| 1 | Biol. Psychiatry 2000 Apr 47: 605-9 |
|---|---|
| PMID | 10745052 |
| Title | Ultradian rapid cycling in prepubertal and early adolescent bipolarity is not in transmission disequilibrium with val/met COMT alleles. |
| Abstract | Prepubertal children and early adolescents with bipolar disorders (PEA-BP) who participate in the ongoing study "Phenomenology and Course of Pediatric Bipolar Disorders" have a high prevalence of ultradian (within 24-hour periods) rapid cycling. Based on a case-control finding reported in bipolar (BP) adults of an association between rapid and ultradian rapid cycling with the low-activity allele of catechol-O-methyltransferase (l-COMT), study of linkage and linkage disequilibrium of l-COMT in the PEA-BP population seemed warranted. Genotypes on a subset of the larger PEA-BP sample, for whom TRIO blood collection was complete (i. e., probands and both of their biological parents), were used to perform transmission disequilibrium tests (TDTs). Diagnoses were established from a comprehensive battery that included WASH-U-KSADS (Washington University Kiddie Schedule for Affective Disorders and schizophrenia) given to both mothers and children and from consensus conferences. Probands with PEA-BP (N = 52) were 10.9 +/- 2.8 years old at index episode; had a mean age of BP onset at 8.0 +/- 3.8 years; were severely impaired, with a mean Children's Global Assessment Scale score of 44.5 +/- 8.9; and manifested the cardinal features of BP (84.6% had euphoric mood, 76.9% had grandiosity, and 57.7% had psychosis). Ultradian rapid cycling occurred in 75%. Genotyping of the single nucleotide polymorphism at COMT was performed using automated capillary electrophoresis single-strand conformational polymorphism with detection by laser-induced fluorescence. Transmission disequilibrium tests were not significant for preferential transmission of l-COMT for the ultradian rapid-cycling subgroup or for the entire PEA-BP sample. The lack of linkage disequilibrium between l-COMT and ultradian rapid cycling in the PEA-BP sample compared to reported findings of an association in case-control studies of adults is discussed in terms of age-specific developmentally relevant phenotypes, anticipatory mechanisms, and heterogeneity. Repeat TDT analyses after these PEA-BP probands reach their adult phenotypes will be informative. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Mol. Psychiatry 2000 Jan 5: 77-84 |
| PMID | 10673772 |
| Title | Family-based linkage disequilibrium mapping using SNP marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11. |
| Abstract | Family-based linkage disequilibrium mapping using SNP markers is expected to be a major route to the identification of susceptibility alleles for complex diseases. However there are a number of methodological issues yet to be resolved, including the handling of extended haplotype data and analysis of haplotype transmission in sib-pair or family TRIO samples. In the present study, we have analysed two dinucleotide repeat and six SNP markers at the COMT locus at chromosome 22q11, a region implicated in psychosis, for transmission distortion in 198 Chinese schizophrenic family TRIOs. When individual markers were analysed using the TDT, two showed modest evidence of transmission distortion (186C/T, P = 0.04; Val158Met, P = 0.01). Using haplotypes of paired markers analysed by the program TRANSMIT, the most significant P value was 0.001, for the Met158Val and 900ins/delC polymorphisms in the COMT gene. The global P value for the haplotypes of all six SNP markers tested was 0.004, largely a result of the excess transmission of two extended haplotypes which differed at the marker 408C/G. The exclusion of this marker from the analysis gave a global P value of 0.002 and produced a five marker haplotype system which was significant at P = 0.0006. This haplotype consisted of the alleles -287G:186C:Val158:900insC:ARVCF930C, which may represent a background haplotype for the transmission of a schizophrenia susceptibility allele at chromosome 22q11. Our results support the hypotheses that either COMT is itself a susceptibility gene, or more likely that this region of chromosome 22 contains a susceptibility gene that is in linkage disequilibrium with COMT alleles. Molecular Psychiatry (2000) 5, 77-84. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | Mol. Psychiatry 2000 Jan 5: 77-84 |
| PMID | 10673772 |
| Title | Family-based linkage disequilibrium mapping using SNP marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11. |
| Abstract | Family-based linkage disequilibrium mapping using SNP markers is expected to be a major route to the identification of susceptibility alleles for complex diseases. However there are a number of methodological issues yet to be resolved, including the handling of extended haplotype data and analysis of haplotype transmission in sib-pair or family TRIO samples. In the present study, we have analysed two dinucleotide repeat and six SNP markers at the COMT locus at chromosome 22q11, a region implicated in psychosis, for transmission distortion in 198 Chinese schizophrenic family TRIOs. When individual markers were analysed using the TDT, two showed modest evidence of transmission distortion (186C/T, P = 0.04; Val158Met, P = 0.01). Using haplotypes of paired markers analysed by the program TRANSMIT, the most significant P value was 0.001, for the Met158Val and 900ins/delC polymorphisms in the COMT gene. The global P value for the haplotypes of all six SNP markers tested was 0.004, largely a result of the excess transmission of two extended haplotypes which differed at the marker 408C/G. The exclusion of this marker from the analysis gave a global P value of 0.002 and produced a five marker haplotype system which was significant at P = 0.0006. This haplotype consisted of the alleles -287G:186C:Val158:900insC:ARVCF930C, which may represent a background haplotype for the transmission of a schizophrenia susceptibility allele at chromosome 22q11. Our results support the hypotheses that either COMT is itself a susceptibility gene, or more likely that this region of chromosome 22 contains a susceptibility gene that is in linkage disequilibrium with COMT alleles. Molecular Psychiatry (2000) 5, 77-84. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | Am. J. Med. Genet. 2002 Apr 114: 315-20 |
| PMID | 11920855 |
| Title | Investigation of linkage and association/linkage disequilibrium of HLA A-, DQA1-, DQB1-, and DRB1-alleles in 69 sib-pair- and 89 trio-families with schizophrenia. |
| Abstract | The hypothesis that HLA antigens confer susceptibility to schizophrenic disorders has been tested by studying linkage and association in a family sample with 69 sib-pair families. Suggestive evidence for linkage was obtained by nonparametric multipoint LOD score analysis with a maximum around DQB CAR (P = 0.0004), a microsatellite marker that is in linkage disequilibrium with the HLA antigen DQB1. Spurious evidence for negative association as calculated by the transmission disequilibrium test was found for HLA- DRB1*11 (chi-square = 11.72, corrected P value = 0.03) and for the haplotype DQB1*301-DQA1*501-DRB1*11 (chi-square = 11.3, corrected P value = 0.043). No evidence of association with these alleles was obtained in a sample of 89 TRIOs with schizophrenic offspring and parents. Our results are not in favor of a direct involvement of the HLA system in development of schizophrenia, but are compatible with the possible existence of a susceptibility gene in the MHC region at chromosome 6p 21.31. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Am. J. Med. Genet. 2002 Apr 114: 315-20 |
| PMID | 11920855 |
| Title | Investigation of linkage and association/linkage disequilibrium of HLA A-, DQA1-, DQB1-, and DRB1-alleles in 69 sib-pair- and 89 trio-families with schizophrenia. |
| Abstract | The hypothesis that HLA antigens confer susceptibility to schizophrenic disorders has been tested by studying linkage and association in a family sample with 69 sib-pair families. Suggestive evidence for linkage was obtained by nonparametric multipoint LOD score analysis with a maximum around DQB CAR (P = 0.0004), a microsatellite marker that is in linkage disequilibrium with the HLA antigen DQB1. Spurious evidence for negative association as calculated by the transmission disequilibrium test was found for HLA- DRB1*11 (chi-square = 11.72, corrected P value = 0.03) and for the haplotype DQB1*301-DQA1*501-DRB1*11 (chi-square = 11.3, corrected P value = 0.043). No evidence of association with these alleles was obtained in a sample of 89 TRIOs with schizophrenic offspring and parents. Our results are not in favor of a direct involvement of the HLA system in development of schizophrenia, but are compatible with the possible existence of a susceptibility gene in the MHC region at chromosome 6p 21.31. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Am. J. Hum. Genet. 2002 Dec 71: 1312-9 |
| PMID | 12439825 |
| Title | RHD maternal-fetal genotype incompatibility increases schizophrenia susceptibility. |
| Abstract | Fetal events and obstetric complications are associated with schizophrenia. Here we report the results of a family-based candidate-gene study that assesses the role of maternal-fetal genotype incompatibility at the RHD locus in schizophrenia. We adapted the case-parent-TRIO log-linear modeling approach to test for RHD maternal-fetal genotype incompatibility and to distinguish this effect from a high-risk allele at or near the RHD locus and from a direct maternal effect alone. Eighty-eight patient-parent TRIOs, 72 patient-mother pairs, and 21 patient-father pairs were genotyped at the RHD locus. Of the 181 patients, 62% were male and 81% were second born or later. Only three patients were born after prophylaxis against maternal isoimmunization had become common practice. There was significant evidence for an RHD maternal-fetal genotype incompatibility, and the incompatibility parameter was estimated at 2.6. There was no evidence to support linkage/association with schizophrenia at or near the RHD locus nor any evidence to support the role of maternal genotype effect alone. Our results replicate previous findings that implicate the RHD locus in schizophrenia, and the candidate-gene design of this study allows the elimination of alternative explanations for the role of this locus in disease. Thus, the present study provides increasing evidence that the RHD locus increases schizophrenia risk through a maternal-fetal genotype incompatibility mechanism that increases risk of an adverse prenatal environment (e.g., Rh incompatibility) rather than through linkage/association with the disorder, linkage disequilibrium with an unknown nearby susceptibility locus, or a direct maternal effect alone. This is the first candidate-gene study to explicitly test for and provide evidence of a maternal-fetal genotype incompatibility mechanism in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2003 Aug 20: 342-4 |
