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

Abstract

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.

Potential Psychiatric Applications of Metabotropic Glutamate Receptor Agonists and Antagonists

“…Botonna et al [78] 105 SZ, 108 HC No significant association with SZ Takaki et al [80] 100 SZ, 100 HC No significant association with SZ after Bonferroni correction; haplotypes significantly associated with SZ bp = base pair; h = human; HC = healthy comparison subjects, i.e. individuals who were not diagnosed with schizophrenia or a confounding medical condition; rs = reference SNP; SNP = single nucleotide polymorphism; SZ = individuals who carry the diagnosis of schizophrenia.…”

Synergistic association of PI4KA and GRM3 genetic polymorphisms with poor antipsychotic response in south Indian schizophrenia patients with low severity of illness

“…Recently, considerable attention has been paid to genetic polymorphism in glutamatergic transmission with an abundance of research reports supporting the hypothesis [Chumakov et al, 2002;Stefansson et al, 2002;Fujii et al, 2003;Makino et al, 2003;Deng et al, 2004;Egan et al, 2004;Takaki et al, 2004;Iwayama-Shigeno et al, 2005;Weis et al, 2007;Horiuchi et al, 2012]. A significant association of several glutamatergic transmission genes including those encoding iGluR and metabotropic receptors such as G72, NRG1, GRIA4, GRM3, GRM8, GRIN2D, GRIN2A, SLC1A1, SLC1A2, and SLC1A4 has been observed with schizophrenia.…”

Association study of polymorphisms in the glutamate transporter genes SLC1A1, SLC1A3, and SLC1A6 with schizophrenia

“…Based on the fact that phencyclidine (PCP) induces schizophreniform psychosis, a glutamatergic dysfunction hypothesis has been proposed for the pathogenesis of schizophrenia [Luby et al, 1959;Javitt and Zukin, 1991;Mohn et al, 1999]. This hypothesis has been supported by recent multiple reports of significant association of schizophrenia with glutamate receptor genes and with the genes related to glutamatergic transmission, such as G72, NRG1, GRIA4, GRM3, GRM8, GRIN2D, and GRIN2A [Chumakov et al, 2002;Stefansson et al, 2002;Fujii et al, 2003;Makino et al, 2003Makino et al, , 2005Egan et al, 2004;Takaki et al, 2004;Iwayama-Shigeno et al, 2005].Other synaptic elements related to glutamate, such as excitatory amino acid transporters (EAATs), also potentially affect glutamatergic neurotransmission. EAATs maintain extracellular glutamate concentrations within physiological levels by reuptaking synaptically released glutamate.…”