| 1 | Schizophr Bull 2008 Jan 34: 118-26 |
|---|---|
| PMID | 17515439 |
| Title | Linkage disequilibrium patterns and functional analysis of RGS4 polymorphisms in relation to schizophrenia. |
| Abstract | The regulator of G-protein signaling 4 (RGS4, chromosome 1q23.3) plays a critical role in G-protein function. Four common single-nucleotide polymorphisms (SNPs) localized between the 5' upstream sequence and the first intron, as well as 2 haplotypes derived from these SNPs may confer liability to schizophrenia (SZ). However, the pattern of associations varies among samples. To help clarify the putative associations, we report the following analyses: (1) a comprehensive catalog of common polymorphisms, (2) linkage disequilibrium (LD) and association analyses using these SNPs, and (3) functional analysis based on dual-luciferase promoter assays. We identified 62 SNPs from a 20-kb genomic region spanning RGS4, of which 26 are common polymorphisms with a minor allele frequency (MAF) of >5%. LD analysis suggested 5 clusters of SNPs (r(2) > .8). Association analyses using the novel SNPs were consistent with the prior reports, but further localization was constrained by significant LD across the region. The 2 haplotypes reported to confer liability to SZ had significant promoter activity compared with promoterless constructs, suggesting a functional role for both haplotypes. Further analyses of promoter sequences are warranted to understand transcriptional regulation at RGS4. This information will be useful for further analysis of samples in which genetic association of RGS4 polymorphisms with SZ has been reported. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 2 | Dis. Markers 2010 -1 28: 315-21 |
| PMID | 20592456 |
| Title | Lack of association between PRNP M129V polymorphism and multiple sclerosis, mild cognitive impairment, alcoholism and schizophrenia in a Korean population. |
| Abstract | The genetic variant at codon 129 (M129V) of the prion protein gene (PRNP) is considered to be a major genetic risk factor for prion diseases. In this study, we examined the possible genetic association of PRNP*129Val with multiple sclerosis (MS, n=681), mild cognitive impairment (MCI, n=801), alcoholism (n=761) and schizophrenia (n=715) in a Korean population, and compared the data with previous genetic association studies of the variant. The minor allele frequency of PRNP*129Val (MAF =0.025) was significantly lower in Korean population (n=2,479) compared to Caucasian populations (P < 0.0001), suggestive of a weak influence of the variant in the previous population. Statistical analysis revealed no significant association between PRNP*129Val and MS (P= 0.76), MCI (P=0.46), alcoholism (P=0.84) and schizophrenia (P =0.69). These findings were discussed in the context of prior inconsistent reports on the role of PRNP*129Val polymorphism in several diseases. Results from this study may provide further evidence that PRNP M129V is not a genetic susceptibility factor for MS, MCI, alcoholism and schizophrenia in a Korean population. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 3 | World J. Biol. Psychiatry 2010 Oct 11: 894-903 |
| PMID | 20653494 |
| Title | Patients' preference for olanzapine orodispersible tablet compared with conventional oral tablet in a multinational, randomized, crossover study. |
| Abstract | The aim of this study was to compare patients' preference for olanzapine orodispersible tablet (ODT) with oral conventional tablet (OCT). A 12-week randomized, crossover, multinational, open-label study was conducted to estimate the proportion of patients preferring ODT or OCT. Outpatients with stable schizophrenia on OCT monotherapy were randomly assigned 1:1 to ODT or OCT. Compliance and drug attitude were measured using the Drug Attitude Inventory (DAI-10) and Medication Adherence Form (MAF) scales; tolerability and safety by Association for Methodology and Documentation in Psychiatry (AMDP-5) questionnaire and adverse event summary. A total of 175 patients answered a preference question: 106 (61%) preferred ODT and 48 (27%) preferred OCT (P<0.001 adjusted for treatment sequence); 21 (12%) expressed no preference. There was no significant change in DAI-10 with either formulation. MAF was above 75% in 94% vs. 93% of patients on ODC and OCT, respectively. Compliance as measured by tablet count was above 98% on both formulations. The adverse event profiles did not differ between formulations. Mean weight increase over 6 weeks on ODT was 0.8 kg and on OCT was 0.6 kg. Given the importance of patients' preference for treatment planning and success, the ODT formulation should be routinely considered as a treatment option. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 4 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Apr 153B: 766-74 |
| PMID | 19859905 |
| Title | Mutation screening of the DTNBP1 exonic sequence in 669 schizophrenics and 710 controls using high-resolution melting analysis. |
