Saini S M, Mancuso S G, Mostaid Md S, Liu C, Pantelis C, Everall I P, Bousman C A
Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, Parkville, VIC, Australia.
Department of Psychiatry, UKM Medical Center, Jalan Yaacob Latif, Cheras, Kuala Lumpur, Malaysia.
Transl Psychiatry. 2017 Aug 8;7(8):e1196. doi: 10.1038/tp.2017.172.
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.
全基因组关联研究（GWAS）证据已确定代谢型谷氨酸受体3（GRM3）基因为精神分裂症风险变异的潜在携带者。然而，先前的荟萃分析驳斥了GRM3单核苷酸多态性（SNP）与精神分裂症风险之间的关联。为了调和这些相互矛盾的发现，我们对GRM3中的14个SNP进行了最大规模、最全面的荟萃分析，共纳入11318例精神分裂症患者、13820例对照和486个亲代-先证者三联体。我们发现三个SNP存在显著关联（rs2237562：优势比（OR）=1.06，95%置信区间（CI）=1.02-1.11，P=0.017；rs13242038：OR=0.90，95%CI=0.85-0.96，P=0.016；rs917071：OR=0.94，95%CI=0.91-0.97，P=0.003）。其中两个SNP（rs2237562、rs917071）与精神病基因组学联盟精神分裂症工作组报告的GRM3全基因组关联研究最显著SNP（rs12704290）处于强至中度连锁不平衡状态。我们还发现了与rs2237562相关的群体分层证据，即“风险”等位基因取决于所研究的人群。我们的研究结果支持了GRM3基因变异与精神分裂症风险之间的全基因组关联研究暗示的联系，以及赋予这种风险的等位基因可能具有人群特异性的观点。