| PMID | 12903048 |
| Title | [Transmission disequilibrium test of polymorphisms of serotonin transporter gene and schizophrenia based on family trios]. |
| Abstract | To investigate the relationship between two polymorphisms (Intronic VNTR and 5-HTTLPR) of the serotonin transporter gene and schizophrenia. A set of 314 schizophrenic TRIO samples collected from Shanghai, Xi'an and Jilin regions of China independently was subjected to analysis of the polymorphisms by transmission/disequilibrium test(TDT). No significantly preferential transmission of any allele was detected from both polymorphisms investigated. The results suggest that the serotonin transporter gene is unlikely to have a major contribution to susceptibility to schizophrenia in Han Chinese population. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2003 Aug 20: 342-4 |
| PMID | 12903048 |
| Title | [Transmission disequilibrium test of polymorphisms of serotonin transporter gene and schizophrenia based on family trios]. |
| Abstract | To investigate the relationship between two polymorphisms (Intronic VNTR and 5-HTTLPR) of the serotonin transporter gene and schizophrenia. A set of 314 schizophrenic TRIO samples collected from Shanghai, Xi'an and Jilin regions of China independently was subjected to analysis of the polymorphisms by transmission/disequilibrium test(TDT). No significantly preferential transmission of any allele was detected from both polymorphisms investigated. The results suggest that the serotonin transporter gene is unlikely to have a major contribution to susceptibility to schizophrenia in Han Chinese population. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | Schizophr. Res. 2003 Dec 65: 19-25 |
| PMID | 14623370 |
| Title | Association of tumor necrosis factor alpha gene -G308A polymorphism with schizophrenia. |
| Abstract | Tumor necrosis factor alpha (TNFalpha), a cytokine involved in inflammatory processes, has been implicated in the pathophysiology of schizophrenia. The chromosomal location in the major histocompatibility complex (MHC) region on 6p21.1-21.3, a region with evidence for linkage, suggests a role in susceptibility to schizophrenia. Association of the minor (A) allele of the -G308A TNFalpha gene polymorphism with schizophrenia has been reported [Mol. Psychiatry 6 (2001) 79]. Association of the -G308A TNFalpha gene and the lymphotoxin alpha (LTalpha)+A252G gene polymorphisms with schizophrenia was studied in 79 sib pair families with linkage in the MHC region and in 128 TRIO families using the transmission disequilibrium test (TDT). Weak association of the common G allele was detected for TNFalpha -G308A in both samples independently with borderline significance in the sib pair families (0.064) and with a nominally significant value of P=0.022 in the TRIO families. Combining both samples produced P=0.003, while LTalpha+A252G, located approximately 2-3 kb distally, revealed P=0.03 and the two locus haplotype yielded a P value of 0.001. Our data suggests association of the common G allele of the -G308A TNFalpha gene polymorphism with schizophrenia in a sample of 207 families. However, linkage disequilibrium with a different allele of the TNFalpha gene or another gene in the MHC region cannot be excluded. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | Neurosci. Lett. 2004 Dec 372: 200-3 |
| PMID | 15542240 |
| Title | Transmission disequilibrium analysis of the GSN gene in a cohort of family trios with schizophrenia. |
| Abstract | Apoptosis is thought to play a role in neuronal pathology in schizophrenia. Recently, the GSN gene was reported to have anti-apoptotic properties. In a genome-wide expression analysis on schizophrenia, GSN was also found to be significantly down-regulated in schizophrenia. All the hints suggest that GSN is a novel candidate gene in occurrence of schizophrenia. In this work, we genotyped 3 SNPs around the GSN locus in 493 sets of the Han Chinese TRIO sample using allele-specific PCR. A weak association or a marginally positive result was detected (0.05 for P-value of the overtransmitted haplotype and 0.02 for a global P-value). |
| SCZ Keywords | schizophrenia, schizophrenic |
| 11 | Mol. Psychiatry 2004 Jul 9: 698-704 |
| PMID | 15007393 |
| Title | Identification of a novel neuregulin 1 at-risk haplotype in Han schizophrenia Chinese patients, but no association with the Icelandic/Scottish risk haplotype. |
| Abstract | To 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 Keywords | schizophrenia, schizophrenic |
| 12 | Soc Psychiatry Psychiatr Epidemiol 2004 May 39: 386-96 |
| PMID | 15133596 |
| Title | Needs for care of chronic schizophrenic patients in long-term community treatment. |
| Abstract | Specific problems of long-term community care of chronic schizophrenic patients are an under-researched area interesting for the provision of regional mental health care. This study focuses on a 4 1/2-year prospective assessment of normative needs for care in a cohort (initially N = 115) living in the Dresden care region (Germany). At six time-points, normative needs for care were assessed with the Needs for Care Assessment (NFCAS). The total number of problems did not change significantly over the study period. The average number of met needs was lower at the longer-term follow-up assessments,due particularly to a decrease in the social section. This trend is also demonstrated for the average number of unmet needs. In contrast, the mean number of "unmeetable needs" increased. Consistently, 70-80% of the patients exhibit problems in positive psychotic and negative symptoms, household affairs and recreational activities. Communication, occupation and recreational activities constitute a TRIO of social needs not met for nearly one-third of the patients disabled in these respects. Logistic analyses of regression could not identify a predictive model for the total needs development within the 4 1/2-year community treatment. The rather stable pattern of needs for care seems to define clear long-lasting tasks for community mental health services. For chronic schizophrenic patients, services should especially focus on social skills training and psychoeducational approaches. Due to a wide range of possible factors of influence, however, planning long-term context-dependent processes of care in the community lacks a clear evidence base. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 13 | Eur. J. Hum. Genet. 2004 Mar 12: 192-8 |
| PMID | 14735156 |
| Title | RHD maternal-fetal genotype incompatibility and schizophrenia: extending the MFG test to include multiple siblings and birth order. |
| Abstract | Rh incompatibility disease (ie Rh hemolytic disease of the fetus and newborn) has been implicated as a risk factor for schizophrenia. Here, we extend the maternal-fetal genotype incompatibility (MFG) test used in an earlier case-parent TRIO study that found significant evidence for an increased risk of schizophrenia in RHD MFG-incompatible children. We modify the MFG test for case-parent TRIOs to include any number of siblings. This modified test enables us to use more of the available data from the earlier study. The increased sample size not only gives us greater power to test for MFG incompatibility but it also enables us to model the impact of previous RHD MFG-incompatible pregnancies on the relative risk of RHD MFG incompatibility in later-born siblings. This modeling is important, because RHD MFG incompatibility is a proxy for Rh incompatibility disease, and the risk of Rh incompatibility disease increases with the number of previous RHD MFG-incompatible pregnancies. The best-fitting models are consistent with the hypothesized effect that previous incompatible pregnancies increase the risk of schizophrenia due to RHD MFG incompatibility. There was significant evidence that the relative risk of schizophrenia in the second- and later-born RHD MFG-incompatible children is 1.7, consistent with earlier estimates. Our extension of the MFG test has general application to family-based studies of maternal-genotype and MFG interaction effects. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 14 | Genet. Epidemiol. 2004 Jan 26: 70-80 |
| PMID | 14691958 |
| Title | Bayesian trio models for association in the presence of genotyping errors. |
| Abstract | Errors in genotyping can greatly affect family-based association studies. If a mendelian inconsistency is detected, the family is usually removed from the analysis. This reduces power, and may introduce bias. In addition, a large proportion of genotyping errors remain undetected, and these also reduce power. We present a Bayesian framework for performing association studies with SNP data on samples of TRIOs consisting of parents with an affected offspring, while allowing for the presence of both detectable and undetectable genotyping errors. This framework also allows for the inclusion of missing genotypes. Associations between the SNP and disease were modelled in terms of the genotypic relative risks. The performances of the analysis methods were investigated under a variety of models for disease association and genotype error, looking at both power to detect association and precision of genotypic relative risk estimates. As expected, power to detect association decreased as genotyping error probability increased. Importantly, however, analyses allowing for genotyping error had similar power to standard analyses when applied to data without genotyping error. Furthermore, allowing for genotyping error yielded relative risk estimates that were approximately unbiased, together with 95% credible intervals giving approximately correct coverage. The methods were also applied to a real dataset: a sample of schizophrenia cases and their parents genotyped at SNPs in the dysbindin gene. The analysis methods presented here require no prior information on the genotyping error probabilities, and may be fitted in WinBUGS. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 15 | Biochem. Biophys. Res. Commun. 2005 Nov 336: 1136-43 |
| PMID | 16168956 |
| Title | Functional polymorphisms of HSPA5: possible association with bipolar disorder. |
| Abstract | Altered endoplasmic reticulum stress (ER) response signaling is suggested in bipolar disorder. Previously, we preliminarily reported the genetic association of HSPA5 (GRP78/BiP) with bipolar disorder. Here, we extended our analysis by increasing the number of Japanese case-control samples and NIMH Genetics Initiative bipolar TRIO samples (NIMH TRIOs), and also analyzed schizophrenia samples. In Japanese, nominally significant association of one haplotype was observed in extended samples of bipolar disorder but not in schizophrenia. In NIMH TRIOs, no association was found in total samples. However, an exploratory analysis suggested that the other haplotype was significantly over-transmitted to probands only from the paternal side. The associated haplotype in Japanese or NIMH pedigrees shared three common polymorphisms in the promotor, which was found to alter promotor activity. These findings suggested promotor polymorphisms of HSPA5 may affect the interindividual variability of ER stress response and may confer a genetic risk factor for bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 16 | Genes Brain Behav. 2005 Oct 4: 444-8 |