| Abstract | A large number of independent studies have reported evidence for association between the dysbindin gene (DTNBP1) and schizophrenia; however, specific risk alleles have been not been implicated as causal. In this study we set out to perform a comprehensive assessment of DNA variation within the exonic sequence of DTNBP1. To achieve this we optimized a high-resolution melting analysis (HRMA) protocol and applied it to screen all 11 DTNBP1 exons for DNA variants in a sample of 669 cases and 710 controls from the UK. Despite identifying seven exonic variants with a minor allele frequency (MAF) >0.01, none was significantly associated with schizophrenia (minimum P = 0.054), showing that the strong association we previously reported in this sample is not the result of association to a common functional variant located within the exonic sequence of any of the three major DTNBP1 transcripts. We also sought additional support for DTNBP1 as a susceptibility gene for schizophrenia by testing the hypothesis that rare exonic highly penetrant variants exist at the DTNBP1 locus. Our analysis failed to identify an enrichment of rare functional variants in the patients compared to the controls. Taken as a whole, this data demonstrate that if DTNBP1 is a risk gene for schizophrenia then risk is not conferred by mutations that affect the structure of the dysbindin protein. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 5 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2010 Apr 153B: 766-74 |
| PMID | 19859905 |
| Title | Mutation screening of the DTNBP1 exonic sequence in 669 schizophrenics and 710 controls using high-resolution melting analysis. |
| Abstract | A large number of independent studies have reported evidence for association between the dysbindin gene (DTNBP1) and schizophrenia; however, specific risk alleles have been not been implicated as causal. In this study we set out to perform a comprehensive assessment of DNA variation within the exonic sequence of DTNBP1. To achieve this we optimized a high-resolution melting analysis (HRMA) protocol and applied it to screen all 11 DTNBP1 exons for DNA variants in a sample of 669 cases and 710 controls from the UK. Despite identifying seven exonic variants with a minor allele frequency (MAF) >0.01, none was significantly associated with schizophrenia (minimum P = 0.054), showing that the strong association we previously reported in this sample is not the result of association to a common functional variant located within the exonic sequence of any of the three major DTNBP1 transcripts. We also sought additional support for DTNBP1 as a susceptibility gene for schizophrenia by testing the hypothesis that rare exonic highly penetrant variants exist at the DTNBP1 locus. Our analysis failed to identify an enrichment of rare functional variants in the patients compared to the controls. Taken as a whole, this data demonstrate that if DTNBP1 is a risk gene for schizophrenia then risk is not conferred by mutations that affect the structure of the dysbindin protein. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 6 | PLoS ONE 2011 -1 6: e23450 |
| PMID | 21853134 |
| Title | Sequencing of DISC1 pathway genes reveals increased burden of rare missense variants in schizophrenia patients from a northern Swedish population. |
| Abstract | In recent years, DISC1 has emerged as one of the most credible and best supported candidate genes for schizophrenia and related neuropsychiatric disorders. Furthermore, increasing evidence--both genetic and functional--indicates that many of its protein interaction partners are also involved in the development of these diseases. In this study, we applied a pooled sample 454 sequencing strategy, to explore the contribution of genetic variation in DISC1 and 10 of its interaction partners (ATF5, Grb2, FEZ1, LIS-1, PDE4B, NDE1, NDEL1, TRAF3IP1, YWHAE, and ZNF365) to schizophrenia susceptibility in an isolated northern Swedish population. Mutation burden analysis of the identified variants in a population of 486 SZ patients and 514 control individuals, revealed that non-synonymous rare variants with a MAF<0.01 were significantly more present in patients compared to controls (8.64% versus 4.7%, P?=?0.018), providing further evidence for the involvement of DISC1 and some of its interaction partners in psychiatric disorders. This increased burden of rare missense variants was even more striking in a subgroup of early onset patients (12.9% versus 4.7%, P?=?0.0004), highlighting the importance of studying subgroups of patients and identifying endophenotypes. Upon investigation of the potential functional effects associated with the identified missense variants, we found that ?90% of these variants reside in intrinsically disordered protein regions. The observed increase in mutation burden in patients provides further support for the role of the DISC1 pathway in schizophrenia. Furthermore, this study presents the first evidence supporting the involvement of mutations within intrinsically disordered protein regions in the pathogenesis of psychiatric disorders. As many important biological functions depend directly on the disordered state, alteration of this disorder in key pathways may represent an intriguing new disease mechanism for schizophrenia and related neuropsychiatric diseases. Further research into this unexplored domain will be required to elucidate the role of the identified variants in schizophrenia etiology. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 7 | PLoS ONE 2011 -1 6: e19073 |
