecent researches have implicated that mutations in the neurexin-3 (NRXN3) gene on chromosome 14q24.3-q31.1 might play a role in addiction, autism, and obesity. In order to explore the association of NRXN3 polymorphisms with schizophrenia, we examined seven single nucleotide polymorphisms (SNPs) in NRXN3 spanning 1.33 MB of this gene, in a Chinese Han sample of 1214 schizophrenic patients and 1517 healthy control subjects. Our results showed that three SNPs were associated with schizophrenia (rs7157669: A>C, p=0.006; rs724373: C>T, p=0.014; rs7154021: C>T, p=0.018). After being corrected for multiple tests, the association of rs7157669 remained significant but those for two others were modest. According to the linkage disequilibrium pattern, the 7 SNPs may construct 3 haplotype blocks. Several haplotypes were significantly associated with schizophrenia, constructed by rs11624704-rs7157669-rs724373 (AAC, p=0.003; ACT, p=0.007, both remained significant after permutation tests), rs7154021-rs7142344 (TT, p=0.024; CT, p=0.012), respectively. Among the patients, 326 ones at first onset have received 6-week monotherapy of risperidone. Further analyses showed that two SNPs were associated with percentage of bodyweight gain following a 6-week therapy of risperidone (rs11624704: p=0.03; rs7154021: p=0.008) and rs7154021 remained significant after permutation test. Our findings suggested that NRXN3 might represent a major susceptibility gene for schizophrenia and have a role in bodyweight gain related to therapy of risperidone in Chinese Han population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
110Prog. Neuropsychopharmacol. Biol. Psychiatry 2013 Jun 43: 197-202
PMID23306218
TitleAssociation study of NRXN3 polymorphisms with schizophrenia and risperidone-induced bodyweight gain in Chinese Han population.
AbstractRecent researches have implicated that mutations in the neurexin-3 (NRXN3) gene on chromosome 14q24.3-q31.1 might play a role in addiction, autism, and obesity. In order to explore the association of NRXN3 polymorphisms with schizophrenia, we examined seven single nucleotide polymorphisms (SNPs) in NRXN3 spanning 1.33 MB of this gene, in a Chinese Han sample of 1214 schizophrenic patients and 1517 healthy control subjects. Our results showed that three SNPs were associated with schizophrenia (rs7157669: A>C, p=0.006; rs724373: C>T, p=0.014; rs7154021: C>T, p=0.018). After being corrected for multiple tests, the association of rs7157669 remained significant but those for two others were modest. According to the linkage disequilibrium pattern, the 7 SNPs may construct 3 haplotype blocks. Several haplotypes were significantly associated with schizophrenia, constructed by rs11624704-rs7157669-rs724373 (AAC, p=0.003; ACT, p=0.007, both remained significant after permutation tests), rs7154021-rs7142344 (TT, p=0.024; CT, p=0.012), respectively. Among the patients, 326 ones at first onset have received 6-week monotherapy of risperidone. Further analyses showed that two SNPs were associated with percentage of bodyweight gain following a 6-week therapy of risperidone (rs11624704: p=0.03; rs7154021: p=0.008) and rs7154021 remained significant after permutation test. Our findings suggested that NRXN3 might represent a major susceptibility gene for schizophrenia and have a role in bodyweight gain related to therapy of risperidone in Chinese Han population.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
111Mol Cytogenet 2014 -1 7: 23
PMID24650298
TitleAdult expression of a 3q13.31 microdeletion.
AbstractThe emerging 3q13.31 microdeletion syndrome appears to encompass diverse neurodevelopmental conditions. However, the 3q13.31 deletion is rare and few adult cases have yet been reported. We examined a cohort with schizophrenia (n?=?459) and adult control subjects (n?=?26,826) using high-resolution microarray technology for deletions and duplications at the 3q13.31 locus.
We report on the extended adult phenotype associated with a 3q13.31 microdeletion in a 41-year-old male proband with schizophrenia and a nonverbal learning disability. He was noted to have a speech impairment, delayed motor skills, and other features consistent with the 3q13.31 microdeletion syndrome. The 2.06MB deletion overlapped two microRNAs and seven RefSeq genes, including GAP43, LSAMP, DRD3, and ZBTB20. No overlapping 3q13.31 deletions or duplications were identified in control subjects.
Later-onset conditions like schizophrenia are increasingly associated with rare copy nuMBer variations and associated genomic disorders like the 3q13.31 microdeletion syndrome. Detailed phenotype information across the lifespan facilitates genotype-phenotype correlations, accurate genetic counselling, and anticipatory care.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
112Epigenetics 2014 Aug 9: 1101-7
PMID24837210
TitleMB-COMT promoter DNA methylation is associated with working-memory processing in schizophrenia patients and healthy controls.
AbstractMany genetic studies report mixed results both for the associations between COMT polymorphisms and schizophrenia and for the effects of COMT variants on common intermediate phenotypes of the disorder. Reasons for this may include small genetic effect sizes and the modulation of environmental influences. To improve our understanding of the role of COMT in the disease etiology, we investigated the effect of DNA methylation in the MB-COMT promoter on neural activity in the dorsolateral prefrontal cortex during working memory processing as measured by fMRI - an intermediate phenotype for schizophrenia. Imaging and epigenetic data were measured in 102 healthy controls and 82 schizophrenia patients of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia. Neural activity during the Sternberg Item Recognition Paradigm was acquired with either a 3T Siemens Trio or 1.5T Siemens Sonata and analyzed using the FMRIB Software Library (FSL). DNA methylation measurements were derived from cryo-conserved blood samples. We found a positive association between MB-COMT promoter methylation and neural activity in the left dorsolateral prefrontal cortex in a model using a region-of-interest approach and could confirm this finding in a whole-brain model. This effect was independent of disease status. Analyzing the effect of MB-COMT promoter DNA methylation on a neuroimaging phenotype can provide further evidence for the importance of COMT and epigenetic risk mechanisms in schizophrenia. The latter may represent trans-regulatory or environmental risk factors that can be measured using brain-based intermediate phenotypes.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
113Nat. Genet. 2014 Dec 46: 1293-302
PMID25326701
TitlePalindromic GOLGA8 core duplicons promote chromosome 15q13.3 microdeletion and evolutionary instability.
AbstractRecurrent deletions of chromosome 15q13.3 associate with intellectual disability, schizophrenia, autism and epilepsy. To gain insight into the instability of this region, we sequenced it in affected individuals, normal individuals and nonhuman primates. We discovered five structural configurations of the human chromosome 15q13.3 region ranging in size from 2 to 3 MB. These configurations arose recently (?0.5-0.9 million years ago) as a result of human-specific expansions of segmental duplications and two independent inversion events. All inversion breakpoints map near GOLGA8 core duplicons-a ?14-kb primate-specific chromosome 15 repeat that became organized into larger palindromic structures. GOLGA8-flanked palindromes also demarcate the breakpoints of recurrent 15q13.3 microdeletions, the expansion of chromosome 15 segmental duplications in the human lineage and independent structural changes in apes. The significant clustering (P = 0.002) of breakpoints provides mechanistic evidence for the role of this core duplicon and its palindromic architecture in promoting the evolutionary and disease-related instability of chromosome 15.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
114Mol. Psychiatry 2014 Jan 19: 37-40
PMID24217254
TitleEvidence that duplications of 22q11.2 protect against schizophrenia.
