Markers in the 5′-Region of GABRG1 Associate to Alcohol Dependence and are in Linkage Disequilibrium with Markers in the Adjacent GABRA2 Gene

Department of Psychiatry, Alcohol Research Center, University of Connecticut School of Medicine, Farmington, CT 06030-1410, USA.
Neuropsychopharmacology (Impact Factor: 7.05). 04/2008; 33(4):837-48. DOI: 10.1038/sj.npp.1301456
Source: PubMed

ABSTRACT Following an initial report, there have been multiple replications of an association of alcohol dependence (AD) to markers within a haplotype block that includes the 3'-half of the gene encoding the GABA(A) alpha-2 subunit (GABRA2), on chromosome 4p. We examined the intergenic extent of this haplotype block and the association to AD of markers in the adjacent 5' haplotype block in GABRG1, which encodes the GABA(A) receptor gamma-1 subunit. We genotyped 15 single nucleotide polymorphisms in the GABRG1-GABRA2 interval as well as at 34 ancestry informative markers in three samples: 435 AD and 635 screened control subjects from Connecticut and 812 participants from a multicenter AD treatment trial. We observed two large haplotype blocks in the GABRG1-GABRA2 intergenic interval with a region of increased recombination midway between the two genes. Markers in the two haplotype blocks were in moderate linkage disequilibrium. Compared with markers in the GABRA2 haplotype block, markers in the 5' GABRG1 haplotype showed greater allelic, genotypic and haplotypic association with AD in European Americans from both AD samples. Logistic regression analysis indicated that genetic elements in the GABRG1 haplotype block likely contribute to AD risk in an additive manner, whereas those in the GABRA2 haplotype block may act in a dominant manner in relation to risk of AD.

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    • "Conversely , among individuals who reported lower drinking in the preceding 30 days, those carrying the T allele showed less tolerance than those with the CC genotype (Fig. 5). The C allele of this SNP has been associated with alcohol dependence (Covault et al., 2008; Fehr et al., 2008). The model that included rs1497577 (in GABRG1) demonstrated no such association. "
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    ABSTRACT: Subjective perceptions of alcohol intoxication are associated with altered risk for alcohol abuse and dependence. Acute adaptation of these perceptions may influence such risk and may involve genes associated with pleasant perceptions or the relief of anxiety. This study assessed the effect of variation in the GABAA receptor genes GABRG1 and GABRA2 and recent drinking history on the acute adaptation of subjective responses to alcohol. One hundred and thirty-two nondependent moderate to heavy drinkers, aged 21 to 27, participated in 2 single-blind, counterbalanced sessions, approximately 1 week apart. One session was an intravenous alcohol "clamp," during which breath alcohol concentration was held steady at 60 mg/dl (60 mg%) for 3 hours, and the other an identical session using saline infusion. Subjective perceptions of Intoxication, Enjoyment, Stimulation, Relaxation, Anxiety, Tiredness, and Estimated Number of Drinks were acquired before (baseline), and during the first and final 45 minutes of the clamp. A placebo-adjusted index of the subject's acute adaptation to alcohol was calculated for each of the 7 subjective measures and used in a principal component analysis to create a single aggregate estimate for each subject's adaptive response to alcohol. Analysis of covariance tested whether GABRA2 and GABRG1 single nucleotide polymorphism (SNP) genotypes, gender, placebo session, family history of alcoholism, recent drinking history, and the genotype × recent drinking history interaction significantly predicted the adaptive response. Recent drinking history (p = 0.01), and recent drinking history × genotype interaction (p = 0.01) were significantly associated with acute adaptation of the subjective responses to alcohol for the GABRA2 SNP rs279858. Higher recent drinking was found to be associated with reduced acute tolerance to positive, stimulating effects of alcohol in carriers of the rs279858 risk allele. We postulate that the GABRA2 effect on alcohol dependence may, in part, be due to its effect on subjective responses to alcohol. Copyright © 2015 by the Research Society on Alcoholism.
    Alcoholism Clinical and Experimental Research 06/2015; 39(7). DOI:10.1111/acer.12749 · 3.21 Impact Factor
    • "Subjects with rs279871 AA genotype had a larger response to alcohol than to control odors in the medial frontal cortical areas associated with reward responses, while heterozygote subjects had a larger alcohol drinking effect in the VTA. Although these results need replication, they suggest that genotypic effects may have unique effects in different brain regions, as recently reported in brain-derived neurotrophic factor (BDNF) and depression (Covault et al., 2008). "
    From linkage to complex associations: The role of GABRA2 as a risk factor for alcohol use, Edited by K Appasani, 01/2015: chapter Genome-Wide Association Studies: From Polymorphism to Personalized Medicine; Cambridge University Press.
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    • "For instance, markers in the 3' region of GABRA2 are in LD with markers at the adjacent GABRG1 (Covault et al, 2008; Ittiwut et al, 2008). It is possible that the association identified in GABRA2 has a component because of LD with GABRG1, with risk loci in both genes (Covault et al, 2008; Enoch et al, 2009). In this meta-analysis, we analyzed all the functional receptor genes with available genotype data sets sufficient for metaanalyses (GABRB2, GABRA6, GABRA1, and GABRG2 on chromosome 5q and GABRA2 on chromosome 4p12). "
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    ABSTRACT: Gamma-Aminobutyric Acid (GABA) is a major inhibitory neurotransmitter in mammalian brain. GABA receptor subunit genes are involved in a number of complex disorders including substance abuse. No associated variants on the commonly-studied GABA receptor genes have been unequivocally identified as directly functional or pathogenic in genetic association studies of addictions. We hypothesize that meta-analysis can increase the statistical power to identify the association signals. To reconcile the conflicting associations with substance dependence traits, we performed a meta-analysis of the GABA receptor genes (GABRB2, GABRA6, GABRA1, and GABRG2 on chromosome 5q and GABRA2 on chromosome 4p12) using genotype data from 4739 cases of alcohol, heroin, opioid, or methamphetamine dependence and 4924 controls. Then, we combined these candidate gene association literature data with two additional samples with alcohol dependence (AD), 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. 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 datasets with a combined P of 9 × 10(-6) (OR=1.17 (1.09, 1.26)). When all of these datasets, including our samples, were meta-analyzed, associations of both GABRA2 SNPs 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 Europeans; for rs279858, P=5 × 10(-6) (OR=1.18 (1.1, 1.26)) in Europeans). The selected threshold of Bonferroni correction for multiple comparisons was 0.007. We report here an extensive meta-analysis between the five GABA receptor candidate genes and substance abuse. Our findings suggest the involvement of the GABA receptor genes, minimally, GABRA2 in the pathogenesis of alcohol dependence. Further replications with larger samples are warranted.Neuropsychopharmacology accepted article preview online, 18 October 2013; doi:10.1038/npp.2013.291.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2013; 39(4). DOI:10.1038/npp.2013.291 · 7.05 Impact Factor
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