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

Abstract

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.

Figure 1

Schematic diagram of the GRM3 structure with locations of SNPs is examined in this meta-analysis. Single-nucleotide polymorphisms (SNPs) significantly associated with schizophrenia in this meta-analysis are underlined. *This SNP was excluded in this meta-analysis due to fewer than three studies but was the most significant GRM3 SNP in the PGC GWAS.

Figure 2

Forest plots of (a) rs2237562, (b) rs13242038 and (c) rs917071 association with schizophrenia before and after excluding outlier/influential studies. CI, confidence interval; OR, odds ratio; RE model, random-effect model.