AbstractA nuMBer of large, rare copy nuMBer variants (CNVs) are deleterious for neurodevelopmental disorders, but large, rare, protective CNVs have not been reported for such phenotypes. Here we show in a CNV analysis of 47?005 individuals, the largest CNV analysis of schizophrenia to date, that large duplications (1.5-3.0?MB) at 22q11.2--the reciprocal of the well-known, risk-inducing deletion of this locus--are substantially less common in schizophrenia cases than in the general population (0.014% vs 0.085%, OR=0.17, P=0.00086). 22q11.2 duplications represent the first putative protective mutation for schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
115Biol. Psychiatry 2014 Oct 76: 648-55
PMID24703509
TitleNeuregulin-3 in the mouse medial prefrontal cortex regulates impulsive action.
AbstractA deficit in impulse control is a prominent, heritable symptom in several psychiatric disorders, such as addiction, attention-deficit/hyperactivity disorder, and schizophrenia. Here, we aimed to identify genes regulating impulsivity, specifically of impulsive action, in mice.
Using the widely used 5-choice serial reaction time task, we measured impulsive action in 1) a panel of 41 BXD recoMBinant inbred strains of mice (n = 13.7 .8 per strain; n = 654 total) to detect underlying genetic loci; 2) congenic mice (n = 23) to replicate the identified locus; 3) mice overexpressing the Nrg3 candidate gene in the medial prefrontal cortex (n = 21); and 4) a Nrg3 loss-of-function mutant (n = 59) to functionally implicate the Nrg3 candidate gene in impulsivity.
Genetic mapping of impulsive action in the BXD panel identified a locus on chromosome 14 (34.5-41.4 MB), syntenic with the human 10q22-q23 schizophrenia-susceptibility locus. Congenic mice carrying the impulsivity locus (Impu1) confirmed its influence on impulsive action. Increased impulsivity was associated with increased Nrg3 gene expression in the medial prefrontal cortex (mPFC). Viral overexpression of Nrg3 in the mPFC increased impulsivity, whereas a constitutive Nrg3 loss-of-function mutation decreased it.
The causal relation between Nrg3 expression in the mPFC and level of impulsive action shown here provides a mechanism by which polymorphism in NRG3 in humans contributes to a specific cognitive deficit seen in several psychiatric diseases, such as addiction, attention-deficit/hyperactivity disorder, and schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
116Am. J. Med. Genet. A 2014 Feb 164A: 456-60
PMID24449200
Title1p34.3 deletion involving GRIK3: Further clinical implication of GRIK family glutamate receptors in the pathogenesis of developmental delay.
AbstractA growing body of evidence suggests an association between microdeletion/microduplication and schizophrenia/intellectual disability. Abnormal neurogenesis and neurotransmission have been implicated in the pathogenesis of these neuropsychiatric and neurodevelopmental disorders. The kainate/AMPA-type ionotropic glutamate receptor (GRIK?=?glutamate receptor, ionotropic, kainate) plays a critical role in synaptic potentiation, which is an essential process for learning and memory. Among the five known GRIK family meMBers, haploinsufficiency of GRIK1, GRIK2, and GRIK4 are known to cause developmental delay, whereas the roles of GRIK3 and GRIK5 remain unknown. Herein, we report on a girl who presented with a severe developmental delay predominantly affecting her language and fine motor skills. She had a 2.6-MB microdeletion in 1p34.3 involving GRIK3, which encodes a principal subunit of the kainate-type ionotropic glutamate receptor. Given its strong expression pattern in the central nervous system and the biological function of GRIK3 in presynaptic neurotransmission, the haploinsufficiency of GRIK3 is likely to be responsible for the severe developmental delay in the proposita. A review of genetic alterations and the phenotypic effects of all the GRIK family meMBers support this hypothesis. The current observation of a microdeletion involving GRIK3, a kainate-type ionotropic glutamate receptor subunit, and the neurodevelopmental manifestation in the absence of major dysmorphism provides further clinical implication of the possible role of GRIK family glutamate receptors in the pathogenesis of developmental delay.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
117Am. J. Med. Genet. B Neuropsychiatr. Genet. 2014 Dec 165B: 619-26
PMID25228354
TitleA genome-wide CNV analysis of schizophrenia reveals a potential role for a multiple-hit model.
Abstractschizophrenia is a chronic and severe psychiatric disorder that is highly heritable. While both common and rare genetic variants contribute to disease risk, many questions still remain about disease etiology. We performed a genome-wide analysis of copy nuMBer variants (CNVs) in 166 schizophrenia subjects and 52 psychiatrically healthy controls. First, overall CNV characteristics were compared between cases and controls. The only statistically significant finding was that deletions comprised a greater proportion of CNVs in cases. High interest CNVs were then identified as conservative using the following filtering criteria: (i) known deleterious CNVs; (ii) CNVs > 1 MB that were novel (not found in a database of control individuals); and (iii) CNVs < 1 MB that were novel and that overlapped the coding region of a gene of interest. Cases did not harbor a higher proportion of conservative CNVs in comparison to controls. However, similar to previous reports, cases had a slightly higher proportion of individuals with clinically significant CNVs (known deleterious or conservative CNVs > 1 MB) or with multiple conservative CNVs. Two case individuals with the highest burden of conservative CNVs also share a recurrent 15q11.2 BP1-2 deletion, indicating a role for a potential multiple-hit CNV model for schizophrenia. In total, we report three 15q11.2 BP1-2 deletion individuals with schizophrenia, adding to a growing body of evidence that this CNV is involved in disease etiology.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
118PLoS ONE 2014 -1 9: e103884
PMID25084529
TitleDecreased DGCR8 expression and miRNA dysregulation in individuals with 22q11.2 deletion syndrome.
AbstractDeletion of the 1.5-3 MB region of chromosome 22 at locus 11.2 gives rise to the chromosome 22q11.2 deletion syndrome (22q11DS), also known as DiGeorge and Velocardiofacial Syndromes. It is the most common micro-deletion disorder in humans and one of the most common multiple malformation syndromes. The syndrome is characterized by a broad phenotype, whose characterization has expanded considerably within the last decade and includes many associated findings such as craniofacial anomalies (40%), conotruncal defects of the heart (CHD; 70-80%), hypocalcemia (20-60%), and a range of neurocognitive anomalies with high risk of schizophrenia, all with a broad phenotypic variability. These phenotypic features are believed to be the result of a change in the copy nuMBer or dosage of the genes located in the deleted region. Despite this relatively clear genetic etiology, very little is known about which genes modulate phenotypic variations in humans or if they are due to coMBinatorial effects of reduced dosage of multiple genes acting in concert. Here, we report on decreased expression levels of genes within the deletion region of chromosome 22, including DGCR8, in peripheral leukocytes derived from individuals with 22q11DS compared to healthy controls. Furthermore, we found dysregulated miRNA expression in individuals with 22q11DS, including miR-150, miR-194 and miR-185. We postulate this to be related to DGCR8 haploinsufficiency as DGCR8 regulates miRNA biogenesis. Importantly we demonstrate that the level of some miRNAs correlates with brain measures, CHD and thyroid abnormalities, suggesting that the dysregulated miRNAs may contribute to these phenotypes and/or represent relevant blood biomarkers of the disease in individuals with 22q11DS.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
119Invest. Ophthalmol. Vis. Sci. 2014 May 55: 3258-64
PMID24764060
TitleGene-rich large deletions are overrepresented in POAG patients of Indian and Caucasian origins.
