Article

Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium. Genome-wide association study identifies five new schizophrenia loci

Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
Nature Genetics (Impact Factor: 29.35). 09/2011; 43(10):969-76. DOI: 10.1038/ng.940
Source: PubMed

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)).

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    • "An important utility of the CM3 method may be selection of a greater proportion of relevant SNPs for gene set enrichment and biological pathway analyses, which often use a less stringent p-value threshold than the established GWAS standard for discovery. Further, the proposed method may improve the efficiency of the two-stage GWAS meta-analysis by better predicting which regions will reach significance in the combined sample, relative to the standard method of picking all SNPs that reach a significance of p<1x10 -6 in Stage I[26,27]. In conclusion, we have presented a novel statistical method, the covariate modulated mixture model (CM3), which incorporates multiple sources of auxiliary information, such as total LD, heterozygosity, genomic annotations, and pleiotropy, for estimating effect sizes and predicting replication rates for SNPs in independent samples. "
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    • "In this perspective, it has to be noted that, among our more significant results in the multivariate analyses, another CpGs (cg14035771) near a miRNA (miR137) was associated with severity of childhood maltreatment (see Table 4). miR137 is mainly found in hippocampus and amygdala and has been strongly associated with schizophrenia, but also with autism spectrum disorders (Pinto et al. 2014; Ripke et al. 2011; Yin et al. 2014). As for miR124, miR137 has also been associated to amygdala functionality and emotion processing (Mothersill et al. 2014). "
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    • "Lambda values did not show evidence of major population stratification factors (lambda = 1.04 ± 0.05). The observed small inflation factor in the total sample was interpreted as indicative of a large number of weakly associated SNPs consistent with the disease's polygenic inheritance, as yet observed in larger mega-analyses (Ripke et al., 2011). "
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