| PMID | 21559500 |
| Title | Comparative linkage meta-analysis reveals regionally-distinct, disparate genetic architectures: application to bipolar disorder and schizophrenia. |
| Abstract | New high-throughput, population-based methods and next-generation sequencing capabilities hold great promise in the quest for common and rare variant discovery and in the search for "missing heritability." However, the optimal analytic strategies for approaching such data are still actively debated, representing the latest rate-limiting step in genetic progress. Since it is likely a majority of common variants of modest effect have been identified through the application of tagSNP-based microarray platforms (i.e., GWAS), alternative approaches robust to detection of low-frequency (1-5% MAF) and rare (<1%) variants are of great importance. Of direct relevance, we have available an accumulated wealth of linkage data collected through traditional genetic methods over several decades, the full value of which has not been exhausted. To that end, we compare results from two different linkage meta-analysis methods--GSMA and MSP--applied to the same set of 13 bipolar disorder and 16 schizophrenia GWLS datasets. Interestingly, we find that the two methods implicate distinct, largely non-overlapping, genomic regions. Furthermore, based on the statistical methods themselves and our contextualization of these results within the larger genetic literatures, our findings suggest, for each disorder, distinct genetic architectures may reside within disparate genomic regions. Thus, comparative linkage meta-analysis (CLMA) may be used to optimize low-frequency and rare variant discovery in the modern genomic era. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 8 | Hum. Genet. 2012 Jul 131: 1047-56 |
| PMID | 22160351 |
| Title | Association of PDE4B polymorphisms and schizophrenia in Northwestern Han Chinese. |
| Abstract | The phosphodiesterase 4B (PDE4B) is a candidate susceptibility gene for schizophrenia (SCZ), interacting with DISC1, a known genetic risk factor for SCZ. To examine if variants within PDE4B gene are associated with SCZ in Northwestern Han Chinese, and if these effects vary in gender-specific subgroup, we analyzed 20 SNPs, selected from previous studies and preliminary HapMap data analyses with minor allele frequency (MAF) ? 20%, in a cohort of 428 cases and 572 controls from genetically independent Northwestern Han Chinese. Single SNP association, haplotype association and sex-specific association analysis were performed. We found that rs472952 is significantly associated with SCZ and rs7537440 is associated with SCZ in females. Further analysis indicated that a haplotype block spanning PDE4B2 splice site is highly associated with SCZ and several haplotypes in this block have about twofold to threefold increase in cases. Our results provide further evidence that PDE4B may play important roles in the etiology of SCZ. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 9 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2012 Jun 159B: 445-55 |
| PMID | 22488871 |
| Title | ASTN1 and alcohol dependence: family-based association analysis in multiplex alcohol dependence families. |
| Abstract | A previous genome-wide linkage study of alcohol dependence (AD) in multiplex families found a suggestive linkage result for a region on Chromosome 1 near microsatellite markers D1S196 and D1S2878. The ASTN1 gene is in this region, a gene previously reported to be associated with substance abuse, bipolar disorder and schizophrenia. Using the same family data consisting of 330 individuals with phenotypic data and DNA, finer mapping of a 26 cM region centered on D1S196 was undertaken using SNPs with minor allele frequency (MAF) ? 0.15 and pair-wise linkage disequilibrium (LD) of r(2) < 0.8 using the HapMap CEU population. Significant FBAT P-values for SNPs within the ASTN1 gene were observed for four SNPs (rs465066, rs228008, rs6668092, and rs172917), the most significant, rs228008, within intron 8 had a P-value of 0.001. Using MQLS, which allows for inclusion of all families, we find three of these SNPs with MQLS P-values < 0.003. In addition, two additional neighboring SNPs (rs10798496 and rs6667588) showed significance at P = 0.002 and 0.03, respectively. Haplotype analysis was performed using the haplotype-based test function of FBAT for a block that included rs228008, rs6668092, and rs172917. This analysis found one block (GCG) over-transmitted and another (ATA) under-transmitted to affected offspring. Linkage analysis identified a region consistent with the association results. Family-based association analysis shows the ASTN1 gene significantly associated with alcohol dependence. The potential importance of the ASTN1 gene for AD risk may be related its role in glial-guided neuronal migration. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 10 | Synapse 2012 Nov 66: 979-83 |