AbstractLarge copy nuMBer variations (CNV) can contribute to increased burden for neurodegenerative diseases. In this study, we analyzed the genome-wide burden of large CNVs > 100 kb in primary open angle glaucoma (POAG), a neurodegenerative disease of the eye that is the largest cause of irreversible blindness.
Genome-wide analysis of CNVs > 100 kb were analyzed in a total of 1720 individuals, including an Indian cohort (347 POAG cases and 345 controls) and a Caucasian cohort (624 cases and 404 controls). All the CNV data were obtained from experiments performed on Illumina 660W-Quad (infinium) arrays.
We observed that for both the populations CNVs > 1 MB was significantly enriched for gene-rich regions unique to the POAG cases (P < 10(-11)). In the Indian cohort CNVs > 1 MB (39 calls) in patients influenced 125 genes while in controls 31 such CNVs influenced only 5 genes with no overlap. In both cohorts we observed 1.9-fold gene enrichment in patients for deletions compared to duplications, while such a bias was not observed in controls (0.3-fold). Overall duplications > 1 MB were more than deletions (Del/Dup = 0.82) confirming that the enrichment of gene-rich deletions in patients was associated with the disease. Of the 39 CNVs > 1 MB from Indian patients, 28 (72%) also were implicated in other neurodegenerative disorders, like autism, schizophrenia, sensorineural hearing loss, and so forth. We found one large duplication encompassing CNTN4 gene in Indian and Caucasian POAG patients that was absent in the controls.
To our knowledge, our study is the first report on large CNV bias for gene-rich regions in glaucomatous neurodegeneration, implicating its impact across populations of contrasting ethnicities. We identified CNTN4 as a novel candidate gene for POAG.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
120Hum. Mol. Genet. 2014 Jun 23: 3316-26
PMID24474471
TitleAn inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis.
AbstractIdentifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100 kb), rare copy-nuMBer variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1564 cases and 1748 controls all from Ireland, and further extended the analysis to include an additional 5196 UK controls. We found association with duplications at chr20p12.2 (P = 0.007) and evidence of replication in large independent European schizophrenia (P = 0.052) and UK bipolar disorder case-control cohorts (P = 0.047). A coMBined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11 707 cases and 10 carriers in 21 204 controls [meta-analysis Cochran-Mantel-Haenszel P-value = 2 10(-4); odds ratio (OR) = 11.3, 95% CI = 3.7, ?]. Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68 MB with similar breakpoints across samples. By haplotype analysis and sequencing, we identified a tandem ~149 kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P = 2.5 10(-21)), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family meMBers of one of the affected probands. We demonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
121Biol. Psychiatry 2014 Mar 75: 371-7
PMID23871472
TitleReciprocal duplication of the Williams-Beuren syndrome deletion on chromosome 7q11.23 is associated with schizophrenia.
AbstractSeveral copy nuMBer variants (CNVs) have been implicated as susceptibility factors for schizophrenia (SZ). Some of these same CNVs also increase risk for autism spectrum disorders, suggesting an etiologic overlap between these conditions. Recently, de novo duplications of a region on chromosome 7q11.23 were associated with autism spectrum disorders. The reciprocal deletion of this region causes Williams-Beuren syndrome.
We assayed an Ashkenazi Jewish cohort of 554 SZ cases and 1014 controls for genome-wide CNV. An excess of large rare and de novo CNVs were observed, including a 1.4 MB duplication on chromosome 7q11.23 identified in two unrelated patients. To test whether this 7q11.23 duplication is also associated with SZ, we obtained data for 14,387 SZ cases and 28,139 controls from seven additional studies with high-resolution genome-wide CNV detection. We performed a meta-analysis, correcting for study population of origin, to assess whether the duplication is associated with SZ.
We found duplications at 7q11.23 in 11 of 14,387 SZ cases with only 1 in 28,139 control subjects (unadjusted odds ratio 21.52, 95% confidence interval: 3.13-922.6, p value 5.5 10(-5); adjusted odds ratio 10.8, 95% confidence interval: 1.46-79.62, p value .007). Of three SZ duplication carriers with detailed retrospective data, all showed social anxiety and language delay premorbid to SZ onset, consistent with both human studies and animal models of the 7q11.23 duplication.
We have identified a new CNV associated with SZ. Reciprocal duplication of the Williams-Beuren syndrome deletion at chromosome 7q11.23 confers an approximately tenfold increase in risk for SZ.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
122Mol. Psychiatry 2014 May 19: 568-72
PMID23689535
TitleHigh rate of disease-related copy number variations in childhood onset schizophrenia.
AbstractCopy nuMBer variants (CNVs) are risk factors in neurodevelopmental disorders, including autism, epilepsy, intellectual disability (ID) and schizophrenia. Childhood onset schizophrenia (COS), defined as onset before the age of 13 years, is a rare and severe form of the disorder, with more striking array of prepsychotic developmental disorders and abnormalities in brain development. Because of the well-known phenotypic variability associated with pathogenic CNVs, we conducted whole genome genotyping to detect CNVs and then focused on a group of 46 rare CNVs that had well-documented risk for adult onset schizophrenia (AOS), autism, epilepsy and/or ID. We evaluated 126 COS probands, 69 of which also had a healthy full sibling. When COS probands were compared with their matched related controls, significantly more affected individuals carried disease-related CNVs (P=0.017). Moreover, COS probands showed a higher rate than that found in AOS probands (P<0.0001). A total of 15 (11.9%) subjects exhibited at least one such CNV and four of these subjects (26.7%) had two. Five of 15 (4.0% of the sample) had a 2.5-3?MB deletion mapping to 22q11.2, a rate higher than that reported for adult onset (0.3-1%) (P<0.001) or autism spectrum disorder and, indeed, the highest rate reported for any clinical population to date. For one COS subject, a duplication found at 22q13.3 had previously only been associated with autism, and for four patients CNVs at 8q11.2, 10q22.3, 16p11.2 and 17q21.3 had only previously been associated with ID. Taken together, these findings support the well-known pleiotropic effects of these CNVs suggesting shared abnormalities early in brain development. Clinically, broad CNV-based population screening is needed to assess their overall clinical burden.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
123Neuropharmacology 2015 Sep 96: 274-88
PMID25701707
TitleThe human CHRNA7 and CHRFAM7A genes: A review of the genetics, regulation, and function.
