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


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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    • "Recent evaluations identify polymorphisms in subjects suffering from cocaine or alcohol addiction (Covault et al. 2004; Edenberg et al. 2004; Lappalainen et al. 2005; Drgon et al. 2006; Covault et al. 2008; Soyka et al. 2008; Dixon et al. 2010; Li et al. 2014). Therefore , ongoing experiments use point-mutated mice to evaluate the relationship between α2-containing GABA A receptor sensitivity to various GABA A receptor ligands and escalated alcohol drinking (Newman et al., in preparation). "
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    ABSTRACT: Rationale: Benzodiazepines (BZDs) are prescribed to reduce anxiety, agitation, and muscle spasms and for their sedative-hypnotic and anticonvulsant effects. Under specific conditions, BZDs escalate aggression in some individuals. Specific effects of BZDs have been linked to the α-subunit subtype composition of GABAA receptors. Objectives: Point-mutated mice rendered selectively insensitive to BZDs at α1-, α2-, or α3-containing GABAA receptors were used to determine which α-subunit subtypes are necessary for BZDs to escalate aggression and social approach and to reduce fear-motivated behavior. Methods: During resident-intruder confrontations, male wild-type (WT) and point-mutated α1(H101R), α2(H101R), and α3(H126R) mice were treated with midazolam (0-1.7 mg/kg, i.p.) and evaluated for aggression in an unfamiliar environment. Separate midazolam-treated WT and point-mutated mice were assessed for social approach toward a female or investigated in a 6-day fear-potentiated startle procedure. Results: Moderate doses of midazolam (0.3-0.56 mg/kg, i.p.) escalated aggression in WT and α3(H126R) mutants and increased social approach in WT and α1(H101R) mice. The highest dose of midazolam (1.0 mg/kg) reduced fear-potentiated startle responding. All mice were sensitive to the sedative effect of midazolam (1.7 mg/kg) except α1(H101R) mutants. Conclusions: Midazolam requires BZD-sensitive α1- and α2-containing GABAA receptors in order to escalate aggression and α2- and α3-containing receptors to reduce social anxiety-like behavior. GABAA receptors containing the α1-subunit are crucial for BZD-induced sedation, while α2-containing GABAA receptors may be a shared site of action for the pro-aggressive and anxiolytic effects of BZDs.
    Psychopharmacology 09/2015; 232(23). DOI:10.1007/s00213-015-4069-9 · 3.88 Impact Factor
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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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