| PMID | 22807112 |
| Title | The C allele of synonymous SNP (rs1142636, Asn170Asn) in SYN1 is a risk factor for the susceptibility of Korean female schizophrenia. |
| Abstract | The aim of this study was to investigate the association between the exonic single nucleotide polymorphisms (SNPs) of synapsin I (SYN1) (rs1142636, Asn170Asn, Xp11.23) and SYN2 (rs2289708, 3'-untranslated region, 3p25) in schizopherenia. Two hundred eighty six schizophrenia patients and 304 control subjects were recruited. SNPs with a know heterozygosity and minor allele frequency (MAF) > 0.1 in Asian populations were selected and genotyped by direct sequencing. The allelic frequencies of rs1142636 (SYN1) were associated with schizophrenia (P < 0.05), respectively. The allelic frequency of rs1142636 in all subjects was associated with schizophrenia [P = 0.000059, OR = 2.17 (95% CI = 1.47-3.18)]. The C allele frequency of rs1142636 was higher in schizophrenia (20.8%) than that in controls (10.8%). In the analysis of gender, the allelic frequency of rs1142636 was also strongly associated with female schizophrenia [P = 0.0001, OR = 2.65 (95% CI = 1.61-4.36)], but not with male schizophrenia. The C allele frequency of rs1142636 was higher in female schizophrenia (22.2%) than that in female controls (9.7%). The rs2289708 SNP (SYN2) did not show any association between schizophrenia and controls. These results suggest that the C allele of a synonymous SNP (rs1142636, Asn170Asn, Xp11.23) in SYN1 may be a risk factor for the susceptibility of Koreran female schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 11 | Am. J. Med. Genet. B Neuropsychiatr. Genet. 2012 Jan 159B: 77-86 |
| PMID | 22162401 |
| Title | Evaluation of conserved and ultra-conserved non-genic sequences in chromosome 15q15-linked periodic catatonia. |
| Abstract | Conserved 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 Keywords | schizophrenia, schizophrenic, schizophrenics |
| 12 | Hum. Genet. 2013 Jul 132: 735-43 |
| PMID | 23468174 |
| Title | Association between common alcohol dehydrogenase gene (ADH) variants and schizophrenia and autism. |
| Abstract | Humans express at least seven alcohol dehydrogenase (ADH) isoforms that are encoded by ADH gene cluster (ADH7-ADH1C-ADH1B-ADH1A-ADH6-ADH4-ADH5) at chromosome 4. ADHs are key catabolic enzymes for retinol and ethanol. The functional ADH variants (mostly rare) have been implicated in alcoholism risk. In addition to catalyzing the oxidation of retinol and ethanol, ADHs may be involved in the metabolic pathways of several neurotransmitters that are implicated in the neurobiology of neuropsychiatric disorders. In the present study, we comprehensively examined the associations between common ADH variants [minor allele frequency (MAF) >0.05] and 11 neuropsychiatric and neurological disorders. A total of 50,063 subjects in 25 independent cohorts were analyzed. The entire ADH gene cluster was imputed across these 25 cohorts using the same reference panels. Association analyses were conducted, adjusting for multiple comparisons. We found 28 and 15 single nucleotide polymorphisms (SNPs), respectively, that were significantly associated with schizophrenia in African-Americans and autism in European-Americans after correction by false discovery rate (FDR) (q < 0.05); and 19 and 6 SNPs, respectively, that were significantly associated with these two disorders after region-wide correction by SNPSpD (8.9 × 10(-5) ? p ? 0.0003 and 2.4 × 10(-5) ? p ? 0.0003, respectively). No variants were significantly associated with the other nine neuropsychiatric disorders, including alcohol dependence. We concluded that common ADH variants conferred risk for both schizophrenia in African-Americans and autism in European-Americans. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 13 | Neuroimage 2013 Nov 82: 146-53 |
| PMID | 23727532 |
| Title | Relation between variants in the neurotrophin receptor gene, NTRK3, and white matter integrity in healthy young adults. |