AbstractThe human ?7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is ubiquitously expressed in both the central nervous system and in the periphery. CHRNA7 is genetically linked to multiple disorders with cognitive deficits, including schizophrenia, bipolar disorder, ADHD, epilepsy, Alzheimer's disease, and Rett syndrome. The regulation of CHRNA7 is complex; more than a dozen mechanisms are known, one of which is a partial duplication of the parent gene. Exons 5-10 of CHRNA7 on chromosome 15 were duplicated and inserted 1.6 MB upstream of CHRNA7, interrupting an earlier partial duplication of two other genes. The chimeric CHRFAM7A gene product, dup?7, asseMBles with ?7 subunits, resulting in a dominant negative regulation of function. The duplication is human specific, occurring neither in primates nor in rodents. The duplicated ?7 sequence in exons 5-10 of CHRFAM7A is almost identical to CHRNA7, and thus is not completely queried in high throughput genetic studies (GWAS). Further, pre-clinical animal models of the ?7nAChR utilized in drug development research do not have CHRFAM7A (dup?7) and cannot fully model human drug responses. The wide expression of CHRNA7, its multiple functions and modes of regulation present challenges for study of this gene in disease. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
124Nat. Genet. 2015 Dec 47: 1385-92
PMID26523775
TitleContrasting genetic architectures of schizophrenia and other complex diseases using fast variance-components analysis.
AbstractHeritability analyses of genome-wide association study (GWAS) cohorts have yielded important insights into complex disease architecture, and increasing sample sizes hold the promise of further discoveries. Here we analyze the genetic architectures of schizophrenia in 49,806 samples from the PGC and nine complex diseases in 54,734 samples from the GERA cohort. For schizophrenia, we infer an overwhelmingly polygenic disease architecture in which ?71% of 1-MB genomic regions harbor ?1 variant influencing schizophrenia risk. We also observe significant enrichment of heritability in GC-rich regions and in higher-frequency SNPs for both schizophrenia and GERA diseases. In bivariate analyses, we observe significant genetic correlations (ranging from 0.18 to 0.85) for several pairs of GERA diseases; genetic correlations were on average 1.3 tunes stronger than the correlations of overall disease liabilities. To accomplish these analyses, we developed a fast algorithm for multicomponent, multi-trait variance-components analysis that overcomes prior computational barriers that made such analyses intractable at this scale.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
125J. Biol. Chem. 2015 Sep 290: 23240-53
PMID26221035
TitleMitochondrial Citrate Transporter-dependent Metabolic Signature in the 22q11.2 Deletion Syndrome.
AbstractThe congenital disorder 22q11.2 deletion syndrome (22qDS), characterized by a hemizygous deletion of 1.5-3 MB on chromosome 22 at locus 11.2, is the most common microdeletion disorder (estimated prevalence of 1 in 4000) and the second risk factor for schizophrenia. Nine of ?30 genes involved in 22qDS have the potential of disrupting mitochondrial metabolism (COMT, UFD1L, DGCR8, MRPL40, PRODH, SLC25A1, TXNRD2, T10, and ZDHHC8). Deficits in bioenergetics during early postnatal brain development could set the basis for a disrupted neuronal metabolism or synaptic signaling, partly explaining the higher incidence in developmental and behavioral deficits in these individuals. Here, we investigated whether mitochondrial outcomes and metabolites from 22qDS children segregated with the altered dosage of one or several of these mitochondrial genes contributing to 22qDS etiology and/or morbidity. Plasma metabolomics, lymphocytic mitochondrial outcomes, and epigenetics (histone H3 Lys-4 trimethylation and 5-methylcytosine) were evaluated in samples from 11 22qDS children and 13 age- and sex-matched neurotypically developing controls. Metabolite differences between 22qDS children and controls reflected a shift from oxidative phosphorylation to glycolysis (higher lactate/pyruvate ratios) accompanied by an increase in reductive carboxylation of ?-ketoglutarate (increased concentrations of 2-hydroxyglutaric acid, cholesterol, and fatty acids). Altered metabolism in 22qDS reflected a critical role for the haploinsufficiency of the mitochondrial citrate transporter SLC25A1, further enhanced by HIF-1?, MYC, and metabolite controls. This comprehensive profiling served to clarify the biochemistry of this disease underlying its broad, complex phenotype.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
126Biol. Psychiatry 2015 Nov -1: -1
PMID26795442
TitleGenome-wide Analysis of the Role of Copy Number Variation in Schizophrenia Risk in Chinese.
AbstractCompelling evidence suggested the role of copy nuMBer variations (CNVs) in schizophrenia susceptibility. Most of the evidence was from studies in populations with European ancestry. We tried to validate the associated CNV loci in a Han Chinese population and identify novel loci conferring risk of schizophrenia.
We performed a genome-wide CNV analysis on 6588 patients with schizophrenia and 11,904 control subjects of Han Chinese ancestry.
Our data confirmed increased genome-wide CNV (>500 kb and <1%) burden in schizophrenia, and the increasing trend was more significant when only >1 MB CNVs were considered. We also replicated several associated loci that were previously identified in European populations, including duplications at 16p11.2, 15q11.2-13.1, 7q11.23, and VIPR2 and deletions at 22q11.2, 1q21.1-q21.2, and NRXN1. In addition, we discovered three additional new potential loci (odds ratio >6, p < .05): duplications at 1p36.32, 10p12.1, and 13q13.3, involving many neurodevelopmental and synaptic related genes.
Our findings provide further support for the role of CNVs in the etiology of schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
127Clin Case Rep 2015 Apr 3: 201-7
PMID25914809
TitleChildhood-onset schizophrenia case with 2.2Mb deletion at chromosome 3p12.2-p12.1 and two large chromosomal abnormalities at 16q22.3-q24.3 and Xq23-q28.
AbstractChildhood-onset schizophrenia is rare, comprising 1% of known schizophrenia cases. Here, we report a patient with childhood-onset schizophrenia who has three large chromosomal abnormalities: an inherited 2.2MB deletion of chromosome 3p12.2-p12.1, a de novo 16.7MB duplication of 16q22.3-24.3, and a de novo 43MB deletion of Xq23-q28.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
128Eur J Med Genet 2015 May 58: 310-8
PMID25817395
TitleSubtelomeric 6p25 deletion/duplication: Report of a patient with new clinical findings and genotype-phenotype correlations.
AbstractThe 6p terminal deletions are rare and present variability of clinical features, which increases the importance of reporting additional cases in order to better characterize genotype-phenotype correlations. We report a 12-year-old girl with a de novo deletion in 6p25.1-pter characterized by high-resolution karyotyping and FISH. Further analysis using oligonucleotide array-CGH revealed a 5.06MB 6p25.1-pter deletion associated with a contiguous 1MB 6p25.1 duplication. The patient presented normal growth, developmental delay, frontal bossing, severe hypertelorism, corectopia, wide and depressed nasal bridge, mild learning disability, hearing loss and diffuse leukopathy. Additionaly, she presented peculiar phenotypic features reported herein for the first time in 6p25 deletion syndrome: cerebrospinal fluid fistula and bones reseMBling those seen in 3-M syndrome. The distinctive phenotype of the 6p25 deletion syndrome has been mainly correlated with the FOXC1 and FOXF2 genes deletions, both related mainly to eye development. We also consider the SERPINB6 as a candidate for sensorineural hearing loss and TUBB2A as a candidate for our patient's skeletal features. In addition, as our patient had a duplication including NRN1, a gene related with neurodevelopment, synaptic plasticity and cognitive dysfunction in schizophrenia, we suggest that this gene could be associated with her white matter abnormalities and neurocognitive phenotype.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
129J. Neurosci. 2015 Dec 35: 16282-94
PMID26658876
TitleMouse Model of Chromosome 15q13.3 Microdeletion Syndrome Demonstrates Features Related to Autism Spectrum Disorder.
