Abstract
Studies of linkage and association in various ethnic populations have revealed many predisposing genes of multiple neurotransmitter systems for alcohol use disorders (AUD). However, evidence often is contradictory regarding the contribution of most candidate genes to the susceptibility of AUD. We, therefore, performed a case-control study to investigate the possible associations of genes selected from multiple neurotransmitter systems with AUD in a homogeneous Tibetan community population in China. AUD cases (N = 281) with an alcohol use disorder identification test (AUDIT) score ≥10, as well as healthy controls (N = 277) with an AUDIT score ≤5, were recruited. All participants were genotyped for 366 single nucleotide polymorphisms (SNPs) of 34 genes selected from those involved in neurotransmitter systems. Association analyses were performed using PLINK version 1.07 software. Allelic analyses before adjustment for multiple tests showed that 15 polymorphisms within seven genes were associated with AUD (p<0.05). After adjustment for the number of SNPs genotyped within each gene, only the association of a single marker (rs10044881) in HTR4 remained statistically significant. Haplotype analysis for two SNPs in HTR4 (rs17777298 and rs10044881) showed that the haplotype AG was significantly associated with the protective effect for AUD. In conclusion, the present study discovered that the HTR4 gene may play a marked role in the pathogenesis of AUD. In addition, this Tibetan population sample marginally replicated previous evidence regarding the associations of six genes in AUD.
Highlights
Alcohol use disorders (AUD) — including alcohol dependence (AD) and alcohol abuse (AA) — are worldwide problems that induce complex clinical symptoms by damaging most organs in the human body, as well as the central and peripheral nervous systems [1,2]
Using DSM-IV diagnostic criteria according to SCID-P assessment as the gold criteria, we identified that the best cut-off point of alcohol use disorder identification test (AUDIT) for diagnosing AUD in this population is 10, with both sensitivity and specificity .0.85, the cut-off point for alcohol use disorders should be 6 if all cases need to be included [44]
single nucleotide polymorphisms (SNPs), including two with p,0.01, were in HTR4 gene, and one and two SNPs were in GABRA1 and GABRB2, respectively
Summary
Alcohol use disorders (AUD) — including alcohol dependence (AD) and alcohol abuse (AA) — are worldwide problems that induce complex clinical symptoms by damaging most organs in the human body, as well as the central and peripheral nervous systems [1,2]. There are two subgroups of gamma-aminobutyric acid (GABA) receptors (the GABAA receptors and the GABAB receptors) They both belong to the GABAergic system, which is a chief inhibitory neurotransmitter in the central nervous system. For this system, genetic investigators have focused on GABAA receptors and have documented conflicting evidence of the contributing role of the GABAA receptors on chromosome 4p (GABRA2, GABRB1, and GABRG1) and 5q33-34 (GABRA1, GABRA6, GABRB2, and GABRG2) in the development of AUD [11,12,13]. The association of the susceptivity, severity, and treatment response of AUD with some polymorphisms of serotonin transporter (5-HTT) and serotonin (5-HT) receptor genes had been reported by several initial studies, and as a result, similar research in different populations has increased in recent years, but results are not conclusive [8,14,15]
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