Genome-wide association study identifies five new schizophrenia loci

Abstract

We 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).

Genome‐wide significant schizophrenia risk variation on chromosome 10q24 is associated with altered cis‐regulation of BORCS7, AS3MT, and NT5C2 in the human brain

“…Variants on chromosome 10q24.32‐q24.33 exhibit robust association with schizophrenia [Schizophrenia Psychiatric Genome‐Wide Association Study Consortium, 2011; Aberg et al, 2013; Ripke et al, 2013; Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014], but, like many regions implicated by GWAS, the actual susceptibility genes cannot be easily resolved through genetic data alone. Using a highly sensitive method for assessing variable cis ‐effects on gene expression [Yan et al, 2002; Bray et al, 2003a,2003b], we have found that several of the principal candidate genes at this locus exhibit altered cis ‐regulation in the developing and adult human brain in association with the most strongly supported schizophrenia risk variants.…”

“…Primer sequences are provided in Supplementary Table S2. We had previously genotyped all adult samples for rs7085104 and rs11191580, two chromosome 10q24 SNPs reported as genome‐wide significant in earlier GWAS of schizophrenia [Schizophrenia Psychiatric Genome‐Wide Association Study Consortium, 2011; Ripke et al, 2013], using SNaPshot® primer extension (Life Technologies). SNP rs7085104 is in strong linkage disequilibrium (LD) with rs11191419 in our samples (r 2  = 0.79), while SNP rs11191580 is in strong LD with ch10_104957618_I (r 2  = 0.82), suggesting that they index the same functional risk variation.…”

“…Chromosome 10q24.32‐q24.33 is one of the best‐supported genetic risk loci to arise from large‐scale genome‐wide association studies (GWAS) of schizophrenia [Schizophrenia Psychiatric Genome‐Wide Association Study Consortium, 2011; Ripke et al, 2013; Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014]. Variation at this locus also exhibits genome‐wide significant association with the five disorders included in the Psychiatric Genomics Consortium combined [Cross‐Disorder Group of the Psychiatric Genomics Consortium, 2013], suggesting that it increases susceptibility to psychiatric disorders in general.…”

Recent Advances in the Genetics of Schizophrenia

“…The biggest collaborative consortium, the Psychiatric Genomics Consortium (PGC), was started in 2007, and according to its website (http://www.med.unc.edu/pgc/pgc-workgroups) its schizophrenia group currently includes over 400 investigators from 40 countries. The PGC published its first GWAS in 2011 identifying five new loci for schizophrenia using a discovery sample of 21,856 Europeans and 29,839 independent subjects for replication [91]. Many other important papers followed until most recently in 2014 they published on 36,989 cases and 113,075 controls [70], reporting 108 significant loci that represent 128 independent association signals, 83 of which had not been previously reported.…”

A Review of Genome-Wide Association Studies of Stimulant and Opioid Use Disorders

“…The success of these studies, with regard to reproducibility and biological insights gained, stands in stark contrast to prior candidate gene-driven approaches. Among these genetic success stories are studies of bipolar disorder [9] and schizophrenia [10,11], as well as several genome-wide association studies (GWAS) of legal drug use (alcohol, cigarette smoking and caffeine consumption) [12,13,14,15]. Combined, these studies have implicated a spectrum of genetic variation with effects on risk that range from barely detectable to moderately large.…”