Association Study of Gene Polymorphisms in GABA, Serotonin, Dopamine, and Alcohol Metabolism Pathways with Alcohol Dependence in Taiwanese Han Men.

ABSTRACT

BACKGROUND: The roles of GABA, serotonin, dopamine, and alcohol metabolism pathways in alcohol dependence (AD) are evident from animal models and human studies. Aims of this study were to investigate associations between genes in the 4 pathways and AD. METHODS: Male subjects from 2 independent samples of Taiwanese Han descent, a family sample of 179 trios and a case-control sample of 262 AD cases and 273 normal controls, were included in this study. The Schedules for Clinical Assessment in Neuropsychiatry was used for phenotype assessment of AD. We genotyped 282 single nucleotide polymorphisms (SNPs) located in 61 candidate genes involving alcohol metabolism, serotonin, and GABA systems among the family sample and replicated the top hits in the case-control sample. RESULTS: Fifteen SNPs located in 10 genes showed signals of associations (FBAT test p < 0.05) with AD in the family sample. Three SNPs, rs1229984 in ADH1B, rs671 in ALDH2, and rs2000292 in HTR1B, were significantly replicated in the case-control sample (p = 5.87 × 10(-14) , 5.12 × 10(-14) , and 0.0051, respectively). In the combined meta-analysis, these 3 SNPs and 1 additional SNP, rs698 in ADH1C, showed significant association after correcting for multiple comparisons, and rs1229984 and rs671 showed the strongest association (p < 10(-16) ). Logistic regression conditioning on rs1229984 and rs671 in the case-control sample showed that rs2000292 in HTR1B remained nominally significant. CONCLUSIONS: Genes in alcohol metabolism pathway, especially ADH1B and ALDH2, conferred the major genetic risk for AD in Taiwanese Han population. Some genes in GABA and serotonin pathways showed nominal association with AD.