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Gamma-aminobutyric acid system genes--no evidence for a role in alcohol use and abuse in a community-based sample.

ABSTRACT: BACKGROUND:While twin and adoption studies point to substantial genetic influence upon alcohol use, dependence, and other alcohol-related phenotypes, few of the genes underlying variation in these phenotypes have been identified. Markers in genes related to GABAergic activity-a system integral to many of alcohol's biological effects-have been implicated in alcohol use and alcohol-related psychopathology in linkage and association studies. METHODS:Using multiple methods, we conducted a comprehensive examination of the effects of markers in ?-aminobutyric acid (GABA) system genes in a community-based sample of 7,224 individuals assessed in early and middle adulthood. In addition to testing the effect of individual single nucleotide polymorphism (SNP) markers on alcohol-related phenotypes, we computed a polygenic score reflecting the aggregated effects of multiple GABA system SNPs. We also estimated the variance in alcohol-related phenotypes attributable to all GABA system markers considered simultaneously and conducted gene-based association tests. RESULTS:No method produced results indicative of an effect of GABA system variants on measures of alcohol use or misuse. CONCLUSIONS:These results reflect alcohol-related behaviors in a population-representative sample, many of whom are still in adolescence, and in which the incidence of heavy drinking and alcohol-related symptomatology are relatively low. Contrasted with existing studies of the association between alcohol use and GABA system genes, our results suggest that the relationship may be limited to particular contexts, such as when accompanied by polysubstance abuse or a familial history of alcoholism.

SUBMITTER: Irons DE

PROVIDER: S-EPMC3984361 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Gamma-aminobutyric acid system genes--no evidence for a role in alcohol use and abuse in a community-based sample.

Irons Daniel E DE Iacono William G WG Oetting William S WS Kirkpatrick Robert M RM Vrieze Scott I SI Miller Michael B MB McGue Matt M

Alcoholism, clinical and experimental research 20140124 4

<h4>Background</h4>While twin and adoption studies point to substantial genetic influence upon alcohol use, dependence, and other alcohol-related phenotypes, few of the genes underlying variation in these phenotypes have been identified. Markers in genes related to GABAergic activity-a system integral to many of alcohol's biological effects-have been implicated in alcohol use and alcohol-related psychopathology in linkage and association studies.<h4>Methods</h4>Using multiple methods, we conduct ...[more]

PMID: 24460875

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Project description:Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in mammalian brain. GABA receptor are involved in a number of complex disorders, including substance abuse. No variants of the commonly studied GABA receptor genes that have been associated with substance dependence have been determined to be functional or pathogenic. To reconcile the conflicting associations with substance dependence traits, we performed a meta-analysis of variants in the GABAA receptor genes (GABRB2, GABRA6, GABRA1, and GABRG2 on chromosome 5q and GABRA2 on chromosome 4p12) using genotype data from 4739 cases of alcohol, opioid, or methamphetamine dependence and 4924 controls. Then, we combined the data from candidate gene association studies in the literature with two alcohol dependence (AD) samples, including 1691 cases and 1712 controls from the Study of Addiction: Genetics and Environment (SAGE), and 2644 cases and 494 controls from our own study. Using a Bonferroni-corrected threshold of 0.007, we found strong associations between GABRA2 and AD (P=9 × 10(-6) and odds ratio (OR) 95% confidence interval (CI)=1.27 (1.15, 1.4) for rs567926, P=4 × 10(-5) and OR=1.21 (1.1, 1.32) for rs279858), and between GABRG2 and both dependence on alcohol and dependence on heroin (P=0.0005 and OR=1.22 (1.09, 1.37) for rs211014). Significant association was also observed between GABRA6 rs3219151 and AD. The GABRA2 rs279858 association was observed in the SAGE data sets with a combined P of 9 × 10(-6) (OR=1.17 (1.09, 1.26)). When all of these data sets, including our samples, were meta-analyzed, associations of both GABRA2 single-nucleotide polymorphisms remained (for rs567926, P=7 × 10(-5) (OR=1.18 (1.09, 1.29)) in all the studies, and P=8 × 10(-6) (OR=1.25 (1.13, 1.38)) in subjects of European ancestry and for rs279858, P=5 × 10(-6) (OR=1.18 (1.1, 1.26)) in subjects of European ancestry. Findings from this extensive meta-analysis of five GABAA receptor genes and substance abuse support their involvement (with the best evidence for GABRA2) in the pathogenesis of AD. Further replications with larger samples are warranted.

Project description:OBJECTIVES:Health outcomes, including chronic disease and mortality, attributed to or associated with alcohol abuse are discrepant between African Americans and Whites. To date, the topic is not fully understood and few studies conducted have used biomarker indicators of health. We investigated whether the association between alcohol abuse and biomarkers of the neuroendocrine system vary between black or African American and White respondents aged 34-84 from the Midlife in the United States Study (MIDUS) II (2004-2006) (n=1129). Alcohol abuse was assessed with a modified version of the Michigan Alcohol Screening Test. Ordinary least squared (OLS) regression was used to evaluate whether race moderated the associations between alcohol abuse and four biomarkers-urinary cortisol and serum dehydroepiandrosterone sulfate (DHEA-S), epinephrine and norepinephrine-and two composite summary scores, each consisting of two components that characterize the hypothalamic pituitary adrenal (HPA)-axis and sympathetic nervous systems (SNS), respectively. Covariates included age, sex, education, income, current drinking, smoking, exercise, fast food consumption, heart disease, blood pressure, diabetes, body mass index, medication use, anxiety/depression, sleep duration, and cholesterol markers. Race significantly moderated the associations between alcohol abuse and norepinephrine concentration (?2 [1]=4.48, p=0.034) and the SNS composite score (?2 [1]=5.83, p=0.016). Alcohol abuse was associated with higher mean norepinephrine levels (b=0.26, standard error (SE)=0.12, p=0.034) and SNS composite score (b=0.23, SE=0.11, p=0.016) for African Americans compared to Whites. Interestingly, for Whites a paradoxical association between alcohol abuse, norepinephrine and SNS levels was observed; those who abused alcohol had lower mean norepinephrine levels than non-abusers. Race differences in neuroendocrine response could be biological pathways that contribute the excess risk of chronic disease and mortality attributed to alcohol abuse among African Americans compared to Whites. Replication of these analyses in larger cohorts are warranted in addition to further studies of underlying mechanisms among Blacks and Whites separately.

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Gamma-aminobutyric acid system genes--no evidence for a role in alcohol use and abuse in a community-based sample.

Publications

Gamma-aminobutyric acid system genes--no evidence for a role in alcohol use and abuse in a community-based sample.

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