| PMID | 16176390 |
| Title | Association analysis of the RGS4 gene in Han Chinese and Scottish populations with schizophrenia. |
| Abstract | We investigated the RGS4 as a susceptibility gene for schizophrenia in Chinese Han (184 TRIOs and 138 sibling pairs, a total of 322 families) and Scottish (580 cases and 620 controls) populations using both a family TRIO and case-control design. Both the samples had statistical power greater than 70% to detect a heterozygote genotype relative risk of >1.2 for frequent RGS4-risk alleles. We genotyped four single nucleotide polymorphisms (SNPs) which have previously been associated with schizophrenia as either individually or part of haplotypes. Allele frequencies and linkage disequilibrium between the SNPs was similar in the two populations. In the Chinese sample, no individual SNPs or any of their haplotypes were associated with schizophrenia. In the Scottish population, one SNP (SNP7) was significantly over-represented in the cases compared with the controls (0.44 vs. 0.38; A allele; chi(2) 7.08, P = 0.011 after correction for correlation between markers by permutation testing). One two-marker haplotype, composed of alleles T and A of SNP4 and SNP7, respectively, showed individual significance after correction by permutation testing (chi(2) 6.8; P = 0.04). None of the full four-marker haplotypes showed association, including the G-G-G-G haplotype previously associated with schizophrenia in more than one sample and the A-T-A-A haplotype. Thus, our data do not directly replicate previous associations of RGS4, but association with SNP 7 in the Scottish population provides some support for a role in schizophrenia susceptibility. We cannot conclusively exclude RGS4, as associated haplotypes are likely to be surrogates for unknown causative alleles, whose relationship with overlying haplotypes may differ between the population groups. Differences in the association seen across the two populations could result from methodological factors such as diagnostic differences but most likely result from ethnic differences in haplotype structures within RGS4. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 17 | Psychiatr. Genet. 2006 Oct 16: 197-203 |
| PMID | 16969274 |
| Title | No evidence for association between NOTCH4 and schizophrenia in a large family-based and case-control association analysis. |
| Abstract | An analysis of 80 British parent-offspring TRIOs by Wei and Hemmings in 2000 revealed thre1e out of five markers within the NOTCH4 locus to be strongly associated with schizophrenia. In our present study, we have examined NOTCH4 markers in large samples of German and Palestinian-Arab origin. Our study population comprised a German case-control sample (n=512 schizophrenia patients and n=232 controls) and two independent parent-offspring TRIO samples of German (n=159 TRIOs) and Palestinian-Arab (n=208 TRIOs) descent. We examined a total of ten single nucleotide polymorphisms within the NOTCH4 locus and the adjacent loci, spanning a region of approximately 100 kb. Neither single marker nor haplotype analyses showed association with schizophrenia. In addition, analyses of the German case-control and TRIO samples revealed no significant association between NOTCH4 polymorphisms and early-onset schizophrenia. Our results suggest that NOTCH4 is unlikely to play a major role in the genetic predisposition to schizophrenia in the German or the Palestinian-Arab population. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 18 | Arch. Gen. Psychiatry 2006 Aug 63: 844-54 |
| PMID | 16894060 |
| Title | Genetic association and brain morphology studies and the chromosome 8p22 pericentriolar material 1 (PCM1) gene in susceptibility to schizophrenia. |
| Abstract | There is evidence of linkage to a schizophrenia susceptibility locus on chromosome 8p21-22 found by several family linkage studies. To fine map and identify a susceptibility gene for schizophrenia on chromosome 8p22 and to investigate the effect of this genetic susceptibility on an endophenotype of abnormal brain structure using magnetic resonance imaging. Fine mapping and identification of a chromosome 8p22 susceptibility gene was carried out by finding linkage disequilibrium between genetic markers and schizophrenia in multiply affected families, a case-control sample, and a TRIO sample. Variation in brain morphology associated with pericenTRIOlar material 1 (PCM1) alleles was examined using voxel-based morphometry and statistical parametric mapping with magnetic resonance imaging. Setting and Patients A family sample of 13 large families multiply affected with schizophrenia, 2 schizophrenia case-control samples from the United Kingdom and Scotland, and a sample of schizophrenic TRIOs from the United States containing parents and 1 affected child with schizophrenia. Tests of transmission disequilibrium between PCM1 locus polymorphisms and schizophrenia using a family sample and tests of allelic association in case-control and TRIO samples. Voxel-based morphometry using statistical parametric mapping. The family and TRIO samples both showed significant transmission disequilibrium between marker D85261 in the PCM1 gene locus and schizophrenia. The case-control sample from the United Kingdom also found significant allelic association between PCM1 gene markers and schizophrenia. Voxel-based morphometry of cases who had inherited a PCM1 genetic susceptibility showed a significant relative reduction in the volume of orbitofrontal cortex gray matter in comparison with patients with non-PCM1-associated schizophrenia, who, by contrast, showed gray matter volume reduction in the temporal pole, hippocampus, and inferior temporal cortex. The PCM1 gene is implicated in susceptibility to schizophrenia and is associated with orbitofrontal gray matter volumetric deficits. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 19 | Arch. Gen. Psychiatry 2006 Aug 63: 844-54 |
| PMID | 16894060 |
| Title | Genetic association and brain morphology studies and the chromosome 8p22 pericentriolar material 1 (PCM1) gene in susceptibility to schizophrenia. |
| Abstract | There is evidence of linkage to a schizophrenia susceptibility locus on chromosome 8p21-22 found by several family linkage studies. To fine map and identify a susceptibility gene for schizophrenia on chromosome 8p22 and to investigate the effect of this genetic susceptibility on an endophenotype of abnormal brain structure using magnetic resonance imaging. Fine mapping and identification of a chromosome 8p22 susceptibility gene was carried out by finding linkage disequilibrium between genetic markers and schizophrenia in multiply affected families, a case-control sample, and a TRIO sample. Variation in brain morphology associated with pericenTRIOlar material 1 (PCM1) alleles was examined using voxel-based morphometry and statistical parametric mapping with magnetic resonance imaging. Setting and Patients A family sample of 13 large families multiply affected with schizophrenia, 2 schizophrenia case-control samples from the United Kingdom and Scotland, and a sample of schizophrenic TRIOs from the United States containing parents and 1 affected child with schizophrenia. Tests of transmission disequilibrium between PCM1 locus polymorphisms and schizophrenia using a family sample and tests of allelic association in case-control and TRIO samples. Voxel-based morphometry using statistical parametric mapping. The family and TRIO samples both showed significant transmission disequilibrium between marker D85261 in the PCM1 gene locus and schizophrenia. The case-control sample from the United Kingdom also found significant allelic association between PCM1 gene markers and schizophrenia. Voxel-based morphometry of cases who had inherited a PCM1 genetic susceptibility showed a significant relative reduction in the volume of orbitofrontal cortex gray matter in comparison with patients with non-PCM1-associated schizophrenia, who, by contrast, showed gray matter volume reduction in the temporal pole, hippocampus, and inferior temporal cortex. The PCM1 gene is implicated in susceptibility to schizophrenia and is associated with orbitofrontal gray matter volumetric deficits. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 20 | Hum. Mol. Genet. 2006 Nov 15: 3329-42 |
| PMID | 17030554 |
| Title | Haplotypes spanning SPEC2, PDZ-GEF2 and ACSL6 genes are associated with schizophrenia. |
| Abstract | Chromosome 5q22-33 is a region where studies have repeatedly found evidence for linkage to schizophrenia. In this report, we took a stepwise approach to systematically map this region in the Irish Study of High Density schizophrenia Families (ISHDSF, 267 families, 1337 subjects) sample. We typed 289 SNPs in the critical interval of 8 million basepairs and found a 758 kb interval coding for the SPEC2/PDZ-GEF2/ACSL6 genes to be associated with the disease. Using sex and genotype-conditioned transmission disequilibrium test analyses, we found that 19 of the 24 typed markers were associated with the disease and the associations were sex-specific. We replicated these findings with an Irish case-control sample (657 cases and 414 controls), an Irish parent-proband TRIO sample (187 families, 564 subjects), a German nuclear family sample (211 families, 751 subjects) and a Pittsburgh nuclear family sample (247 families, 729 subjects). In all four samples, we replicated the sex-specific associations at the levels of both individual markers and haplotypes using sex- and genotype-conditioned analyses. Three risk haplotypes were identified in the five samples, and each haplotype was found in at least two samples. Consistent with the discovery of multiple estrogen-response elements in this region, our data showed that the impact of these haplotypes on risk for schizophrenia differed in males and females. From these data, we concluded that haplotypes underlying the SPEC2/PDZ-GEF2/ACSL6 region are associated with schizophrenia. However, due to the extended high LD in this region, we were unable to distinguish whether the association signals came from one or more of these genes. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 21 | Schizophr. Res. 2006 Oct 87: 32-44 |
| PMID | 16887335 |
| Title | Project among African-Americans to explore risks for schizophrenia (PAARTNERS): recruitment and assessment methods. |