AbstractThe chromosome 15q13.3 microdeletion is a pathogenic copy nuMBer variation conferring epilepsy, intellectual disability, schizophrenia, and autism spectrum disorder (ASD). We generated mice carrying a deletion of 1.2 MB homologous to the 15q13.3 microdeletion in human patients. Here, we report that mice with a heterozygous deletion on a C57BL/6 background (D/+ mice) demonstrated phenotypes including enlarged/heavier brains (macrocephaly) with enlarged lateral ventricles, decreased social interactions, increased repetitive grooming behavior, reduced ultrasonic vocalizations, decreased auditory-evoked gamma band EEG, and reduced event-related potentials. D/+ mice had normal body weight, activity levels, sensory gating, and cognitive abilities and no signs of epilepsy/seizures. Our results demonstrate that D/+ mice represent ASD-related phenotypes associated with 15q13.3 microdeletion syndrome. Further investigations using this chromosome-engineered mouse model may uncover the common mechanism(s) underlying ASD and other neurodevelopmental/psychiatric disorders representing the 15q13.3 microdeletion syndrome, including epilepsy, intellectual disability, and schizophrenia.
Recently discovered pathologic copy nuMBer variations (CNVs) from patients with neurodevelopmental/psychiatric disorders show very strong penetrance and thus are excellent candidates for mouse models of disease that can mirror the human genetic conditions with high fidelity. A 15q13.3 microdeletion in humans results in a range of neurodevelopmental/psychiatric disorders, including epilepsy, intellectual disability, schizophrenia, and autism spectrum disorder (ASD). The disorders conferred by a 15q13.3 microdeletion also have overlapping genetic architectures and comorbidity in other patient populations such as those with epilepsy and schizophrenia/psychosis, as well as schizophrenia and ASD. We generated mice carrying a deletion of 1.2 MB homologous to the 15q13.3 microdeletion in human patients, which allowed us to investigate the potential causes of neurodevelopmental/psychiatric disorders associated with the CNV.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
130PLoS ONE 2015 -1 10: e0132542
PMID26201030
TitleTranscriptome Profiling of Peripheral Blood in 22q11.2 Deletion Syndrome Reveals Functional Pathways Related to Psychosis and Autism Spectrum Disorder.
Abstract22q11.2 Deletion Syndrome (22q11DS) represents one of the greatest known genetic risk factors for the development of psychotic illness, and is also associated with high rates of autistic spectrum disorders (ASD) in childhood. We performed integrated genomic analyses of 22q11DS to identify genes and pathways related to specific phenotypes.
We used a high-resolution aCGH array to precisely characterize deletion breakpoints. Using peripheral blood, we examined differential expression (DE) and networks of co-expressed genes related to phenotypic variation within 22q11DS patients. Whole-genome transcriptional profiling was performed using Illumina Human HT-12 microarrays. Data mining techniques were used to validate our results against independent samples of both peripheral blood and brain tissue from idiopathic psychosis and ASD cases.
Eighty-five percent of 22q11DS individuals (N = 39) carried the typical 3 MB deletion, with significant variability in deletion characteristics in the remainder of the sample (N = 7). DE analysis and weighted gene co-expression network analysis (WGCNA) identified expression changes related to psychotic symptoms in patients, including a module of co-expressed genes which was associated with psychosis in 22q11DS and involved in pathways associated with transcriptional regulation. This module was enriched for brain-expressed genes, was not related to antipsychotic medication use, and significantly overlapped with transcriptional changes in idiopathic schizophrenia. In 22q11DS-ASD, both DE and WGCNA analyses implicated dysregulation of immune response pathways. The ASD-associated module showed significant overlap with genes previously associated with idiopathic ASD.
These findings further support the use of peripheral tissue in the study of major mutational models of diseases affecting the brain, and point towards specific pathways dysregulated in 22q11DS carriers with psychosis and ASD.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
131J Neurodev Disord 2015 -1 7: 18
PMID26137170
TitleComparative mapping of the 22q11.2 deletion region and the potential of simple model organisms.
Abstract22q11.2 deletion syndrome (22q11.2DS) is the most common micro-deletion syndrome. The associated 22q11.2 deletion conveys the strongest known molecular risk for schizophrenia. Neurodevelopmental phenotypes, including intellectual disability, are also prominent though variable in severity. Other developmental features include congenital cardiac and craniofacial anomalies. Whereas existing mouse models have been helpful in determining the role of some genes overlapped by the hemizygous 22q11.2 deletion in phenotypic expression, much remains unknown. Simple model organisms remain largely unexploited in exploring these genotype-phenotype relationships.
We first developed a comprehensive map of the human 22q11.2 deletion region, delineating gene content, and brain expression. To identify putative orthologs, standard methods were used to interrogate the proteomes of the zebrafish (D. rerio), fruit fly (D. melanogaster), and worm (C. elegans), in addition to the mouse. Spatial locations of conserved homologues were mapped to examine syntenic relationships. We systematically cataloged available knockout and knockdown models of all conserved genes across these organisms, including a comprehensive review of associated phenotypes.
There are 90 genes overlapped by the typical 2.5 MB deletion 22q11.2 region. Of the 46 protein-coding genes, 41 (89.1 %) have documented expression in the human brain. Identified homologues in the zebrafish (n = 37, 80.4 %) were comparable to those in the mouse (n = 40, 86.9 %) and included some conserved gene cluster structures. There were 22 (47.8 %) putative homologues in the fruit fly and 17 (37.0 %) in the worm involving multiple chromosomes. Individual gene knockdown mutants were available for the simple model organisms, but not for mouse. Although phenotypic data were relatively limited for knockout and knockdown models of the 17 genes conserved across all species, there was some evidence for roles in neurodevelopmental phenotypes, including four of the six mitochondrial genes in the 22q11.2 deletion region.
Simple model organisms represent a powerful but underutilized means of investigating the molecular mechanisms underlying the elevated risk for neurodevelopmental disorders in 22q11.2DS. This comparative multi-species study provides novel resources and support for the potential utility of non-mouse models in expression studies and high-throughput drug screening. The approach has implications for other recurrent copy nuMBer variations associated with neurodevelopmental phenotypes.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
132Cytogenet. Genome Res. 2015 -1 146: 33-8
PMID26112830
Title2q37.3 Deletion Syndrome: Two Cases with Highly Distinctive Facial Phenotype, Discordant Association with Schizophrenic Psychosis, and Shared Deletion Breakpoint Region on 2q37.3.