| Abstract | The NTRK3 gene (also known as TRKC) encodes a high affinity receptor for the neurotrophin 3'-nucleotidase (NT3), which is implicated in oligodendrocyte and myelin development. We previously found that white matter integrity in young adults is related to common variants in genes encoding neurotrophins and their receptors. This underscores the importance of neurotrophins for white matter development. NTRK3 variants are putative risk factors for schizophrenia, bipolar disorder, and obsessive-compulsive disorder hoarding, suggesting that some NTRK3 variants may affect the brain. To test this, we scanned 392 healthy adult twins and their siblings (mean age, 23.6 ± 2.2 years; range: 20-29 years) with 105-gradient 4-Tesla diffusion tensor imaging (DTI). We identified 18 single nucleotide polymorphisms (SNPs) in the NTRK3 gene that have been associated with neuropsychiatric disorders. We used a multi-SNP model, adjusting for family relatedness, age, and sex, to relate these variants to voxelwise fractional anisotropy (FA) - a DTI measure of white matter integrity. FA was optimally predicted (based on the highest false discovery rate critical p), by five SNPs (rs1017412, rs2114252, rs16941261, rs3784406, and rs7176429; overall FDR critical p=0.028). Gene effects were widespread and included the corpus callosum genu and inferior longitudinal fasciculus - regions implicated in several neuropsychiatric disorders and previously associated with other neurotrophin-related genetic variants in an overlapping sample of subjects. NTRK3 genetic variants, and neurotrophins more generally, may influence white matter integrity in brain regions implicated in neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 14 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2013 Oct 46: 64-9 |
| PMID | 23778016 |
| Title | Genetic analysis of common variants in the CMYA5 (cardiomyopathy-associated 5) gene with schizophrenia. |
| Abstract | Recently, CMYA5 was suggested as a susceptibility gene for schizophrenia based on two independent studies utilizing different ethnic samples. We designed a case-control study to examine whether 21 SNPs contained within CMYA5 were associated with the disorder in a western Han Chinese sample comprised of 488 schizophrenia patients and 516 healthy control subjects. The allele distribution of SNPs rs7714250, rs16877135 and rs13158477 showed significant association with schizophrenia (Puncorrected=0.008, Puncorrected=0.04, and Puncorrected=0.009, respectively) as well as the genotype distribution in the Cochran-Armitage trend test (Puncorrected=0.008, Puncorrected=0.037 and Puncorrected=0.011, respectively). After Bonferroni correction, rs7714250 showed a trend of association with schizophrenia both in allele distribution (Pcorrected=0.088) and genotype distribution (Pcorrected=0.088). Furthermore, significant associations were found in several two-, three-, four-, and five-SNP tests of haplotype analyses. Replications of the association of CMYA5 with schizophrenia across various studies suggest that it is very likely a potential common schizophrenia-related gene worldwide. Functional studies correlating CMYA5 with DTNBP1 and PKA warrant further investigation of the molecular basis of this gene in relationship to the signal transduction pathway(s) underlying the pathogenesis of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 15 | Transl Psychiatry 2013 -1 3: e301 |
| PMID | 24002087 |
| Title | A rare WNT1 missense variant overrepresented in ASD leads to increased Wnt signal pathway activation. |
| Abstract | Wnt signaling, which encompasses multiple biochemical pathways that regulate neural development downstream of extracellular Wnt glycoprotein ligands, has been suggested to contribute to major psychiatric disorders including autism spectrum disorders (ASD). We used next-generation sequencing and Sequenom genotyping technologies to resequence 10 Wnt signaling pathway genes in 198 ASD patients and 240 matched controls. Results for single-nucleotide polymorphisms (SNPs) of interest were confirmed in a second set of 91 ASD and 144 control samples. We found a significantly increased burden of extremely rare missense variants predicted to be deleterious by PolyPhen-2, distributed across seven genes in the ASD sample (3.5% in ASD vs 0.8% in controls; Fisher's exact test, odds ratio (OR)=4.37, P=0.04). We also found a missense variant in WNT1 (S88R) that was overrepresented in the ASD sample (8 A/T in 267 ASD (minor allele frequency (MAF)=1.69%) vs 1 A/T in 377 controls (MAF=0.13%), OR=13.0, Fisher's exact test, P=0.0048; OR=8.2 and P=0.053 after correction for population stratification). Functional analysis revealed that WNT1-S88R is more active than wild-type WNT1 in assays for the Wnt/?-catenin signaling pathway. Our findings of a higher burden in ASD of rare missense variants distributed across 7 of 10 Wnt signaling pathway genes tested, and of a functional variant at the WNT1 locus associated with ASD, support that dysfunction of this pathway contributes to ASD susceptibility. Given recent findings of common molecular mechanisms in ASD, schizophrenia and affective disorders, these loci merit scrutiny in other psychiatric conditions as well. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 16 | Mol Autism 2014 -1 5: 1 |