| Abstract | The Project among African-Americans to Explore Risks for schizophrenia (PAARTNERS) is a multi-site, NIMH-funded study that seeks to identify genetic polymorphisms that confer susceptibility to schizophrenia among African-Americans by linkage mapping and targeted association analyses. Because deficits in certain dimensions of cognitive ability are thought to underlie liability to schizophrenia, the project also examines cognitive abilities in individuals affected by schizophrenia and their extended family members. This article describes PAARTNERS study design, ascertainment methods and preliminary sample characteristics. We aim to recruit a sample of 1260 African-American families, all of whom have at least one proband with schizophrenia or schizoaffective disorder. The data collection protocol includes a structured Diagnostic Interview for Genetic Studies, Family Interview for Genetic Studies, focused neurocognitive assessment, medical records review, and the collection of blood or buccal cells for genetic analyses. We have currently completed study procedures for 106 affected sib-pair, 457 case-parent TRIO and 23 multiplex families. A total of 289 probands have completed the best estimate final diagnosis process and 1153 probands and family members have been administered the computerized neuropsychological battery. This project lays the foundation for future analysis of cognitive and behavioral endophenotypes. This novel integration of diagnostic, neurocognitive and genetic data will also generate valuable information for future phenotypic and genetic studies of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 22 | Neurosci. Lett. 2007 May 417: 316-21 |
| PMID | 17346882 |
| Title | Association analysis of ATF4 and ATF5, genes for interacting-proteins of DISC1, in bipolar disorder. |
| Abstract | Disrupted in schizophrenia 1 (DISC1) and its molecular cascade are implicated in the pathophysiology of schizophrenia and bipolar disorder. As interacting-proteins with DISC1, Nudel, ATF4, ATF5, LIS1, alpha-tubulin, PDE4B, eIF3, FEZ1, Kendrin, MAP1A and MIPT3 were identified. We previously showed the down-regulation of ATF5 in the lymphoblastoid cells derived from affected co-twin of monozygotic twins discordant for bipolar disorder. We also suggested the contribution of endoplasmic reticulum stress response pathway to the illness, and ATF4 is one of major components in the pathway. Truncated mutant DISC1 reportedly cannot interact with ATF4 and ATF5. These findings suggest the role of these genes in the pathophysiology of bipolar disorder. In this study, we tested genetic association of ATF4 and ATF5 genes with bipolar disorder by a case-control study in Japanese population (438 patients and 532 controls) and transmission disequilibrium test in 237 TRIO samples from NIMH Genetics Initiative Pedigrees. We also performed gene expression analysis in lymphoblastoid cells. We did not find any significant association in both genetic study and expression analysis. By the exploratory haplotype analysis, nominal association of ATF4 with bipolar II patients was observed, but it was not significant after correction of multiple testing. Contribution of common variations of ATF4 and ATF5 to the pathophysiology of bipolar disorder may be minimal if any. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 23 | Mol. Psychiatry 2007 Mar 12: 273-82 |
| PMID | 17179997 |
| Title | Interleukin 3 and schizophrenia: the impact of sex and family history. |
| Abstract | Chromosome 5q21-33 has been implicated in harboring risk genes for schizophrenia. In this paper, we report evidence that multiple single nucleotide polymorphisms in and around interleukin 3 (IL3) are associated with the disease in the Irish Study of High-Density schizophrenia Families (ISHDSF), the Irish Case-Control Study of schizophrenia (ICCSS) and the Irish TRIO Study of schizophrenia (ITRIO). The associations are sex-specific and depend on the family history (FH) of schizophrenia. In all three samples, rs31400 shows female-specific and FH-dependent associations (P=0.0062, 0.0647 and 0.0284 for the ISHDSF, ICCSS and ITRIO, respectively). Several markers have similar associations in one or two of the three samples. In haplotype analyses, identical risk and protective haplotypes are identified in the ISHDSF and ITRIO samples in several multimarker combinations. For ICCSS, the same haplotypes are implicated; however, the risk haplotypes observed in the family samples become protective. Several significant markers, rs440970, rs31400 and rs2069803, are located in and around known estrogen response elements, promoter and enhancer of the IL3 gene. They may explain the sex-specific associations and be functional for the expression of IL3 gene. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 24 | Br. J. Pharmacol. 2007 May 151: 161-2 |
| PMID | 17375084 |
| Title | Optimisation of anti-psychotic therapeutics: a balancing act? |
| Abstract | schizophrenia is a complex and debilitating disorder. Although effective therapeutic strategies are available, these are not without problems and are not universally efficacious. In this issue of the British Journal of Pharmacology, a TRIO of papers describe the characterisation of a potential, novel anti-psychotic medication, F15063. This compound combines antagonism of dopamine D(2)-like receptors with agonism at 5-HT(1A) receptors. Based on in vitro and in vivo profiles, the authors suggest that this compound approaches the 'optimal balance' for activity at these receptor systems. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 25 | Neurosci. Lett. 2007 Apr 416: 96-100 |
| PMID | 17293043 |
| Title | Association of DAOA polymorphisms with schizophrenia and clinical symptoms or therapeutic effects. |
| Abstract | The present study examined the correlation between variants in the d-amino acid oxidase activator (DAOA) locus and clinical symptoms and response to antipsychotics in schizophrenia. Case-control analysis and the family-based association test (FBAT) were performed to investigate whether four single nucleotide polymorphisms (SNPs) at DAOA gene are associated with schizophrenia. The association between the DAOA risk haplotype and clinical symptoms were examined by the positive and negative syndrome scale (PANSS) and the brief psychiatric rating scale (BPRS). Our findings showed that the SNP rs947267 was significantly associated with schizophrenia in both case control and familial TRIO samples (A>C, chi(2)=8.36, p=0.004; Z=2.335, p=0.019), as well as with specific haplotypes, in particular those formed by the A allele of rs947267. In addition, the risk haplotype AAG was significantly correlated with negative, depression and cognitive impairment factors of PANSS, even with the BPRS change scores after 6-week treatment of atypical antipsychotic drugs (p<0.05). These results support the hypothesis that variations in DAOA may play a role in schizophrenia and clinical characteristics. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 26 | Schizophr. Res. 2007 Aug 94: 342-53 |
| PMID | 17561376 |
| Title | Polymorphisms in MICB are associated with human herpes virus seropositivity and schizophrenia risk. |
| Abstract | Viral infection may be a risk factor for schizophrenia and has been associated with decreased cognitive functioning in patients. We report associations of SNPs at MICB (MHC class I polypeptide-related sequence B, chromosome 6p21) with cytomegalovirus and herpes simplex virus 1 seropositivity. We previously found associations with schizophrenia on chromosome 6p21 among patients seropositive for cytomegalovirus (CMV) and herpes simplex virus 1 (HSV1). To localize the associations further, we genotyped 26 SNPs spanning 100 kb in a sample of 236 Caucasian schizophrenia patients and 240 controls. Based on suggestive associations, we selected five SNPs at MICB to assay among two additional Caucasian samples that had been serotyped for CMV and HSV1: a case-control sample recruited in Baltimore (n=272 cases, 108 controls), and a case-parent TRIO sample recruited in Pittsburgh (n=221). Among Baltimore control individuals there were significant associations with antibody status for infectious agents: rs1051788 with HSV1 seropositivity (p=0.006) and rs2523651 with cytomegalovirus seropositivity (p=0.001). The former association was also detectable among the parents of cases recruited in Pittsburgh (p=0.024). Neither viral association was noted among the schizophrenia cases. With respect to schizophrenia risk, significant transmission distortion was noted at rs1051788 and rs1055569 among the case-parent TRIOs regardless of antibody status (p=0.014 and 0.036 respectively). A similar trend for association with schizophrenia liability at rs1051788 in the Baltimore sample did not attain statistical significance. There are a number of explanations for the associations, including chance variation, as well as gene-virus interactions. Further replicate studies are warranted, as are functional studies of these polymorphisms. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 27 | Schizophr. Res. 2007 Feb 90: 302-7 |
| PMID | 17141478 |
| Title | Disruption of hippocampal connectivity in children and adolescents with schizophrenia--a voxel-based diffusion tensor imaging study. |
| Abstract | One hypothesis that unifies the diversity of symptoms associated with schizophrenia involves the disruption of connectivity between brain regions. As white matter provides rapid and efficient communication between brain regions, this study was initiated to assess the early disruption of white matter pathways in children and adolescent with schizophrenia. Diffusion tensor images were acquired on 14 children and adolescents with schizophrenia, one subject with schizoaffective disorder, and 15 age and gender matched controls. The DTI images were acquired in twelve directions on a 3 T Siemens TRIO scanner. The images were transformed into fractional anisotropy and mean diffusivity maps and a group analysis was performed using SPM2. Children and adolescent patients with schizophrenia demonstrated a significant decrease in FA and associated increase in AD in the left posterior hippocampus (p<0.001, Bonferroni corrected on the cluster-level). These diffusion differences were not statistically significant when IQ was used as a covariate in the analysis. These findings suggest hippocampal white matter abnormalities that present early in the development of schizophrenia. The lack of significant differences when IQ is used as a covariate suggests that this hippocampal region is associated with cognitive changes associated with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 28 | Biol. Psychiatry 2008 Dec 64: 1093-6 |
| PMID | 18708184 |
| Title | Neuregulin 3 genetic variations and susceptibility to schizophrenia in a Chinese population. |