Abstract2q37.3 deletion syndrome belongs to the chromosomal 2q37 deletion spectrum which clinically reseMBles Albright hereditary osteodystrophy (AHO) syndrome. It is is mainly characterized by short stature, obesity, round face, brachydactyly type E, intellectual disability, behavioral problems, and variable intellectual deficits. Different from classical AHO syndrome, patients with 2q37 deletion syndrome lack renal parathyroid hormone resistance (pseudohypoparathyroidism) and soft tissue ossification. So far, deletion mapping or molecular breakpoint analyses of 2q37 have been performed in only few patients. Here, we report on 2 patients with 2q37.3 deletion syndrome. In both patients the breakpoint of the 5.5-MB terminal microdeletion could be narrowed down to the same ? 200-kb interval on 2q37.3 by BAC-FISH and/or array-CGH. Flanking low-copy repeats may indicate a classical microdeletion syndrome genesis for the 2q37.3 microdeletion subgroup. Clinical evaluation revealed intellectual deficits and type E brachydactyly typical for classical AHO syndrome together with distinctive facial dysmorphisms not present in the former. Furthermore, one patient presented with schizophrenic psychosis, an observation that would be in accordance with previous reports about an association between schizophrenia susceptibility and an unknown gene within the chromosomal region 2q37.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
133PLoS ONE 2015 -1 10: e0127681
PMID25993409
TitleHairy/Enhancer-of-Split MEGANE and Proneural MASH1 Factors Cooperate Synergistically in Midbrain GABAergic Neurogenesis.
AbstractGABAergic neurons are the primary inhibitory cell type in the mature brain and their dysfunction is associated with important neurological conditions like schizophrenia and anxiety. We aimed to discover the underlying mechanisms for dorsal/ventral midbrain GABAergic neurogenesis. Previous work by us and others has provided crucial insights into the key function of Mgn and Mash1 genes in determining GABAergic neurotransmitter fate. Induction of dorsal midbrain GABAergic neurons does not take place at any time during development in either of the single mutant mice. However, GABAergic neurons in the ventral midbrain remained unchanged. Thus, the similarities in MB-GABAergic phenotype observed in the Mgn and Mash1 single mutants suggest the existence of other factors that take over the function of MGN and MASH1 in the ventral midbrain or the existence of different molecular mechanisms. We show that this process essentially depends on heterodimers and homodimers formed by MGN and MASH1 and deciphered the in vivo relevance of the interaction by phenotypic analysis of Mgn/Mash1 double knockout and compound mice. Furthermore, the coMBination of gain- and loss-of-function experiments in the developing midbrain showed co-operative roles for Mgn and Mash1 genes in determining GABAergic identity. Transcription factors belonging to the Enhancer-of-split-related and proneural families have long been believed to counterpart each other's function. This work uncovers a synergistic cooperation between these two families, and provides a novel paradigm for how these two families cooperate for the acquisition of MB-GABAergic neuronal identity. Understanding their molecular mechanisms is essential for cell therapy strategies to amend GABAergic deficits.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
134Tumour Biol. 2015 Sep 36: 7881-9
PMID25953261
TitleA novel biomarker C6orf106 promotes the malignant progression of breast cancer.
AbstractC6orf106 (chromosome 6 open reading frame 106) is a recently discovered protein encoded by the 6th chromosome. Though many proteins encoded by chromosome 6 are reportedly related to cancer, schizophrenia, autoimmunity and many other diseases, the function of C6orf106 was not well demonstrated so far. As measured by immunohistochemical staining, C6orf106 was positive in normal breast duct myoepithelial cells (92.31 %, 72/78), but negative in normal breast duct glandular epithelial cells (3.85 %, 3/78). In breast ductal carcinoma in situ, C6orf106 showed weakly or moderately positive (77.97 %, 46/59), but it was significantly strongly positive in invasive ductal carcinoma (79.57 %, 148/186). The expression intensity of C6orf106 seemed increased significantly along with the malignancy of breast cancer (p?MB-231 and BT-549, accompanied by the decrease of cyclin A2, cyclin B1, c-myc, and N-cadherin and the increase of E-cadherin. Collectively, these results indicate that C6orf106 may promote tumor progression in the invasive breast cancer, particularly in triple-negative breast cancer, and C6orf106 might serve as a novel therapeutic target of breast cancer, especially for triple-negative breast cancer.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
135BMC Neurosci 2015 -1 16: 9
PMID25887360
TitleEffects of nitric oxide-related compounds in the acute ketamine animal model of schizophrenia.
AbstractBetter treatments for schizophrenia are urgently needed. The therapeutic use of the nitric oxide (NO)-donor sodium nitroprusside (SNP) in patients with schizophrenia has shown promising results. The role of NO in schizophrenia is still unclear, and NO modulation is unexplored in ketamine (KET) animal models to date. In the present study, we compared the behavioral effects of pre- and post-treatment with SNP, glyceryl trinitrate (GTN), and methylene blue (MB) in the acute KET animal model of schizophrenia. The present study was designed to test whether acute SNP, GTN, and MB treatment taken after (therapeutic effect) or before (preventive effect) a single KET injection would influence the behavior of rats in the sucrose preference test, object recognition task and open field.
The results showed that KET induced cognitive deficits and hyperlocomotion. Long- term memory improvement was seen with the therapeutic GTN and SNP treatment, but not with the preventive one. MB pretreatment resulted in long-term memory recovery. GTN pre-, but not post-treatment, tended to increase vertical and horizontal activity in the KET model. Therapeutic and preventive SNP treatment consistently decreased KET-induced hyperlocomotion.
NO donors - especially SNP - are promising new pharmacological candidates in the treatment of schizophrenia. In addition, we showed that the potential impact of NO-related compounds on KET-induced behavioral changes may depend on the temporal window of drug administration.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
136Prog. Neurobiol. 2015 Jul 130: 1-28
PMID25866365
TitleModeling a model: Mouse genetics, 22q11.2 Deletion Syndrome, and disorders of cortical circuit development.
AbstractUnderstanding the developmental etiology of autistic spectrum disorders, attention deficit/hyperactivity disorder and schizophrenia remains a major challenge for establishing new diagnostic and therapeutic approaches to these common, difficult-to-treat diseases that compromise neural circuits in the cerebral cortex. One aspect of this challenge is the breadth and overlap of ASD, ADHD, and SCZ deficits; another is the complexity of mutations associated with each, and a third is the difficulty of analyzing disrupted development in at-risk or affected human fetuses. The identification of distinct genetic syndromes that include behavioral deficits similar to those in ASD, ADHC and SCZ provides a critical starting point for meeting this challenge. We summarize clinical and behavioral impairments in children and adults with one such genetic syndrome, the 22q11.2 Deletion Syndrome, routinely called 22q11DS, caused by micro-deletions of between 1.5 and 3.0 MB on human chromosome 22. Among many syndromic features, including cardiovascular and craniofacial anomalies, 22q11DS patients have a high incidence of brain structural, functional, and behavioral deficits that reflect cerebral cortical dysfunction and fall within the spectrum that defines ASD, ADHD, and SCZ. We show that developmental pathogenesis underlying this apparent genetic "model" syndrome in patients can be defined and analyzed mechanistically using genomically accurate mouse models of the deletion that causes 22q11DS. We conclude that "modeling a model", in this case 22q11DS as a model for idiopathic ASD, ADHD and SCZ, as well as other behavioral disorders like anxiety frequently seen in 22q11DS patients, in genetically engineered mice provides a foundation for understanding the causes and improving diagnosis and therapy for these disorders of cortical circuit development.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
137Psychol Med 2015 -1 45: 2557-69
PMID25817407
TitleExpression quantitative trait loci (eQTLs) in microRNA genes are enriched for schizophrenia and bipolar disorder association signals.