| PMID | 24410847 |
| Title | Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders. |
| Abstract | Autism spectrum disorders (ASDs) comprise a range of neurodevelopmental conditions of varying severity, characterized by marked qualitative difficulties in social relatedness, communication, and behavior. Despite overwhelming evidence of high heritability, results from genetic studies to date show that ASD etiology is extremely heterogeneous and only a fraction of autism genes have been discovered. To help unravel this genetic complexity, we performed whole exome sequencing on 100 ASD individuals from 40 families with multiple distantly related affected individuals. All families contained a minimum of one pair of ASD cousins. Each individual was captured with the Agilent SureSelect Human All Exon kit, sequenced on the Illumina Hiseq 2000, and the resulting data processed and annotated with Burrows-Wheeler Aligner (BWA), Genome Analysis Toolkit (GATK), and SeattleSeq. Genotyping information on each family was utilized in order to determine genomic regions that were identical by descent (IBD). Variants identified by exome sequencing which occurred in IBD regions and present in all affected individuals within each family were then evaluated to determine which may potentially be disease related. Nucleotide alterations that were novel and rare (minor allele frequency, MAF, less than 0.05) and predicted to be detrimental, either by altering amino acids or splicing patterns, were prioritized. We identified numerous potentially damaging, ASD associated risk variants in genes previously unrelated to autism. A subset of these genes has been implicated in other neurobehavioral disorders including depression (SLIT3), epilepsy (CLCN2, PRICKLE1), intellectual disability (AP4M1), schizophrenia (WDR60), and Tourette syndrome (OFCC1). Additional alterations were found in previously reported autism candidate genes, including three genes with alterations in multiple families (CEP290, CSMD1, FAT1, and STXBP5). Compiling a list of ASD candidate genes from the literature, we determined that variants occurred in ASD candidate genes 1.65 times more frequently than in random genes captured by exome sequencing (P?=?8.55 × 10-5). By studying these unique pedigrees, we have identified novel DNA variations related to ASD, demonstrated that exome sequencing in extended families is a powerful tool for ASD candidate gene discovery, and provided further evidence of an underlying genetic component to a wide range of neurodevelopmental and neuropsychiatric diseases. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 17 | Am. J. Hum. Genet. 2014 Dec 95: 744-53 |
| PMID | 25434007 |
| Title | A rare functional noncoding variant at the GWAS-implicated MIR137/MIR2682 locus might confer risk to schizophrenia and bipolar disorder. |
| Abstract | schizophrenia (SZ) genome-wide association studies (GWASs) have identified common risk variants in >100 susceptibility loci; however, the contribution of rare variants at these loci remains largely unexplored. One of the strongly associated loci spans MIR137 (miR137) and MIR2682 (miR2682), two microRNA genes important for neuronal function. We sequenced ?6.9 kb MIR137/MIR2682 and upstream regulatory sequences in 2,610 SZ cases and 2,611 controls of European ancestry. We identified 133 rare variants with minor allele frequency (MAF) <0.5%. The rare variant burden in promoters and enhancers, but not insulators, was associated with SZ (p = 0.021 for MAF < 0.5%, p = 0.003 for MAF < 0.1%). A rare enhancer SNP, 1:g.98515539A>T, presented exclusively in 11 SZ cases (nominal p = 4.8 × 10(-4)). We further identified its risk allele T in 2 of 2,434 additional SZ cases, 11 of 4,339 bipolar (BP) cases, and 3 of 3,572 SZ/BP study controls and 1,688 population controls; yielding combined p values of 0.0007, 0.0013, and 0.0001 for SZ, BP, and SZ/BP, respectively. The risk allele T of 1:g.98515539A>T reduced enhancer activity of its flanking sequence by >50% in human neuroblastoma cells, predicting lower expression of MIR137/MIR2682. Both empirical and computational analyses showed weaker transcription factor (YY1) binding by the risk allele. Chromatin conformation capture (3C) assay further indicated that 1:g.98515539A>T influenced MIR137/MIR2682, but not the nearby DPYD or LOC729987. Our results suggest that rare noncoding risk variants are associated with SZ and BP at MIR137/MIR2682 locus, with risk alleles decreasing MIR137/MIR2682 expression. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 18 | Schizophr. Res. 2014 Aug 157: 169-74 |
| PMID | 24972756 |
| Title | Resequencing and association study of the NFKB activating protein-like gene (NKAPL) in schizophrenia. |
