Meta-analysis reveals associations between genetic variation in the 5' and 3' regions of Neuregulin-1 and schizophrenia.

Genetic, post-mortem and neuroimaging studies repeatedly implicate neuregulin-1 (NRG1) as a critical component in the pathophysiology of schizophrenia. Although a number of risk haplotypes along with several genetic polymorphisms in the 5' and 3' regions of NRG1 have been linked with schizophrenia, results have been mixed. To reconcile these conflicting findings, we conducted a meta-analysis examining 22 polymorphisms and two haplotypes in NRG1 among 16 720 cases, 20 449 controls and 2157 family trios. We found significant associations for three polymorphisms (rs62510682, rs35753505 and 478B14-848) at the 5'-end and two (rs2954041 and rs10503929) near the 3'-end of NRG1. Population stratification effects were found for the rs35753505 and 478B14-848(4) polymorphisms. There was evidence of heterogeneity for all significant markers and the findings were robust to publication bias. No significant haplotype associations were found. Our results suggest genetic variation at the 5' and 3' ends of NRG1 are associated with schizophrenia and provide renewed justification for further investigation of NRG1's role in the pathophysiology of schizophrenia.

Meta-analysis supports GWAS-implicated link between GRM3 and schizophrenia risk.

Genome-wide association study (GWAS) evidence has identified the metabotropic glutamate receptor 3 (GRM3) gene as a potential harbor for schizophrenia risk variants. However, previous meta-analyses have refuted the association between GRM3 single-nucleotide polymorphisms (SNPs) and schizophrenia risk. To reconcile these conflicting findings, we conducted the largest and most comprehensive meta-analysis of 14 SNPs in GRM3 from a total of 11 318 schizophrenia cases, 13 820 controls and 486 parent-proband trios. We found significant associations for three SNPs (rs2237562: odds ratio (OR)=1.06, 95% confidence interval (CI)=1.02-1.11, P=0.017; rs13242038: OR=0.90, 95% CI=0.85-0.96, P=0.016 and rs917071: OR=0.94, 95% CI=0.91-0.97, P=0.003). Two of these SNPs (rs2237562, rs917071) were in strong-to-moderate linkage disequilibrium with the top GRM3 GWAS significant SNP (rs12704290) reported by the Schizophrenia Working Group of the Psychiatric Genomics Consortium. We also found evidence for population stratification related to rs2237562 in that the 'risk' allele was dependent on the population under study. Our findings support the GWAS-implicated link between GRM3 genetic variation and schizophrenia risk as well as the notion that alleles conferring this risk may be population specific.