1Nat. Genet. 2011 Oct 43: 969-76
TitleGenome-wide association study identifies five new schizophrenia loci.
AbstractWe examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 10(-9)), ANK3 (rs10994359, P = 2.5 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 10(-9)).
SCZ Keywordsschizophrenia
2Nat. Genet. 2011 Oct 43: 977-83
TitleLarge-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4.
AbstractWe conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 10(-7)). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci.
SCZ Keywordsschizophrenia
3Mol. Psychiatry 2013 Jun 18: 708-12
TitleGenome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC.
AbstractThe schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC) highlighted 81 single-nucleotide polymorphisms (SNPs) with moderate evidence for association to schizophrenia. After follow-up in independent samples, seven loci attained genome-wide significance (GWS), but multi-locus tests suggested some SNPs that did not do so represented true associations. We tested 78 of the 81 SNPs in 2640 individuals with a clinical diagnosis of schizophrenia attending a clozapine clinic (CLOZUK), 2504 cases with a research diagnosis of bipolar disorder, and 2878 controls. In CLOZUK, we obtained significant replication to the PGC-associated allele for no fewer than 37 (47%) of the SNPs, including many prior GWS major histocompatibility complex (MHC) SNPs as well as 3/6 non-MHC SNPs for which we had data that were reported as GWS by the PGC. After combining the new schizophrenia data with those of the PGC, variants at three loci (ITIH3/4, CACNA1C and SDCCAG8) that had not previously been GWS in schizophrenia attained that level of support. In bipolar disorder, we also obtained significant evidence for association for 21% of the alleles that had been associated with schizophrenia in the PGC. Our study independently confirms association to three loci previously reported to be GWS in schizophrenia, and identifies the first GWS evidence in schizophrenia for a further three loci. Given the number of independent replications and the power of our sample, we estimate 98% (confidence interval (CI) 78-100%) of the original set of 78 SNPs represent true associations. We also provide strong evidence for overlap in genetic risk between schizophrenia and bipolar disorder.
SCZ Keywordsschizophrenia
4Front Neurosci 2014 -1 8: 331
TitleNeuroinformatic analyses of common and distinct genetic components associated with major neuropsychiatric disorders.
AbstractMajor neuropsychiatric disorders are highly heritable, with mounting evidence suggesting that these disorders share overlapping sets of molecular and cellular underpinnings. In the current article we systematically test the degree of genetic commonality across six major neuropsychiatric disorders-attention deficit hyperactivity disorder (ADHD), anxiety disorders (Anx), autistic spectrum disorders (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). We curated a well-vetted list of genes based on large-scale human genetic studies based on the NHGRI catalog of published genome-wide association studies (GWAS). A total of 180 genes were accepted into the analysis on the basis of low but liberal GWAS p-values (<10(-5)). 22% of genes overlapped two or more disorders. The most widely shared subset of genes-common to five of six disorders-included ANK3, AS3MT, CACNA1C, CACNB2, CNNM2, CSMD1, DPCR1, ITIH3, NT5C2, PPP1R11, SYNE1, TCF4, TENM4, TRIM26, and ZNRD1. Using a suite of neuroinformatic resources, we showed that many of the shared genes are implicated in the postsynaptic density (PSD), expressed in immune tissues and co-expressed in developing human brain. Using a translational cross-species approach, we detected two distinct genetic components that were both shared by each of the six disorders; the 1st component is involved in CNS development, neural projections and synaptic transmission, while the 2nd is implicated in various cytoplasmic organelles and cellular processes. Combined, these genetic components account for 20-30% of the genetic load. The remaining risk is conferred by distinct, disorder-specific variants. Our systematic comparative analysis of shared and unique genetic factors highlights key gene sets and molecular processes that may ultimately translate into improved diagnosis and treatment of these debilitating disorders.
SCZ Keywordsschizophrenia
5J Affect Disord 2014 Jul 163: 110-4
TitleAssociation analysis between suicidal behaviour and candidate genes of bipolar disorder and schizophrenia.
