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Genetic influences of dopamine transport gene on alcohol dependence: a pooled analysis of 13 studies with 2483 cases and 1753 controls.

ABSTRACT: Previous genetic association studies have reported a possible role of the dopamine transporter (DAT, gene symbol: SLC6A3) gene in the etiology of alcohol dependence, but the results were conflicting with each other. We conducted a pooled analysis of published population-based case-control genetic studies investigating associations between polymorphisms in SLC6A3 and alcohol dependence. We also explored whether geographic area, ethnicity, gender, and diagnostic criteria moderated any association by using stratified analysis. Through combining 13 studies with 2483 cases and 1753 controls, the 40-base pair variable number tandem repeat (VNTR) in the 3' un-translated region, the well studied polymorphism in SLC6A3, did not show any association with alcohol dependence in general or in stratified analyses according to geographic area, ethnicity, gender, and diagnostic criteria. Due to limited studies focused on polymorphisms in other regions of the SLC6A3 gene, we cannot rule out the role of the SLC6A3 gene in the involvement of the genetic risk of alcohol dependence. Further clarification of the genetic role of SLC6A3 in the susceptibility to alcohol dependence should be centered on other potential functional regions of the SLC6A3 gene.

SUBMITTER: Xu M

PROVIDER: S-EPMC5335908 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Genetic influences of dopamine transport gene on alcohol dependence: a pooled analysis of 13 studies with 2483 cases and 1753 controls.

Xu Mingqing M Lin Zhicheng Z

Progress in neuro-psychopharmacology & biological psychiatry 20101113 5

Previous genetic association studies have reported a possible role of the dopamine transporter (DAT, gene symbol: SLC6A3) gene in the etiology of alcohol dependence, but the results were conflicting with each other. We conducted a pooled analysis of published population-based case-control genetic studies investigating associations between polymorphisms in SLC6A3 and alcohol dependence. We also explored whether geographic area, ethnicity, gender, and diagnostic criteria moderated any association ...[more]

PMID: 21078357

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Project description:BackgroundOver 50 years of evidence from research has established that the central dopaminergic reward pathway is likely involved in alcohol dependence (AD). Additional evidence supports a role for dopamine (DA) in other disinhibitory psychopathology, which is often comorbid with AD. Family and twin studies demonstrate that a common genetic component accounts for most of the genetic variance in these traits. Thus, DA-related genes represent putative candidates for the genetic risk that underlies not only AD but also behavioral disinhibition. Many linkage and association studies have examined these relationships with inconsistent results, possibly because of low power, poor marker coverage, and/or an inappropriate correction for multiple testing.MethodsWe conducted an association study on the products encoded by 10 DA-related genes (DRD1-D5, SLC18A2, SLC6A3, DDC, TH, COMT) using a large, ethnically homogeneous sample with severe AD (n = 545) and screened controls (n = 509). We collected genotypes from linkage disequilibrium (LD)-tagging single nucleotide polymorphisms (SNPs) and employed a gene-based method of correction. We tested for association with AD diagnosis in cases and controls and with a variety of alcohol-related traits (including age-at-onset, initial sensitivity, tolerance, maximum daily drinks, and a withdrawal factor score), disinhibitory symptoms, and a disinhibitory factor score in cases only. A total of 135 SNPs were genotyped using the Illumina GoldenGate and Taqman Assays-on-Demand protocols.ResultsOf the 101 SNPs entered into standard analysis, 6 independent SNPs from 5 DA genes were associated with AD or a quantitative alcohol-related trait. Two SNPs across 2 genes were associated with a disinhibitory symptom count, while 1 SNP in DRD5 was positive for association with the general disinhibitory factor score.ConclusionsOur study provides evidence of modest associations between a small number of DA-related genes and AD as well as a range of alcohol-related traits and measures of behavioral disinhibition. While we did conduct gene-based correction for multiple testing, we did not correct for multiple traits because the traits are correlated. However, false-positive findings remain possible, so our results must be interpreted with caution.

Project description:The development of alcohol dependence (AD) involves transitions through multiple stages of drinking behaviors and is shaped by both heritable and environmental influences. We attempted to capture this dynamic process by characterizing genetic and environmental contributions to the rate at which women progressed through 3 significant transitions along the pathway to AD: nonuse to initiation, initiation to onset of first alcohol-related problem, and first problem to onset of AD.The sample consisted of 3,546 female twins from the Missouri Adolescent Female Twin Study. Participants ranged in age from 18 to 29 years. Retrospective reports of alcohol use histories were collected by telephone diagnostic interview and transition times between drinking milestones were coded ordinally. Standard genetic analyses were conducted in Mx to derive a trivariate model that provided estimates of genetic and environmental influences that were common as well as specific to the 3 transition times.Heritable influences were found for rate of progression across all 3 transitions, accounting for 30 to 47% of the variance in transition times. Shared environmental contributions were evident only in rate of progression from nonuse to initiation (i.e., age at first drink). Heritable contributions to the rate of movement through successive drinking milestones were attributable to a common factor, whereas environmental influences were transition-specific.The current study is unique in its use of a genetically informative design to document the rate of movement between drinking milestones in a female sample and to examine genetic contributions to multiple transition times over the course of AD development. Results indicate that an earlier report of heritability for males in rate of progression from regular drinking to AD generalizes to women and to other alcohol stage transitions. Findings also suggest the need to consider stage-specific environmental contributions to alcohol outcomes in developing interventions.

Dataset Information

Genetic influences of dopamine transport gene on alcohol dependence: a pooled analysis of 13 studies with 2483 cases and 1753 controls.

Publications

Genetic influences of dopamine transport gene on alcohol dependence: a pooled analysis of 13 studies with 2483 cases and 1753 controls.

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