| Abstract | The study investigated the possible association of NRG3 gene and schizophrenia in a Han Chinese population. Of a total of 1345, 270 unrelated schizophrenia inpatients, 235 normal control subjects, and 280 nuclear families (TRIOs) with schizophrenia probands were studied. Nine single nucleotide polymorphisms (SNPs) spanning intron 1 to exon 9 of the NRG3 gene were analyzed, starting with the case-control samples. The SNPs showing significant association with schizophrenia in the case-control samples were subsequently studied in the independent TRIO samples with family-based association analysis. In case-control samples, two SNPs (rs1937970 and rs677221) showed significant genotypic and allelic association with schizophrenia (all p < .05) with rs677221-C being the risk allele for schizophrenia (uncorrected p = .001, odds ratio = 1.439, 95% confidence interval = 1.115-1.858). Haplotypes GC constructed by the two SNPs was also significantly associated with schizophrenia (permutation p value = .0047). In the independent TRIO samples, rs1937970-A and rs677221-G consistently showed significant under-transmission to schizophrenic offspring (unadjusted p = .003 and p = .004, respectively). In the haplotype-transmission disequilibrium test (TDT) for allelic combination of rs1937970-rs677221, significant under-transmission for haplotype AG (uncorrected p = .006) and over-transmission for haplotype GC (uncorrected p = .004) to the affected schizophrenia offspring were observed. The result supports that the NRG3 gene is a susceptibility gene for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 29 | Biol. Psychiatry 2008 Dec 64: 1093-6 |
| PMID | 18708184 |
| Title | Neuregulin 3 genetic variations and susceptibility to schizophrenia in a Chinese population. |
| Abstract | The study investigated the possible association of NRG3 gene and schizophrenia in a Han Chinese population. Of a total of 1345, 270 unrelated schizophrenia inpatients, 235 normal control subjects, and 280 nuclear families (TRIOs) with schizophrenia probands were studied. Nine single nucleotide polymorphisms (SNPs) spanning intron 1 to exon 9 of the NRG3 gene were analyzed, starting with the case-control samples. The SNPs showing significant association with schizophrenia in the case-control samples were subsequently studied in the independent TRIO samples with family-based association analysis. In case-control samples, two SNPs (rs1937970 and rs677221) showed significant genotypic and allelic association with schizophrenia (all p < .05) with rs677221-C being the risk allele for schizophrenia (uncorrected p = .001, odds ratio = 1.439, 95% confidence interval = 1.115-1.858). Haplotypes GC constructed by the two SNPs was also significantly associated with schizophrenia (permutation p value = .0047). In the independent TRIO samples, rs1937970-A and rs677221-G consistently showed significant under-transmission to schizophrenic offspring (unadjusted p = .003 and p = .004, respectively). In the haplotype-transmission disequilibrium test (TDT) for allelic combination of rs1937970-rs677221, significant under-transmission for haplotype AG (uncorrected p = .006) and over-transmission for haplotype GC (uncorrected p = .004) to the affected schizophrenia offspring were observed. The result supports that the NRG3 gene is a susceptibility gene for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 30 | Schizophr. Res. 2008 Apr 101: 1-8 |
| PMID | 18282690 |
| Title | Failure to replicate the association between NRG1 and schizophrenia using Japanese large sample. |
| Abstract | Systematic linkage disequilibrium (LD) mapping of 8p12-21 in the Icelandic population identified neuregulin 1 (NRG1) as a prime candidate gene for schizophrenia. However, results of replication studies have been inconsistent, and no large sample analyses have been reported. Therefore, we designed this study with the aim of assessing this putative association between schizophrenia and NRG1 (especially HAP(ICE) region and exon region) using a gene-based association approach in the Japanese population. This study was a two-stage association analysis with a different panel of samples, in which the significant association found in the first-set screening samples (1126 cases and 1022 controls) was further assessed in the confirmation samples (1262 cases and 1172 controls, and 166 TRIO samples). In the first-set scan, 60 SNPs (49 tagging SNPs from HapMap database, four SNPs from other papers, and seven SNPs detected in the mutation scan) were examined. One haplotype showed a significant association in the first-set screening samples (Global P-value=0.0244, uncorrected). However, we could not replicate this association in the following independent confirmation samples. Moreover, we could not find sufficient evidence for association of the haplotype identified as being significant in the first-set samples by imputing ungenotyped SNPs from HapMap database. These results indicate that the positionally and functionally attractive regions of NRG1 are unlikely to contribute to susceptibility to schizophrenia in the Japanese population. Moreover, the nature of our results support that two-stage analysis with large sample size is appropriate to examine the susceptibility genes for common diseases. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 31 | Hum. Hered. 2009 -1 67: 163-73 |
| PMID | 19077434 |
| Title | Evidence for a role of the NOS1AP (CAPON) gene in schizophrenia and its clinical dimensions: an association study in a South American population isolate. |
| Abstract | Recent studies have implicated a region on chromosome 1q21-23, including the NOS1AP gene, in susceptibility to schizophrenia. However, replication studies have been inconsistent, a fact that could partly relate to the marked psychopathological heterogeneity of schizophrenia. The aim of this study is to evaluate association of polymorphisms in the NOS1AP gene region to schizophrenia, in patients from a South American population isolate, and to assess if these variants are associated with specific clinical dimensions of the disorder. We genotyped 24 densely spaced SNPs in the NOS1AP gene region in a schizophrenia TRIO sample. The transmission disequilibrium test (TDT) was applied to single marker and haplotype data. Association to clinical dimensions (identified by factor analysis) was evaluated using a quantitative transmission disequilibrium test (QTDT). We found significant association between eight SNPs in the NOS1AP gene region to schizophrenia (minimum p value = 0.004). The QTDT analysis of clinical dimensions revealed an association to a dimension consisting mainly of negative symptoms (minimum p value 0.001). Our findings are consistent with a role for NOS1AP in susceptibility to schizophrenia, especially for the 'negative syndrome' of the disorder. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 32 | Aust N Z J Psychiatry 2009 Jun 43: 561-70 |
| PMID | 19440889 |
| Title | Design and clinical characteristics of a homogeneous schizophrenia pedigree sample from Tamil Nadu, India. |
| Abstract | The genetic complexity of schizophrenia may be compounded by the diagnostic imprecision inherent in distinguishing schizophrenia from closely related mood and substance use disorders. Further complexity may arise from studying genetically and/or environmentally diverse ethnic groups. Reported here are the ascertainment, demographic features and clinical characteristics, of a diagnostically and ethnically homogeneous schizophrenia pedigree sample from Tamil Nadu, India. Also reported is the theoretical power to detect genetic linkage in the subset of affected sibling pairs. Affected sibling pair and TRIO pedigrees were identified by caste/ethnicity. Affected probands and siblings fulfilled DSM-IV criteria for schizophrenia or schizoaffective disorder. The present sample consisted of 159 affected sibling pairs and 187 parent-offspring TRIOs originating primarily from the Tamil Brahmin caste, but also incorporating pedigrees from genetically similar, geographically proximal caste groups. Consistent with previous studies in Tamil Nadu, a very low prevalence of affective psychoses such as schizoaffective disorder, was observed, with most affected individuals having schizophrenia (499/504). Also observed were extremely low rates of nicotine (12.4%), alcohol (1.1%) and illicit drug use (0%). Most affected individuals exhibited negative symptoms (>90%) and a severe, chronic course. All participants lived in the same geographic and climatic region and most affected individuals resided with close family members, increasing uniformity of the sociocultural environment. In affected sibling pairs, power to detect linkage to small-effect risk loci was modest, but this homogeneous sample may be enriched for loci of larger effect. This Indian schizophrenia sample exhibits diagnostic and ethnic homogeneity with high consistency of sociocultural environmental features. These characteristics should assist efforts to identify risk genes for schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 33 | Genet. Epidemiol. 2010 Jul 34: 396-406 |
| PMID | 20568257 |
| Title | Detection of SNP-SNP interactions in trios of parents with schizophrenic children. |
| Abstract | schizophrenia (SZ) is a heritable and complex psychiatric disorder with an estimated worldwide prevalence of about 1%. Research on the risk factors for SZ has thus far yielded few clues to causes, but has pointed to a heterogeneous etiology that likely involves multiple genes and gene-environment interactions. In this manuscript, we apply a novel method (TRIO logic regression, Li et al., 2009) to case-parent TRIO data from a SZ candidate gene study conducted on families of Ashkenazi Jewish descent, and demonstrate the method's ability to detect multi-gene models for SZ risk in the family-based design. In particular, we demonstrate how this method revealed a genotype-phenotype association that includes an allele without marginal effect. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 34 | Genet. Epidemiol. 2010 Jul 34: 396-406 |
| PMID | 20568257 |
| Title | Detection of SNP-SNP interactions in trios of parents with schizophrenic children. |
| Abstract | schizophrenia (SZ) is a heritable and complex psychiatric disorder with an estimated worldwide prevalence of about 1%. Research on the risk factors for SZ has thus far yielded few clues to causes, but has pointed to a heterogeneous etiology that likely involves multiple genes and gene-environment interactions. In this manuscript, we apply a novel method (TRIO logic regression, Li et al., 2009) to case-parent TRIO data from a SZ candidate gene study conducted on families of Ashkenazi Jewish descent, and demonstrate the method's ability to detect multi-gene models for SZ risk in the family-based design. In particular, we demonstrate how this method revealed a genotype-phenotype association that includes an allele without marginal effect. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 35 | Schizophr. Res. 2010 Sep 122: 53-62 |
| PMID | 20385471 |
| Title | Disturbed sexual dimorphism of brain activation during mental rotation in schizophrenia. |