| Abstract | schizophrenia is a highly inheritable disorder, but many aspects of its etiology and pathophysiology remain poorly understood. Recently, in the Han Chinese population, a SNP rs1635 located within the exon of the NKAPL gene (encoding NFKB activating protein-like) achieved genome-wide significance in schizophrenia. In order to find the causal variants of the NKAPL gene in schizophrenia, we searched for genetic variants in the promoter region, and exons (including both UTR ends) using direct sequencing in a sample of patients with schizophrenia (n=515) and non-psychotic controls (n=456), all Han Chinese from Taiwan, and conducted an association and rudimentary functional study. We identified 5 common SNPs (defined as minor allele frequency (MAF)>0.01) in the NKAPL gene. In a case-control association analysis, the minor allele (A) of rs1635 was significantly more common among patients than controls (P=0.0003, OR=1.41, 95% CI=1.17-1.71). A haplotype analysis of the 5 common SNPs indicated a risk haplotype (rs12000C-rs1635A-rs9461446C-rs3734564G-rs1679709G) associated with schizophrenia (P=2.77e-005, OR=1.53, 95% CI=1.25-1.87). In addition, we identified 4 patient-specific rare SNPs (MAF<0.01) (c.137G>A, c.213G>A, c.752C>T (rs370337122), and c.844G>A (rs147161729)) within the NKAPL gene. In silico analysis demonstrated their functional impact on the protein; however, there was also 1 control-specific rare SNP (c.119G>A) detected within the NKAPL gene, indicating that the clinical relevance of these putatively pathological rare SNPs is not straightforward. This study suggested that rs1635 in the NKAPL gene appeared to play a role in conferring susceptibility to schizophrenia. In addition, some rare SNPs in the NKAPL gene with possibly damaging effects may be important in our patients. Our study provides genetic clues to indicate the involvement of NKAPL in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 19 | Schizophr. Res. 2015 Aug 166: 119-24 |
| PMID | 26091878 |
| Title | De novo mutations from sporadic schizophrenia cases highlight important signaling genes in an independent sample. |
| Abstract | schizophrenia is a debilitating syndrome with high heritability. Genomic studies reveal more than a hundred genetic variants, largely nonspecific and of small effect size, and not accounting for its high heritability. De novo mutations are one mechanism whereby disease related alleles may be introduced into the population, although these have not been leveraged to explore the disease in general samples. This paper describes a framework to find high impact genes for schizophrenia. This study consists of two different datasets. First, whole exome sequencing was conducted to identify disruptive de novo mutations in 14 complete parent-offspring trios with sporadic schizophrenia from Jerusalem, which identified 5 sporadic cases with de novo gene mutations in 5 different genes (PTPRG, TGM5, SLC39A13, BTK, CDKN3). Next, targeted exome capture of these genes was conducted in 48 well-characterized, unrelated, ethnically diverse schizophrenia cases, recruited and characterized by the same research team in New York (NY sample), which demonstrated extremely rare and potentially damaging variants in three of the five genes (MAF<0.01) in 12/48 cases (25%); including PTPRG (5 cases), SCL39A13 (4 cases) and TGM5 (4 cases), a higher number than usually identified by whole exome sequencing. Cases differed in cognition and illness features based on which mutation-enriched gene they carried. Functional de novo mutations in protein-interaction domains in sporadic schizophrenia can illuminate risk genes that increase the propensity to develop schizophrenia across ethnicities. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 20 | PeerJ 2015 -1 3: e1149 |
| PMID | 26290802 |
| Title | Selection in the dopamine receptor 2 gene: a candidate SNP study. |
| Abstract | Dopamine is a major neurotransmitter in the human brain and is associated with various diseases. schizophrenia, for example, is treated by blocking the dopamine receptors type 2. Shaner, Miller & Mintz (2004) stated that schizophrenia was the low fitness variant of a highly variable mental trait. We therefore explore whether the dopamine receptor 2 gene (DRD2) underwent any selection processes. We acquired genotype data of the 1,000 Genomes project (phase I), which contains 1,093 individuals from 14 populations. We included single nucleotide polymorphisms (SNPs) with two minor allele frequencies (MAFs) in the analysis: MAF over 0.05 and over 0.01. This is equivalent to 151 SNPs (MAF > 0.05) and 246 SNPs (MAF > 0.01) for DRD2. We used two different approaches (an outlier approach and a Bayesian approach) to detect loci under selection. The combined results of both approaches yielded nine (MAF > 0.05) and two candidate SNPs (MAF > 0.01), under balancing selection. We also found weak signs for directional selection on DRD2, but in our opinion these were too weak to draw any final conclusions on directional selection in DRD2. All candidates for balancing selection are in the intronic region of the gene and only one (rs12574471) has been mentioned in the literature. Two of our candidate SNPs are located in specific regions of the gene: rs80215768 lies within a promoter flanking region and rs74751335 lies within a transcription factor binding site. We strongly encourage research on our candidate SNPs and their possible effects. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 21 | Transl Psychiatry 2015 -1 5: e607 |
