BACKGROUND: Glutamate neurotransmission plays an important role in a variety of alcohol-related phenomena, including alcohol self-administration by both animals and humans. Because the risk for alcohol dependence (AD) is genetically influenced, genes encoding glutamate receptors are candidates to contribute to the risk for AD. We examined the role of variation in the 3' region of GRIK1, the gene that encodes the GluR5 receptor subunit of the kainic acid glutamate receptor, on risk for AD. We focused specifically on this gene because topiramate, a glutamate modulator that binds to the GluR5 subunit, has shown robust efficacy in the treatment of AD. METHODS: We genotyped 7 single nucleotide polymorphisms (SNPs) in the 3'-half of GRIK1, which includes 3 differentially spliced exons, in a sample of EA control subjects (n = 507) and subjects with AD (n = 1,057). RESULTS: We found nominally significant evidence of association to AD for 3 SNPs (rs2832407 in intron 9, rs2186305 in intron 17, and rs2832387 in the 3'UTR). Empirical p-value estimation revealed that only rs2832407 was significantly associated to phenotype (p = 0.043). DISCUSSION: These findings provide support for the hypothesis that variation in the 3' portion of the gene encoding the GluR5 kainate receptor subunit contributes to the risk for AD. Further research is needed to ascertain whether this SNP is itself functional or whether the association reflects linkage disequilibrium with functional variation elsewhere in the gene and whether this SNP moderates topiramate's effects in the treatment of AD.
BACKGROUND:Glutamate neurotransmission plays an important role in a variety of alcohol-related phenomena, including alcohol self-administration by both animals and humans. Because the risk for alcohol dependence (AD) is genetically influenced, genes encoding glutamate receptors are candidates to contribute to the risk for AD. We examined the role of variation in the 3' region of GRIK1, the gene that encodes the GluR5 receptor subunit of the kainic acid glutamate receptor, on risk for AD. We focused specifically on this gene because topiramate, a glutamate modulator that binds to the GluR5 subunit, has shown robust efficacy in the treatment of AD. METHODS: We genotyped 7 single nucleotide polymorphisms (SNPs) in the 3'-half of GRIK1, which includes 3 differentially spliced exons, in a sample of EA control subjects (n = 507) and subjects with AD (n = 1,057). RESULTS: We found nominally significant evidence of association to AD for 3 SNPs (rs2832407 in intron 9, rs2186305 in intron 17, and rs2832387 in the 3'UTR). Empirical p-value estimation revealed that only rs2832407 was significantly associated to phenotype (p = 0.043). DISCUSSION: These findings provide support for the hypothesis that variation in the 3' portion of the gene encoding the GluR5kainate receptor subunit contributes to the risk for AD. Further research is needed to ascertain whether this SNP is itself functional or whether the association reflects linkage disequilibrium with functional variation elsewhere in the gene and whether this SNP moderates topiramate's effects in the treatment of AD.
Authors: Mario Carta; Olusegun J Ariwodola; Jeff L Weiner; C Fernando Valenzuela Journal: Proc Natl Acad Sci U S A Date: 2003-05-05 Impact factor: 11.205
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