| Abstract | Sex differences in visuo-spatial abilities have been well documented in the general population, but there are only a few inconsistent reports in schizophrenia. The purpose of the present study was to examine potential sex differences in performance and pattern of brain activations during mental rotation in schizophrenia patients relative to control participants. Thirty three schizophrenia patients (17 women and 16 men) were compared to thirty five healthy control participants (17 women and 18 men), while performing a classic mental rotation task (3-D figures). Blood oxygen level dependent (BOLD) echo-planar images were acquired on a 3-Tesla Siemens TRIO system. Random-effect analyses were performed using SPM5 (UK Wellcome Institute). Behavioural data revealed a diagnosis-by-sex interaction with healthy men (HM) performing significantly better than schizophrenia men (SZ-M) and no significant difference between healthy women (HW) and schizophrenia women (SZ-W). fMRI results revealed an overall similar pattern of extensive cerebral activations (in the parietal and lateral prefrontal cortex) and deactivations (in the medial prefrontal cortex) in HM and SZ-W during performance of the mental rotation versus control task. In contrast, both HW and SZ-M showed much more restricted activations and no significant deactivations. Sex differences in performance and cerebral activations during mental rotation in schizophrenia patients deviated significantly from what we observed in healthy volunteers. This finding supports and extends existing evidence of a disturbed sexual dimorphism in schizophrenia. Moreover, the results emphasize the importance of including both sexes in neurocognitive and neuroimaging studies of schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 36 | PLoS ONE 2011 -1 6: e20468 |
| PMID | 21674006 |
| Title | Genome-wide association study of schizophrenia in Japanese population. |
| Abstract | schizophrenia is a devastating neuropsychiatric disorder with genetically complex traits. Genetic variants should explain a considerable portion of the risk for schizophrenia, and genome-wide association study (GWAS) is a potentially powerful tool for identifying the risk variants that underlie the disease. Here, we report the results of a three-stage analysis of three independent cohorts consisting of a total of 2,535 samples from Japanese and Chinese populations for searching schizophrenia susceptibility genes using a GWAS approach. Firstly, we examined 115,770 single nucleotide polymorphisms (SNPs) in 120 patient-parents TRIO samples from Japanese schizophrenia pedigrees. In stage II, we evaluated 1,632 SNPs (1,159 SNPs of p<0.01 and 473 SNPs of p<0.05 that located in previously reported linkage regions). The second sample consisted of 1,012 case-control samples of Japanese origin. The most significant p value was obtained for the SNP in the ELAVL2 [(embryonic lethal, abnormal vision, Drosophila)-like 2] gene located on 9p21.3 (p?=?0.00087). In stage III, we scrutinized the ELAVL2 gene by genotyping gene-centric tagSNPs in the third sample set of 293 family samples (1,163 individuals) of Chinese descent and the SNP in the gene showed a nominal association with schizophrenia in Chinese population (p?=?0.026). The current data in Asian population would be helpful for deciphering ethnic diversity of schizophrenia etiology. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 37 | Proc. Natl. Acad. Sci. U.S.A. 2011 Apr 108: 5861-6 |
| PMID | 21422296 |
| Title | Disrupted-in-Schizophrenia 1-mediated axon guidance involves TRIO-RAC-PAK small GTPase pathway signaling. |
| Abstract | Defects in neuronal connectivity of the brain are well documented among schizophrenia patients. Although the schizophrenia susceptibility gene Disrupted-in-schizophrenia 1 (DISC1) has been implicated in various neurodevelopmental processes, its role in regulating axonal connections remains elusive. Here, a heterologous DISC1 transgenic system in the relatively simple and well-characterized Caenorhabditis elegans motor neurons has been established to investigate whether DISC1 regulates axon guidance during development. Transgenic DISC1 in C. elegans motor neurons is enriched in the migrating growth cones and causes guidance defects of their growing axons. The abnormal axonal phenotypes induced by DISC1 are similar to those by gain-of-function rac genes. In vivo genetic interaction studies revealed that the UNC-73/TRIO-RAC-PAK signaling pathway is activated by ectopic DISC1 in C. elegans motor axons. Using in vitro GST pull-down and coimmunoprecipitation assays, we found that DISC1 binds specifically to the amino half of spectrin repeats of TRIO, thereby preventing TRIO's amino half of spectrin repeats from interacting with its first guanine nucleotide exchange factor (GEF) domain, GEF1, and facilitating the recruitment of RAC1 to TRIO. In cultured mammalian cells, RAC1 is activated by increased TRIO's GEF activity when DISC1 is present. These results together indicate that the TRIO-RAC-PAK signaling pathway can be exploited and modulated by DISC1 to regulate axonal connectivity in the developing brain. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 38 | Mol. Psychiatry 2011 Jan 16: 59-66 |
| PMID | 20048749 |
| Title | Expanding the range of ZNF804A variants conferring risk of psychosis. |
| Abstract | A TRIO of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 × 10(-8)) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 × 10(-7), and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 × 10(-8). In this study, using 5164 schizophrenia cases and 20,709 controls, we replicated the association with schizophrenia (odds ratio OR = 1.08, P = 0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N = 609, OR = 1.09, P = 0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]-common and with low relative risk-may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39,481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P = 0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P = 0.0016 for association with the larger set of psychiatric disorders). |
| SCZ Keywords | schizophrenia, schizophrenic |
| 39 | Schizophr. Res. 2012 Nov 141: 274-6 |
| PMID | 22986046 |
| Title | Absence of de novo point mutations in exons of GRIN2B in a large schizophrenia trio sample. |
| Abstract | -1 |
| SCZ Keywords | schizophrenia, schizophrenic |
| 40 | Am. J. Hum. Genet. 2012 Oct 91: 597-607 |
| PMID | 23040492 |
| Title | Discovery and statistical genotyping of copy-number variation from whole-exome sequencing depth. |
| Abstract | Sequencing of gene-coding regions (the exome) is increasingly used for studying human disease, for which copy-number variants (CNVs) are a critical genetic component. However, detecting copy number from exome sequencing is challenging because of the noncontiguous nature of the captured exons. This is compounded by the complex relationship between read depth and copy number; this results from biases in targeted genomic hybridization, sequence factors such as GC content, and batching of samples during collection and sequencing. We present a statistical tool (exome hidden Markov model [XHMM]) that uses principal-component analysis (PCA) to normalize exome read depth and a hidden Markov model (HMM) to discover exon-resolution CNV and genotype variation across samples. We evaluate performance on 90 schizophrenia TRIOs and 1,017 case-control samples. XHMM detects a median of two rare (<1%) CNVs per individual (one deletion and one duplication) and has 79% sensitivity to similarly rare CNVs overlapping three or more exons discovered with microarrays. With sensitivity similar to state-of-the-art methods, XHMM achieves higher specificity by assigning quality metrics to the CNV calls to filter out bad ones, as well as to statistically genotype the discovered CNV in all individuals, yielding a TRIO call set with Mendelian-inheritance properties highly consistent with expectation. We also show that XHMM breakpoint quality scores enable researchers to explicitly search for novel classes of structural variation. For example, we apply XHMM to extract those CNVs that are highly likely to disrupt (delete or duplicate) only a portion of a gene. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 41 | Hum Brain Mapp 2012 Aug 33: 1803-11 |
| PMID | 21674696 |
| Title | Evidence for intact local connectivity but disrupted regional function in the occipital lobe in children and adolescents with schizophrenia. |
| Abstract | It has long been known that specific visual frequencies result in greater blood flow to the striate cortex. These peaks are thought to reflect synchrony of local neuronal firing that is reflective of local cortical networks. Since disrupted neural connectivity is a possible etiology for schizophrenia, our goal was to investigate whether localized connectivity, as measured by aberrant synchrony, is abnormal in children and adolescents with schizophrenia. Subjects included 25 children and adolescents with schizophrenia and 39 controls matched for age and gender. Subjects were scanned on a Siemens 3 Tesla TRIO scanner while observing flashing checkerboard presented at either 1, 4, 8, or 12 Hz. Image processing included both a standard GLM model and a Fourier transform analysis. Patients had significantly smaller volume of activation in the occipital lobe compared to controls. There were no differences in the integral or percent signal change of the hemodynamic response function for each of the four frequencies. Occipital activation was stable during development between childhood and late adolescence. Finally, both patients and controls demonstrated an increased response between 4 and 8 Hz consistent with synchrony or entrainment in the neuronal response. Children and adolescents with schizophrenia had a significantly lower volume of activation in the occipital lobe in response to the flashing checkerboard task. However, features of intact local connectivity in patients, such as the hemodynamic response function and maximal response at 8 Hz, were normal. These results are consistent with abnormalities in regional connectivity with preserved local connectivity in early-onset schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 42 | J Psychiatr Res 2013 Nov 47: 1615-22 |
| PMID | 23932573 |
| Title | Dopaminergic gene polymorphisms and cognitive function in a north Indian schizophrenia cohort. |