| PMID | 26196440 |
| Title | Analysis of exome sequence in 604 trios for recessive genotypes in schizophrenia. |
| Abstract | Genetic associations involving both rare and common alleles have been reported for schizophrenia but there have been no systematic scans for rare recessive genotypes using fully phased trio data. Here, we use exome sequencing in 604 schizophrenia proband-parent trios to investigate the role of recessive (homozygous or compound heterozygous) nonsynonymous genotypes in the disorder. The burden of recessive genotypes was not significantly increased in probands at either a genome-wide level or in any individual gene after adjustment for multiple testing. At a system level, probands had an excess of nonsynonymous compound heterozygous genotypes (minor allele frequency, MAF ? 1%) in voltage-gated sodium channels (VGSCs; eight in probands and none in parents, P = 1.5 × 10(-)(4)). Previous findings of multiple de novo loss-of-function mutations in this gene family, particularly SCN2A, in autism and intellectual disability provide biological and genetic plausibility for this finding. Pointing further to the involvement of VGSCs in schizophrenia, we found that these genes were enriched for nonsynonymous mutations (MAF ? 0.1%) in cases genotyped using an exome array, (5585 schizophrenia cases and 8103 controls), and that in the trios data, synaptic proteins interacting with VGSCs were also enriched for both compound heterozygosity (P = 0.018) and de novo mutations (P = 0.04). However, we were unable to replicate the specific association with compound heterozygosity at VGSCs in an independent sample of Taiwanese schizophrenia trios (N = 614). We conclude that recessive genotypes do not appear to make a substantial contribution to schizophrenia at a genome-wide level. Although multiple lines of evidence, including several from this study, suggest that rare mutations in VGSCs contribute to the disorder, in the absence of replication of the original findings regarding compound heterozygosity, this conclusion requires evaluation in a larger sample of trios. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |
| 22 | Schizophr Bull 2016 Mar 42: 288-300 |
| PMID | 26405221 |
| Title | Exome Sequence Data From Multigenerational Families Implicate AMPA Receptor Trafficking in Neurocognitive Impairment and Schizophrenia Risk. |
| Abstract | schizophrenia is a mental disorder characterized by impairments in behavior, thought, and neurocognitive performance. We searched for susceptibility loci at a quantitative trait locus (QTL) previously reported for abstraction and mental flexibility (ABF), a cognitive function often compromised in schizophrenia patients and their unaffected relatives. Exome sequences were determined for 134 samples in 8 European American families from the original linkage study, including 25 individuals with schizophrenia or schizoaffective disorder. At chromosome 5q32-35.3, we analyzed 407 protein-altering variants for association with ABF and schizophrenia status. For replication, significant, Bonferroni-corrected findings were tested against cognitive traits in Mexican American families (n = 959), as well as interrogated for schizophrenia risk using GWAS results from the Psychiatric Genomics Consortium (PGC). From the gene SYNPO, rs6579797 (MAF = 0.032) shows significant associations with ABF (P = .015) and schizophrenia (P = .040), as well as jointly (P = .0027). In the Mexican American pedigrees, rs6579797 exhibits significant associations with IQ (P = .011), indicating more global effects on neurocognition. From the PGC results, other SYNPO variants were identified with near significant effects on schizophrenia risk, with a local linkage disequilibrium block displaying signatures of positive selection. A second missense variant within the QTL, rs17551608 (MAF = 0.19) in the gene WWC1, also displays a significant effect on schizophrenia in our exome sequences (P = .038). Remarkably, the protein products of SYNPO and WWC1 are interaction partners involved in AMPA receptor trafficking, a brain process implicated in synaptic plasticity. Our study reveals variants in these genes with significant effects on neurocognition and schizophrenia risk, identifying a potential pathogenic mechanism for schizophrenia spectrum disorders. |
| SCZ Keywords | schizophrenia, schizophrenic, schizophrenics |