Positive associations of polymorphisms in the metabotropic glutamate receptor type 8 gene (GRM8) with schizophrenia.

The glutamatergic dysfunction has been implicated in pathophysiology of schizophrenia. The Group III metabotropic glutamate receptor 4 (mGluR4), 6, 7, and 8 are thought to modulate glutamatergic transmission in the brain by inhibiting glutamate release at the synapse. We tested association of schizophrenia with GRM8 using 22 single nucleofide polymorphisms (SNPs) with the average intervals of 40.3 kb in the GRM8 region in 100 case-control pairs for the SNPs. Although we observed significant associations of schizophrenia with two SNPs, SNP18 (rs2237748, allele: P = 0.0279; genotype: P = 0.0124) and SNP19 (rs2299472, allele: P = 0.0302; genotype: P = 0.0127), none of two SNPs showed significant association with disease after Bonferroni correction. Both SNP18 and SNP19 were included in a large region (>330 kb) in which SNPs are in linkage disequilibrium (LD) at the 3' region of GRM8. We also tested haplotype association of schizophrenia with constructed haplotypes of the SNPs in LD. Significant associations were detected for the combinations of SNP5-SNP6 (chi(2) = 18.12, df = 3, P = 0.0004, P corr = 0.0924 with Bonferroni correction), SNP4-SNP5-SNP6 (chi(2) = 27.50, df = 7, P = 0.0075, P corr = 0.015 with Bonferroni correction), and SNP5-SNP6-SNP7 (chi(2) = 23.92, df = 7, P = 0.0011, P corr = 0.0022 with Bonferroni correction). Thus, we conclude that at least one susceptibility locus for schizophrenia is located within the GRM8 region in Japanese.