| Abstract | Associations of polymorphisms from dopaminergic neurotransmitter pathway genes have mostly been reported in Caucasian ancestry schizophrenia (SZ) samples. As studies investigating single SNPs with SZ have been inconsistent, more detailed analyses utilizing multiple SNPs with the diagnostic phenotype as well as cognitive function may be more informative. Therefore, these analyses were conducted in a north Indian sample. Indian SZ case-parent TRIOs (n = 601 families); unscreened controls (n = 468) and an independent set of 118 TRIO families were analyzed. Representative SNPs in the Dopamine D3 receptor (DRD3), dopamine transporter (SLC6A3), vesicular monoamine transporter 2 (SLC18A2), catechol-o-methyltransferase (COMT) and dopamine beta-hydroxylase (DBH) were genotyped using SNaPshot/SNPlex assays (n = 59 SNPs). The Trail Making Test (TMT) was administered to a subset of the sample (n = 260 cases and n = 302 parents). Eight SNPs were nominally associated with SZ in either case-control or family based analyses (p < 0.05, rs7631540 and rs2046496 in DRD3; rs363399 and rs10082463 in SLC18A2; rs4680, rs4646315 and rs9332377 in COMT). rs6271 at DBH was associated in both analyses. Haplotypes of DRD3 SNPs incorporating rs7631540-rs2134655-rs3773678-rs324030-rs6280-rs905568 showed suggestive associations in both case-parent and TRIO samples. At SLC18A2, rs10082463 was nominally associated with psychomotor performance and rs363285 with executive functions using the TMT but did not withstand multiple corrections. Suggestive associations with dopaminergic genes were detected in this study, but convincing links between dopaminergic polymorphisms and SZ or cognitive function were not observed. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 43 | Epigenetics 2014 Aug 9: 1101-7 |
| PMID | 24837210 |
| Title | MB-COMT promoter DNA methylation is associated with working-memory processing in schizophrenia patients and healthy controls. |
| Abstract | Many 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 Keywords | schizophrenia, schizophrenic |
| 44 | Hum Psychopharmacol 2014 Jan 29: 31-7 |
| PMID | 24155145 |
| Title | Interleukin 1 beta gene and risk of schizophrenia: detailed case-control and family-based studies and an updated meta-analysis. |
| Abstract | Interleukin-1 beta (IL-1?) has been implicated in the pathophysiology of schizophrenia. To assess whether the IL1B gene confers increased susceptibility to schizophrenia, we conducted case-control and family-based studies and an updated meta-analysis. We tested the association between IL1B and schizophrenia in 1229 case-control and 112 TRIO samples using 12 markers, including common tagging single nucleotide variations (SNVs) and a rare non-synonymous variation detected by resequencing the coding regions. We also performed a meta-analysis of rs16944 using a total of 8724 case-control and 201 TRIO samples from 16 independent populations. We found no significant associations between any of the 12 SNVs examined and schizophrenia in either case-control or TRIO samples. Moreover, our meta-analysis results showed no significant association between the common SNV, rs16944, and schizophrenia. The present study does not support a role for IL1B in schizophrenia susceptibility. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 45 | PLoS ONE 2014 -1 9: e111196 |
| PMID | 25333879 |
| Title | Aggregation of the protein TRIOBP-1 and its potential relevance to schizophrenia. |
| Abstract | We have previously proposed that specific proteins may form insoluble aggregates as a response to an illness-specific proteostatic dysbalance in a subset of brains from individuals with mental illness, as is the case for other chronic brain conditions. So far, established risk factors DISC1 and dysbindin were seen to specifically aggregate in a subset of such patients, as was a novel schizophrenia-related protein, CRMP1, identified through a condition-specific epitope discovery approach. In this process, antibodies are raised against the pooled insoluble protein fractions (aggregomes) of post mortem brain samples from schizophrenia patients, followed by epitope identification and confirmation using additional techniques. Pursuing this epitope discovery paradigm further, we reveal TRIO binding protein (TRIOBP) to be a major substrate of a monoclonal antibody with a high specificity to brain aggregomes from patients with chronic mental illness. TRIOBP is a gene previously associated with deafness which encodes for several distinct protein species, each involved in actin cytoskeletal dynamics. The 3' splice variant TRIOBP-1 is found to be the antibody substrate and has a high aggregation propensity when over-expressed in neuroblastoma cells, while the major 5' splice variant, TRIOBP-4, does not. Endogenous TRIOBP-1 can also spontaneously aggregate, doing so to a greater extent in cell cultures which are post-mitotic, consistent with aggregated TRIOBP-1 being able to accumulate in the differentiated neurons of the brain. Finally, upon expression in Neuroscreen-1 cells, aggregated TRIOBP-1 affects cell morphology, indicating that TRIOBP-1 aggregates may directly affect cell development, as opposed to simply being a by-product of other processes involved in major mental illness. While further experiments in clinical samples are required to clarify their relevance to chronic mental illness in the general population, TRIOBP-1 aggregates are thus implicated for the first time as a biological element of the neuropathology of a subset of chronic mental illness. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 46 | Psychiatr. Genet. 2014 Aug 24: 176-80 |
| PMID | 24842237 |
| Title | Anxiety disorders and anxiety-related traits and serotonin transporter gene-linked polymorphic region (5-HTTLPR) in adolescents: case-control and trio studies. |
| Abstract | The role of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) in anxiety disorder and anxiety-related traits is controversial. Besides this study, few studies have evaluated the triallelic genotype in adolescents. The aim of this study was to investigate whether anxiety disorders and anxiety-related traits are associated with 5-HTTLPR (biallelic and triallelic) in adolescents, integrating both case-control-based and family-based designs in a community sample. This is a cross-sectional community study of 504 individuals and their families: 225 adolescents (129 adolescents with anxiety disorder and 96 controls) and their biological families. We assessed psychiatric diagnosis using the Kiddie Schedule for Affective Disorders and schizophrenia. The Temperament and Character Inventory and the Resnick Behavioral Inhibition Scale were used to evaluate harm avoidance and behavioral inhibition. DNA was extracted from saliva and genotyped, including biallelic and triallelic 5-HTTLPR classification, by PCR-RFLP followed by agarose gel electrophoresis. We were not able to find any associations between 5-HTTLPR and anxiety-related phenotypes in both case-control and TRIO analyses. Further investigation and meta-analytic studies are needed to better clarify the inconsistent results with regard to the association between 5-HTTLPR and anxiety-related phenotypes in adolescents. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 47 | J. Neuroimmunol. 2015 Aug 285: 62-7 |
| PMID | 26198920 |
| Title | Family-based association study of interleukin 6 (IL6) and its receptor (IL6R) functional polymorphisms in schizophrenia in the Polish population. |
| Abstract | schizophrenia is a heterogeneous disorder and its etiology remains incompletely elucidated. Among possible causes, immunological factors have been implicated in its pathogenesis and course. The inflammatory system may trigger or modulate the course of schizophrenia through complex mechanisms influencing neurodevelopment, neuroplasticity and neurotransmission. Recent studies indicate a role of excessive interleukin-6 (IL6) signaling in the pathogenesis of schizophrenia. Findings regarding changes in the circulating levels of soluble interleukin-6 receptor (sIL6R) in schizophrenia have been equivocal. The study was performed on a group of 147 TRIO (patients diagnosed with schizophrenia and their healthy parents). Polymorphisms of IL6 (rs1800795, rs1800797) and IL6R (rs4537545, rs4845617, rs2228145) genes were genotyped with the use of TaqMan SNP Genotyping Assays. No association of the polymorphisms from IL6 and IL6R genes with schizophrenia was found. We also investigated haplotypes in IL6 gene (consisting of rs1800795 and rs1800797) and in IL6R gene (consisting of rs4537545, rs2228145). We also found no preference in transmission of any haplotype. Our results do not support the theory that polymorphisms of IL6 and IL6R genes are involved in the pathogenesis of schizophrenia. It seems advisable to carry out further examinations of the role of these polymorphisms in schizophrenia by means of TDT method and classical (case-control) association method. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 48 | Schizophr. Res. 2015 Feb 161: 202-9 |
| PMID | 25480359 |
| Title | Investigation of Heschl's gyrus and planum temporale in patients with schizophrenia and bipolar disorder: a proton magnetic resonance spectroscopy study. |
| Abstract | Superior temporal cortices include brain regions dedicated to auditory processing and several lines of evidence suggest structural and functional abnormalities in both schizophrenia and bipolar disorder within this brain region. However, possible glutamatergic dysfunction within this region has not been investigated in adult patients. Thirty patients with schizophrenia (38.67±12.46years of age), 28 euthymic patients with bipolar I disorder (35.32±9.12years of age), and 30 age-, gender- and education-matched healthy controls were enrolled. Proton magnetic resonance spectroscopy data were acquired using a 3.0T Siemens MAGNETOM TIM TRIO MR system and single voxel Point REsolved Spectroscopy Sequence (PRESS) in order to quantify brain metabolites within the left and right Heschl's gyrus and planum temporale of superior temporal cortices. There were significant abnormalities in glutamate (Glu) (F(2,78)=8.52, p<0.0001), N-acetyl aspartate (tNAA) (F(2,81)=5.73, p=0.005), creatine (tCr) (F(2,83)=5.91, p=0.004) and inositol (Ins) (F(2,82)=8.49, p<0.0001) concentrations in the left superior temporal cortex. In general, metabolite levels were lower for bipolar disorder patients when compared to healthy participants. Moreover, patients with bipolar disorder exhibited significantly lower tCr and Ins concentrations when compared to schizophrenia patients. In addition, we have found significant correlations between the superior temporal cortex metabolites and clinical measures. As the left auditory cortices are associated with language and speech, left hemisphere specific abnormalities may have clinical significance. Our findings are suggestive of shared glutamatergic abnormalities in schizophrenia and bipolar disorder. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 49 | 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 |
| 50 | Am. J. Hum. Genet. 2015 Aug 97: 272-83 |
| PMID | 26235986 |
| Title | Incorporating Functional Information in Tests of Excess De Novo Mutational Load. |
