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.

Identification of the gene signature reflecting schizophrenia’s etiology by constructing artificial intelligence‐based method of enhanced reproducibility

“…Based on the result, forest plots (Figure ) were drawn to depict the effects of different methods (new strategy, t test, and SAM) on reproducibility. Forest plots have been widely adopted in current analyses to discover SZ risk alleles or assess the drug response rates in patients with SZ . In this study, the comparisons between the new strategy and SAM, between new strategy and t test, and between t test and SAM were shown in Figure A‐C, respectively.…”

“…Moreover, the analytical methodology together with multiple randomized sampling is known as capable of validating the robustness of analytic results and usefulness of identified markers by drawing conclusion over multiple independent studies . Due to its ability to produce the more comprehensive and broader conclusions than traditional measurements, the comprehensive analyses have been applied to empirically investigate the replicability failure in current SZ research, substantially facilitate the discovery of risk allele or gene marker of SZ, and systematically assess the drug response rate of patient with SZ . It is therefore of great interest in constructing novel feature selection strategy of significantly enhanced reproducibility.…”

Antiviral signalling in human IPSC-derived neurons recapitulates neurodevelopmental disorder phenotypes

“…Interestingly, GRM3 has been implicated as a SZ risk gene (29), whereas LHX6 is required for specification and correct spatial positioning of parvalbumin interneurons, neurite outgrowth, and has been reported to be deficient in prefrontal cortices of individuals with SZ (30) ( Fig 2F).…”

Modulation on Glutamic Pathway of Frontal-Striatum-Thalamus by rs11146020 and rs3813296 Gene Polymorphism in First-Episode Negative Schizophrenia

“…Several SNPs have been associated with increased risk for developing schizophrenia, although few of these findings have been replicated (Jagannath et al, 2018). If confirmed in additional studies, these genetic markers would implicate glutamatergic neurotransmitter pathways in the pathogenesis of schizophrenia (Dauvermann et al, 2017;Saini et al, 2017;Han et al, 2018).…”