Abstractschizophrenia (SZ) and bipolar disorder (BD) have substantial negative impact on the quality of human life. Both, microRNA (miRNA) expression profiling in SZ and BD postmortem brains [and genome-wide association studies (GWAS)] have implicated miRNAs in disease etiology. Here, we aim to determine whether significant GWAS signals observed in the Psychiatric Genetic Consortium (PGC) are enriched for miRNAs.
A two-stage approach was used to determine whether association signals from PGC affect miRNAs: (i) statistical assessment of enrichment using a Simes test and sum of squares test (SST) and (ii) biological evidence that quantitative trait loci (eQTL) mapping to known miRNA genes affect their expression in an independent sample of 78 postmortem brains from the Stanley Medical Research Institute.
A total of 2567 independent single nucleotide polymorphisms (SNPs) (R2 > 0.8) were mapped locally, within 1 MB, to all known miRNAs (miRBase v. 21). We show robust enrichment for SZ- and BD-related SNPs with miRNAs using Simes (SZ: p ? 0.0023, BD: p ? 0.038), which remained significant after adjusting for background inflation in SZ (empirical p = 0.018) and approached significance in BD (empirical p = 0.07). At a false discovery rate of 10%, we identified a total of 32 eQTLs to influence miRNA expression; 11 of these overlapped with BD.
Our approach of integrating PGC findings with eQTL results can be used to generate specific hypotheses regarding the role of miRNAs in SZ and BD.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
138Int J Clin Exp Med 2015 -1 8: 1349-55
PMID25785136
TitleEffects of modified electroconvulsive therapy on the cognitive function and blood parameters in female patients with schizophrenia.
AbstractThis study aimed to investigate the effects of modified electroconvulsive therapy (MECT) on cognitive function and blood parameters in female patients with schizophrenia.
Female patients with schizophrenia (n = 23) received MECT while maintaining antipsychotic therapy. 1) White blood cell (WBC), alanine aminotransferase (ALT), creatine kinase (CK) and creatine kinase MB (CKMB) were measured at 10 min before and after MECT. 2) The severity of symptoms was evaluated before and after MECT by using the Positive and Negative Symptoms Scale (PANSS) and then the therapeutic effects of MECT were assessed. 3) Single nerve psychology test was used to assess the cognitive function.
1) There were no significant differences in WBC, ALT, CK and CKMB before and after MECT (P > 0.05). 2) WBC, ALT and CKMB remained stable at different time points after MECT treatment (P > 0.05). But CK had statistical differences at different times before or after MECT treatment (P < 0.05). CK decreased since the first MECT and thereafter increased after the 7th treatment (P < 0.05). 3) The total score of PANSS decreased significantly after MECT (P < 0.05). 4) Digit span test showed no statistically significant differences in different time points (P > 0.05); Digital sign test and verbal fluency test showed significant differences in different times (P < 0.05).
The CK figure decreased from the first to sixth MECT treatment and increased in the 7th MECT treatment, and the CKMB also increased in the 7th treatment. MECT treatment had significant effects on female patients with schizophrenia and could obviously improve patient's cognitive function.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
139Am. J. Med. Genet. B Neuropsychiatr. Genet. 2015 Jun 168B: 229-35
PMID25776014
TitleCase history and genome-wide scans for copy number variants in a family with patient having 15q11.1-q11.2 duplication and 22q11.2 deletion, and schizophrenia.
AbstractMany studies have indicated that chromosomes 15q11 and 22q11 may be associated with the genetic etiologies of schizophrenia. We have followed an adult schizophrenia case with 15q11.1-q11.2 duplication and 22q11.2 deletion. Here we report his clinical history, and copy nuMBer variants (CNVs) identified by microarray and real-time PCR in the patient and his parents. This is the first report describing a detailed phenotype of an adult schizophrenic case with both 15q11 and 22q11 CNVs as revealed by novel and trustworthy technologies. Subjects were a 33-year-old male patient with 15q11 and 22q11 CNVs, and his normal parents. He fulfilled the DSM-IV criteria for schizophrenia at age 18 years. He was also diagnosed with 22q11.2 deletion syndrome by fluorescence in situ hybridization (FISH) at age 18 years. To search for CNVs in more detail, whole-genome array-CGH analyses including ? 420,000 probes were carried out in the patient and his parents. For validations of the CNVs detected by array-CGH, real-time PCR analyses of these CNVs were performed. The patient had two disease-specific CNVs, 15q11.1-q11.2 duplication (? 2.7 MB) and 22q11.21 deletion (? 2.9 MB). These two regions are important for the development of schizophrenia, and this patient had shown symptoms of schizophrenia. Thus, the two areas may contain causal genes for schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
140Cytogenet. Genome Res. 2015 -1 146: 33-8
PMID26112830
Title2q37.3 Deletion Syndrome: Two Cases with Highly Distinctive Facial Phenotype, Discordant Association with Schizophrenic Psychosis, and Shared Deletion Breakpoint Region on 2q37.3.
Abstract2q37.3 deletion syndrome belongs to the chromosomal 2q37 deletion spectrum which clinically reseMBles Albright hereditary osteodystrophy (AHO) syndrome. It is is mainly characterized by short stature, obesity, round face, brachydactyly type E, intellectual disability, behavioral problems, and variable intellectual deficits. Different from classical AHO syndrome, patients with 2q37 deletion syndrome lack renal parathyroid hormone resistance (pseudohypoparathyroidism) and soft tissue ossification. So far, deletion mapping or molecular breakpoint analyses of 2q37 have been performed in only few patients. Here, we report on 2 patients with 2q37.3 deletion syndrome. In both patients the breakpoint of the 5.5-MB terminal microdeletion could be narrowed down to the same ? 200-kb interval on 2q37.3 by BAC-FISH and/or array-CGH. Flanking low-copy repeats may indicate a classical microdeletion syndrome genesis for the 2q37.3 microdeletion subgroup. Clinical evaluation revealed intellectual deficits and type E brachydactyly typical for classical AHO syndrome together with distinctive facial dysmorphisms not present in the former. Furthermore, one patient presented with schizophrenic psychosis, an observation that would be in accordance with previous reports about an association between schizophrenia susceptibility and an unknown gene within the chromosomal region 2q37.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
141Am. J. Med. Genet. B Neuropsychiatr. Genet. 2015 Jun 168B: 229-35
PMID25776014
TitleCase history and genome-wide scans for copy number variants in a family with patient having 15q11.1-q11.2 duplication and 22q11.2 deletion, and schizophrenia.
