Genome-wide association analysis identifies 13 new risk loci for schizophrenia

Abstract

Schizophrenia is a heritable disorder with substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases, 6,243 controls) followed by meta-analysis with prior schizophrenia GWAS (8,832 cases, 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls, and 581 trios). In total, 22 regions met genome-wide significance (14 novel and one previously implicated in bipolar disorder). The results strongly implicate calcium signaling in the etiology of schizophrenia, and include genome-wide significant results for CACNA1C and CACNB2 whose protein products interact. We estimate that ∼8,300 independent and predominantly common SNPs contribute to risk for schizophrenia and that these collectively account for most of its heritability. Common genetic variation plays an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this devastating disorder.

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

“…The Schizophrenia Working Group of the Psychiatric Genomics Consortium study [2014] included analyses that sought to relate credible GWAS risk variants to genome‐wide eQTL data, finding rs11191419 to be in strong linkage disequilibrium (r 2  = 0.85) with an eQTL SNP (rs7096169) influencing AS3MT expression in blood. Using several brain eQTL datasets, Roussos et al [2014] identified SNPs influencing BORCS7 (C10ORF32) , AS3MT , WBP1L , and NT5C2 expression that are in linkage disequilibrium with rs7085104, identified in an earlier GWAS of schizophrenia [Ripke et al, 2013], which we found to be in strong linkage disequilibrium (r 2  = 0.79) with rs11191419 in the samples genotyped in the present study. These authors also assessed whether schizophrenia‐associated eQTLs were located in predicted cis ‐regulatory elements (CREs); expression of BORCS7 and AS3MT was reported to be influenced by SNPs within individual CRE, while expression of NT5C2 was associated with SNPs in 14 such elements [Roussos et al, 2014].…”

“…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.…”

A commentary on the gender-specific association of TSNAX/DISC1 locus for schizophrenia and bipolar affective disorder in South Indian population

“…Although the results of genetic replication studies between SCZ and the DISC1 gene must be interpreted with extreme caution, 5 a critical issue in positive DISC1 association studies is a lack of replication for the same alleles in the same direction and the same haplotypes across the studies. In addition, recent genome-wide association studies (GWAS) 6,7 as well as a large association study 8 and a meta-analysis of variants in the DISC1 gene 9 failed to replicate significant associations of the DISC1 gene with SCZ. The second concern is a gender-specific association of DISC1 in SCZ.…”