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Polymorphisms of genes in neurotransmitter systems were associated with alcohol use disorders in a Tibetan population.

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.

SUBMITTER: Xu Y

PROVIDER: S-EPMC3842251 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Polymorphisms of genes in neurotransmitter systems were associated with alcohol use disorders in a Tibetan population.

Xu Yan Y Guo Wan-Jun WJ Wang Qiang Q Lanzi Gongga G Luobu Ouzhu O Ma Xiao-Hong XH Wang Ying-Cheng YC Zhen Puo P Deng Wei W Liu Xiang X Zhuoma Basang B Liu Xie-He XH Li Tao T Hu Xun X

PloS one 20131127 11

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 Chi ...[more]

PMID: 24312204

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Project description:American Indians (AI) demonstrate the highest rates of both suicidal behaviors (SB) and alcohol use disorders (AUD) among all ethnic groups in the US. Rates of suicide and AUD vary substantially between tribal groups and across different geographical regions, underscoring a need to delineate more specific risk and resilience factors. Using data from over 740 AI living within eight contiguous reservations, we assessed genetic risk factors for SB by investigating: (1) possible genetic overlap with AUD, and (2) impacts of rare and low frequency genomic variants. Suicidal behaviors included lifetime history of suicidal thoughts and acts, including verified suicide deaths, scored using a ranking variable for the SB phenotype (range 0-4). We identified five loci significantly associated with SB and AUD, two of which are intergenic and three intronic on genes AACSP1 , ANK1 , and FBXO11 . Nonsynonymous rare mutations in four genes including SERPINF1 (PEDF), ZNF30 , CD34 , and SLC5A9 , and non-intronic rare mutations in genes OPRD1 , HSD17B3 and one lincRNA were significantly associated with SB. One identified pathway related to hypoxia-inducible factor (HIF) regulation, whose 83 nonsynonymous rare variants on 10 genes were significantly linked to SB as well. Four additional genes, and two pathways related to vasopressin-regulated water metabolism and cellular hexose transport, also were strongly associated with SB. This study represents the first investigation of genetic factors for SB in an American Indian population that has high risk for suicide. Our study suggests that bivariate association analysis between comorbid disorders can increase statistical power; and rare variant analysis in a high-risk population enabled by whole-genome sequencing has the potential to identify novel genetic factors. Although such findings may be population specific, rare functional mutations relating to PEDF and HIF regulation align with past reports and suggest a biological mechanism for suicide risk and a potential therapeutic target for intervention.

Dataset Information

Polymorphisms of genes in neurotransmitter systems were associated with alcohol use disorders in a Tibetan population.

Publications

Polymorphisms of genes in neurotransmitter systems were associated with alcohol use disorders in a Tibetan population.

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