AbstractMany studies have indicated that chromosomes 15q11 and 22q11 may be associated with the genetic etiologies of schizophrenia. We have followed an adult schizophrenia case with 15q11.1-q11.2 duplication and 22q11.2 deletion. Here we report his clinical history, and copy nuMBer variants (CNVs) identified by microarray and real-time PCR in the patient and his parents. This is the first report describing a detailed phenotype of an adult schizophrenic case with both 15q11 and 22q11 CNVs as revealed by novel and trustworthy technologies. Subjects were a 33-year-old male patient with 15q11 and 22q11 CNVs, and his normal parents. He fulfilled the DSM-IV criteria for schizophrenia at age 18 years. He was also diagnosed with 22q11.2 deletion syndrome by fluorescence in situ hybridization (FISH) at age 18 years. To search for CNVs in more detail, whole-genome array-CGH analyses including ? 420,000 probes were carried out in the patient and his parents. For validations of the CNVs detected by array-CGH, real-time PCR analyses of these CNVs were performed. The patient had two disease-specific CNVs, 15q11.1-q11.2 duplication (? 2.7 MB) and 22q11.21 deletion (? 2.9 MB). These two regions are important for the development of schizophrenia, and this patient had shown symptoms of schizophrenia. Thus, the two areas may contain causal genes for schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
142Mol. Psychiatry 2016 Jan 21: 89-93
PMID25560756
TitleCopy number variation in bipolar disorder.
AbstractLarge (>100 kb), rare (<1% in the population) copy nuMBer variants (CNVs) have been shown to confer risk for schizophrenia (SZ), but the findings for bipolar disorder (BD) are less clear. In a new BD sample from the United Kingdom (n=2591), we have examined the occurrence of CNVs and compared this with previously reported samples of 6882 SZ and 8842 control subjects. When coMBined with previous data, we find evidence for a contribution to BD for three SZ-associated CNV loci: duplications at 1q21.1 (P=0.022), deletions at 3q29 (P=0.03) and duplications at 16p11.2 (P=2.3 10(-4)). The latter survives multiple-testing correction for the nuMBer of recurrent large CNV loci in the genome. Genes in 20 regions (total of 55 genes) were enriched for rare exonic CNVs among BD cases, but none of these survives correction for multiple testing. Finally, our data provide strong support for the hypothesis of a lesser contribution of very large (>500 kb) CNVs in BD compared with SZ, most notably for deletions >1 MB (P=9 10(-4)).
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
143Mol. Psychiatry 2016 Jun 21: 749-57
PMID27067015
TitleGenome-wide analysis of over 106?000 individuals identifies 9 neuroticism-associated loci.
AbstractNeuroticism is a personality trait of fundamental importance for psychological well-being and public health. It is strongly associated with major depressive disorder (MDD) and several other psychiatric conditions. Although neuroticism is heritable, attempts to identify the alleles involved in previous studies have been limited by relatively small sample sizes. Here we report a coMBined meta-analysis of genome-wide association study (GWAS) of neuroticism that includes 91?370 participants from the UK Biobank cohort, 6659 participants from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and 8687 participants from a QIMR (Queensland Institute of Medical Research) Berghofer Medical Research Institute (QIMR) cohort. All participants were assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised (EPQ-R-S) Short Form's Neuroticism scale. We found a single-nucleotide polymorphism-based heritability estimate for neuroticism of ?15% (s.e.=0.7%). Meta-analysis identified nine novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (P=1.5 10(-15)) spanning 4?MB and containing at least 36 genes. Other associated loci included interesting candidate genes on chromosome 1 (GRIK3 (glutamate receptor ionotropic kainate 3)), chromosome 4 (KLHL2 (Kelch-like protein 2)), chromosome 17 (CRHR1 (corticotropin-releasing hormone receptor 1) and MAPT (microtubule-associated protein Tau)) and on chromosome 18 (CELF4 (CUGBP elav-like family meMBer 4)). We found no evidence for genetic differences in the common allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a strong genetic correlation between neuroticism and MDD and a less strong but significant genetic correlation with schizophrenia, although not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank sample captured ?1% of the variance in neuroticism in the GS:SFHS and QIMR samples, although most of the genome-wide significant alleles identified within a UK Biobank-only GWAS of neuroticism were not independently replicated within these cohorts. The identification of nine novel neuroticism-associated loci will drive forward future work on the neurobiology of neuroticism and related phenotypes.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
144Am. J. Med. Genet. B Neuropsychiatr. Genet. 2016 Mar 171: 290-9
PMID26620927
TitleA novel 3q29 deletion associated with autism, intellectual disability, psychiatric disorders, and obesity.
AbstractCopy nuMBer variation (CNV) has been associated with a variety of neuropsychiatric disorders, including intellectual disability/developmental delay (ID/DD), autism spectrum disorder (ASD), and schizophrenia (SCZ). Often, individuals carrying the same pathogenic CNV display high clinical variability. By array-CGH analysis, we identified a novel familial 3q29 deletion (1.36?MB), centromeric to the 3q29 deletion region, which manifests with variable expressivity. The deletion was identified in a 3-year-old girl diagnosed with ID/DD and autism and segregated in six family meMBers, all affected by severe psychiatric disorders including schizophrenia, major depression, anxiety disorder, and personality disorder. All individuals carrying the deletion were overweight or obese, and anomalies compatible with optic atrophy were observed in three out of four cases examined. Amongst the 10 genes encompassed by the deletion, the haploinsufficiency of Optic Atrophy 1 (OPA1), associated with autosomal dominant optic atrophy, is likely responsible for the ophthalmological anomalies. We hypothesize that the haploinsufficiency of ATPase type 13A4 (ATP13A4) and/or Hairy/Enhancer of Split Drosophila homolog 1 (HES1) contribute to the neuropsychiatric phenotype, while HES1 deletion might underlie the overweight/obesity. In conclusion, we propose a novel contiguous gene syndrome due to a proximal 3q29 deletion variably associated with autism, ID/DD, psychiatric traits and overweight/obesity. 2015 Wiley Periodicals, Inc.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal
145Am. J. Med. Genet. A 2016 Apr 170: 999-1006
PMID26738761
TitleNovel features of 3q29 deletion syndrome: Results from the 3q29 registry.
Abstract3q29 deletion syndrome is caused by a recurrent, typically de novo heterozygous 1.6 MB deletion, but because incidence of the deletion is rare (1 in 30,000 births) the phenotype is not well described. To characterize the range of phenotypic manifestations associated with 3q29 deletion syndrome, we have developed an online registry (3q29deletion.org) for ascertainment of study subjects and phenotypic data collection via Internet-based survey instruments. We report here on data collected during the first 18 months of registry operation, from 44 patients. This is the largest cohort of 3q29 deletion carriers ever asseMBled and surveyed in a systematic way. Our data reveal that 28% of registry participants report neuropsychiatric phenotypes, including anxiety disorder, panic attacks, depression, bipolar disorder, and schizophrenia. Other novel findings include a high prevalence (64%) of feeding problems in infancy and reduced weight at birth for 3q29 deletion carriers (average reduction 13.9 oz (394?g), adjusted for gestational age and sex, P?=?6.5e-07). We further report on the frequency of heart defects, autism, recurrent ear infections, gastrointestinal phenotypes, and dental phenotypes, among others. We also report on the expected timing of delayed developmental milestones. This is the most comprehensive description of the 3q29 deletion phenotype to date. These results are clinically actionable toward improving patient care for 3q29 deletion carriers, and can guide the expectations of physicians and parents. These data also demonstrate the value of patient-reported outcomes to reveal the full phenotypic spectrum of rare genomic disorders. 2016 Wiley Periodicals, Inc.
SCZ Keywordsschizophrenia, schizophrenic, schizophrenics, schizotypal