AbstractThe present study investigated associations between the strongest joint genetic risk variants for bipolar disorder (BD) and schizophrenia (SCZ) and a history of suicide attempt in patients with BD, SCZ and related psychiatric disorders.
A history of suicide attempt was assessed in a sample of 1009 patients with BD, SCZ and related psychosis spectrum disorders, and associations with the joint genetic risk variants for BD and SCZ (rs2239547 (ITIH3/4-region), rs10994359 (ANK3) and rs4765905 (CACNA1C)) were investigated. Previously reported susceptibility loci for suicide attempt in BD were also investigated. Associations were tested by logistic regression with Bonferroni correction for multiple testing.
The risk allele in rs2239547 (ITIH3/4-region) was significantly associated with a history of suicide attempt (p=0.01) after multiple testing correction (p threshold<0.017). The previous suicide attempt susceptibility loci were only nominally associated, but had the same direction of risk in the replication sample (sign test, p=0.02).
Relatively small sample size and retrospective clinical assessment.
We detected a novel association between suicide attempt and the ITIH3/4-region in a combined group of patients with BD, SCZ and related psychosis spectrum disorders. This may be useful in understanding molecular mechanisms of suicidal behaviour in severe mental disorders, although replication is warranted.
SCZ Keywordsschizophrenia
6Int J Epidemiol 2014 Apr 43: 465-75
TitleRecent challenges to the psychiatric diagnostic nosology: a focus on the genetics and genomics of neurodevelopmental disorders.
AbstractRecent advances in the genetics of neurodevelopmental disorder (NDD) have demonstrated that rare mutations play a role not only in Mendelian syndromes, but in complex, common forms of NDDs as well. Strikingly, both common polymorphisms and rare variations in a single gene or genetic locus have been found to carry risk for conditions previously considered to be clinically and aetiologically distinct. Recent developments in the methods and tools available for studying complex NDDs have led to systematic and reliable genome-wide variant discovery. Both common as well as rare, and structural as well as sequence, genetic variations have been identified as contributing to NDDs. There are multiple examples in which the identical variant had been found to contribute to a wide range of formerly distinct diagnoses, including autism, schizophrenia, epilepsy, intellectual disability and language disorders. These include variations in chromosomal structure at 16p11.2, rare de novo point mutations at the gene SCN2A, and common single nucleotide polymorphisms (SNPs) mapping near loci encoding the genes ITIH3, AS3MT, CACNA1C and CACNB2. These selected examples point to the challenges to current diagnostic approaches. Widely used categorical schema have been adequate to provide an entr into molecular mechanisms of NDDs, but there is a need to develop an alternative, more biologically-relevant nosology. Thus recent advances in gene discovery in the area of NDDs are leading to a re-conceptualization of diagnostic boundaries. Findings suggest that epidemiological samples may provide important new insights into the genetics and diagnosis of NDDs and that other areas of medicine may provide useful models for developing a new diagnostic nosology, one that simultaneously integrates categorical diagnoses, biomarkers and dimensional variables.
SCZ Keywordsschizophrenia
7Transl Psychiatry 2014 -1 4: e426
TitleInvestigation of manic and euthymic episodes identifies state- and trait-specific gene expression and STAB1 as a new candidate gene for bipolar disorder.