| Abstract | A number of recent studies have investigated the role of de novo mutations in various neurodevelopmental and neuropsychiatric disorders. These studies attempt to implicate causal genes by looking for an excess load of de novo mutations within those genes. Current statistical methods for assessing this excess are based on the implicit assumption that all qualifying mutations in a gene contribute equally to disease. However, it is well established that different mutations can have radically different effects on the ultimate protein product and, as a result, on disease risk. Here, we propose a method, fitDNM, that incorporates functional information in a test of excess de novo mutational load. Specifically, we derive score statistics from a retrospective likelihood that incorporates the probability of a mutation being damaging to gene function. We show that, under the null, the resulting test statistic is distributed as a weighted sum of Poisson random variables and we implement a saddlepoint approximation of this distribution to obtain accurate p values. Using simulation, we have shown that our method outperforms current methods in terms of statistical power while maintaining validity. We have applied this approach to four de novo mutation datasets of neurodevelopmental and neuropsychiatric disorders: autism spectrum disorder, epileptic encephalopathy, schizophrenia, and severe intellectual disability. Our approach also implicates genes that have been implicated by existing methods. Furthermore, our approach provides strong statistical evidence supporting two potentially causal genes: SUV420H1 in autism spectrum disorder and TRIO in a combined analysis of the four neurodevelopmental and neuropsychiatric disorders investigated here. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 51 | Psychiatry Clin. Neurosci. 2015 Feb 69: 65-76 |
| PMID | 25319632 |
| Title | Whole genome/exome sequencing in mood and psychotic disorders. |
| Abstract | Recent developments in DNA sequencing technologies have allowed for genetic studies using whole genome or exome analysis, and these have been applied in the study of mood and psychotic disorders, including bipolar disorder, depression, schizophrenia, and schizoaffective disorder. In this review, the current situation, recent findings, methodological problems, and future directions of whole genome/exome analysis studies of these disorders are summarized. Whole genome/exome studies of bipolar disorder have included pedigree analysis and case-control studies, demonstrating the role of previously implicated pathways, such as calcium signaling, cyclic adenosine monophosphate response element binding protein (CREB) signaling, and potassium channels. Extensive analysis of TRIO families and case-control studies showed that de novo mutations play a role in the genetic architecture of schizophrenia and indicated that mutations in several molecular pathways, including chromatin regulation, activity-regulated cytoskeleton, post-synaptic density, N-methyl-D-aspartate receptor, and targets of fragile X mental retardation protein, are associated with this disorder. Depression is a heterogeneous group of diseases and studies using exome analysis have been conducted to identify rare mutations causing Mendelian diseases that accompany depression. In the near future, clarification of the genetic architecture of bipolar disorder and schizophrenia is expected. Identification of causative mutations using these new technologies will facilitate neurobiological studies of these disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 52 | Magn Reson Med 2016 Feb 75: 498-502 |
| PMID | 25762462 |
| Title | Reproducibility of phase rotation stimulated echo acquisition mode at 3T in schizophrenia: Emphasis on glutamine. |
| Abstract | To determine the reproducibility and reliability of glutamine (Gln), measured with a very short echo time phase rotation stimulated echo acquisition mode (VTE-PR STEAM) sequence at 3T, in subjects with schizophrenia. Seven subjects with schizophrenia were scanned twice with VTE-PR STEAM in a Siemens 3T TIM TRIO scanner with a 32-channel head coil. Spectroscopic data were collected from two voxels in gray matter, one in the dorsal anterior cingulate and the other in the medial occipital cortex. Reproducibility was assessed using coefficients of variation (CVs) and reliability with standard error of measurement and intraclass correlations (ICCs). Phantoms containing increasing concentrations of Gln in a physiologic solution of other neurometabolites with overlapping resonances were scanned to assess the validity of spectral Gln measurement. Very good reliability and reproducibility for Gln in both regions of interest were supported by CVs of ?10.0% and ICCs of ?0.6, respectively. Phantom studies documented a robust correspondence between known Gln concentrations and VTE-PR STEAM measurements of this metabolite (R(2) ?=?0.988). The VTE-PR STEAM approach at 3T permits the longitudinal assessment of Gln and other (1) H MR spectroscopy neurometabolites in a clinically plausible setting. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 53 | Mol. Psychiatry 2016 Feb 21: 290-7 |
| PMID | 25849321 |
| Title | Genes with de novo mutations are shared by four neuropsychiatric disorders discovered from NPdenovo database. |
| Abstract | Currently, many studies on neuropsychiatric disorders have utilized massive TRIO-based whole-exome sequencing (WES) and whole-genome sequencing (WGS) to identify numerous de novo mutations (DNMs). Here, we retrieved 17,104 DNMs from 3555 TRIOs across four neuropsychiatric disorders: autism spectrum disorder, epileptic encephalopathy, intellectual disability and schizophrenia, in addition to unaffected siblings (control), from 36 studies by WES/WGS. After eliminating non-exonic variants, we focused on 3334 exonic DNMs for evaluation of their association with these diseases. Our results revealed a higher prevalence of DNMs in the probands of all four disorders compared with the one in the controls (P<1.3 × 10(-7)). The elevated DNM frequency is dominated by loss-of-function/deleterious single-nucleotide variants and frameshift indels (that is, extreme mutations, P<4.5 × 10(-5)). With extensive annotation of these 'extreme' mutations, we prioritized 764 candidate genes in these four disorders. A combined analysis of Gene Ontology, microRNA targets and transcription factor targets revealed shared biological process and non-coding regulatory elements of candidate genes in the pathology of neuropsychiatric disorders. In addition, weighted gene co-expression network analysis of human laminar-specific neocortical expression data showed that candidate genes are convergent on eight shared modules with specific layer enrichment and biological process features. Furthermore, we identified that 53 candidate genes are associated with more than one disorder (P<0.000001), suggesting a possibly shared genetic etiology underlying these disorders. Particularly, DNMs of the SCN2A gene are frequently occurred across all four disorders. Finally, we constructed a freely available NPdenovo database, which provides a comprehensive catalog of the DNMs identified in neuropsychiatric disorders. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 54 | Mol. Psychiatry 2016 May -1: -1 |
| PMID | 27217147 |
| Title | Exome sequencing for bipolar disorder points to roles of de novo loss-of-function and protein-altering mutations. |
| Abstract | Although numerous genetic studies have been conducted for bipolar disorder (BD), its genetic architecture remains elusive. Here we perform, to the best of our knowledge, the first TRIO-based exome sequencing study for BD to investigate potential roles of de novo mutations in the disease etiology. We identified 71 de novo point mutations and one de novo copy-number mutation in 79 BD probands. Among the genes hit by de novo loss-of-function (LOF; nonsense, splice site or frameshift) or protein-altering (LOF, missense and inframe indel) mutations, we found significant enrichment of genes highly intolerant (first percentile of intolerant genes assessed by Residual Variation Intolerance Score) to protein-altering variants in general population, an observation that is also reported in autism and schizophrenia. When we performed a joint analysis using the data of schizoaffective disorder in published studies, we found global enrichment of de novo LOF and protein-altering mutations in the combined group of bipolar I and schizoaffective disorders. Considering relationship between de novo mutations and clinical phenotypes, we observed significantly earlier disease onset among the BD probands with de novo protein-altering mutations when compared with non-carriers. Gene ontology enrichment analysis of genes hit by de novo protein-altering mutations in bipolar I and schizoaffective disorders did not identify any significant enrichment. These results of exploratory analyses collectively point to the roles of de novo LOF and protein-altering mutations in the etiology of bipolar disorder and warrant further large-scale studies.Molecular Psychiatry advance online publication, 24 May 2016; doi:10.1038/mp.2016.69. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 55 | J. Med. Genet. 2016 Feb 53: 138-44 |
| PMID | 26566883 |
| Title | Homozygous missense mutation in the LMAN2L gene segregates with intellectual disability in a large consanguineous Pakistani family. |
| Abstract | Intellectual disability (ID) is a neurodevelopmental disorder affecting 1%-3% of the population worldwide. It is characterised by high phenotypic and genetic heterogeneity and in most cases the underlying cause of the disorder is unknown. In our study we investigated a large consanguineous family from Baluchistan, Pakistan, comprising seven affected individuals with a severe form of autosomal recessive ID (ARID) and epilepsy, to elucidate a putative genetic cause. Whole exome sequencing (WES) of a TRIO, including a child with ID and epilepsy and its healthy parents that were part of this large family, revealed a homozygous missense variant p.R53Q in the lectin mannose-binding 2-like (LMAN2L) gene. This homozygous variant was co-segregating in the family with the phenotype of severe ID and infantile epilepsy; unaffected family members were heterozygous variant carriers. The variant was predicted to be pathogenic by five different in silico programmes and further three-dimensional structure modelling of the protein suggests that variant p.R53Q may impair protein-protein interaction. LMAN2L (OMIM: 609552) encodes for the lectin, mannose-binding 2-like protein which is a cargo receptor in the endoplasmic reticulum important for glycoprotein transport. Genome-wide association studies have identified an association of LMAN2L to different neuropsychiatric disorders. This is the first report linking LMAN2L to a phenotype of severe ARID and seizures, indicating that the deleterious homozygous p.R53Q variant very likely causes the disorder. |
| SCZ Keywords | schizophrenia, schizophrenic |