AbstractBipolar disorder (BD) is a highly heritable psychiatric disease characterized by recurrent episodes of mania and depression. To identify new BD genes and pathways, the present study employed a three-step approach. First, gene-expression profiles of BD patients were assessed during both a manic and an euthymic phase. These profiles were compared intra-individually and with the gene-expression profiles of controls. Second, those differentially expressed genes that were considered potential trait markers of BD were validated using data from the Psychiatric Genomics Consortiums' genome-wide association study (GWAS) of BD. Third, the implicated molecular mechanisms were investigated using pathway analytical methods. In the present patients, this novel approach identified: (i) sets of differentially expressed genes specific to mania and euthymia; and (ii) a set of differentially expressed genes that were common to both mood states. In the GWAS data integration analysis, one gene (STAB1) remained significant (P=1.9 10(-4)) after adjustment for multiple testing. STAB1 is located in close proximity to PBMR1 and the NEK4-ITIH1-ITIH3-ITIH4 region, which are the top findings from GWAS meta-analyses of mood disorder, and a combined BD and schizophrenia data set. Pathway analyses in the mania versus control comparison revealed three distinct clusters of pathways tagging molecular mechanisms implicated in BD, for example, energy metabolism, inflammation and the ubiquitin proteasome system. The present findings suggest that STAB1 is a new and highly promising candidate gene in this region. The combining of gene expression and GWAS data may provide valuable insights into the biological mechanisms of BD.
SCZ Keywordsschizophrenia
8J Psychiatr Res 2014 Mar 50: 79-83
TitleITIH3 polymorphism may confer susceptibility to psychiatric disorders by altering the expression levels of GLT8D1.
AbstractA recent genome-wide analysis indicated that a polymorphism (rs2535629) of ITIH3 showed the strongest association signal with susceptibility to psychiatric disorders in Caucasian populations. The aim of the study was to replicate the association of rs2535629 with schizophrenia and major depressive disorder (MDD) in Japanese subjects. A total of 611 patients with schizophrenia, 868 with MDD, and 1193 healthy controls were successfully genotyped for rs2535629. A significant difference in allele distribution was found between patients with schizophrenia and controls (odds ratio [OR]=1.21, 95% confidence interval [CI]: 1.05-1.39, P=0.0077). A similar trend was found for patients with MDD (OR=1.11, 95% CI: 0.98-1.26, P=0.092). The allele distribution in the combined patient group (schizophrenia and MDD) was significantly different from that of the control group (OR=1.15, 95% CI: 1.03-1.28, P=0.011). Gene expression microarray analysis of whole blood samples in 39 MDD patients and 40 healthy controls showed that rs2535629 has a strong influence on the expression levels of ITIH4 and GLT8D1. The expression levels of GLT8D1 were significantly higher in patients with MDD than in controls (P=0.021). To our knowledge, the present study showed for the first time the association of rs2535629 with psychiatric disorders in an Asian population. Our findings suggest that rs2535629 influences the susceptibility to psychiatric disorders by affecting the expression level of GLT8D1.
SCZ Keywordsschizophrenia
9Br J Psychiatry 2015 Dec 207: 490-4
TitleLoci with genome-wide associations with schizophrenia in the Han Chinese population.
AbstractA large schizophrenia genome-wide association study (GWAS) and a subsequent extensive replication study of individuals of European ancestry identified eight new loci with genome-wide significance and suggested that the MIR137-mediated pathway plays a role in the predisposition for schizophrenia.
To validate the above findings in a Han Chinese population.
We analysed the single nucleotide polymorphisms (SNPs) in the newly identified schizophrenia candidate loci and predicted MIR137 target genes based on our published Han Chinese populations (BIOX) GWAS data. We then analysed 18 SNPs from the candidate regions in an independent cohort that consisted of 3585 patients with schizophrenia and 5496 controls of Han Chinese ancestry.
We replicated the associations of five markers (P<0.05), including three that were located in the predicted MIR137 target genes. Two loci (ITIH3/4: rs2239547, P = 1.17 10(-10) and CALN1: rs2944829, P = 9.97 10(-9)) exhibited genome-wide significance in the Han Chinese population.
The ITIH3/4 locus has been reported to be of genome-wide significance in the European population. The successful replication of this finding in a different ethnic group provides stronger evidence for the association between schizophrenia and ITIH3/4. We detected the first genome-wide significant association of schizophrenia with CALN1, which is a predicted target of MIR137, and thus provide new evidence for the associations between MIR137 targets and schizophrenia.
SCZ Keywordsschizophrenia