GABRA2 markers moderate the subjective effects of alcohol.
- Authors
- Uhart, Magdalena; Weerts, Elise M; McCaul, Mary E; Guo, Xiuqing; Yan, Xiaofei; Kranzler, Henry R; Li, Ning; Wand, Gary S
- Year
- 2013
- Journal
- Addiction biology
- PMID
- 22501025
- DOI
- 10.1111/j.1369-1600.2012.00457.x
- PMCID
- PMC3402582
Individual differences in subjective responses (SRs) to alcohol are moderated by genetic variants and may be risk factors for the development of alcohol use disorders. Variation in the GABA(A) α2 receptor subunit gene (GABRA2) has been associated with alcohol dependence (AD). Therefore, we examined whether individual differences in SRs, which reflect sensitivity to the effects of alcohol, are associated with variation in GABRA2. Sixty-nine healthy subjects (21-30 years) underwent a laboratory-based within-session cumulative oral alcohol dosing procedure, achieving a mean peak blood alcohol level of 100.4 mg/dl (standard error = 2.5). Subjective assessments were obtained throughout the session, including ascending and descending limbs of the alcohol curve. We genotyped single nucleotide polymorphisms (SNPs) across the chromosome 4 region spanning GABRA2 and analyzed the effect of genotype and haplotypes on subjective responses to alcohol. Population substructure was characterized through the use of ancestry informative markers. Individual SNP analysis demonstrated that carriers of the minor alleles for SNPs rs279858, rs279844, rs279845, rs279826, rs279828 and rs279836 had lower 'Negative' alcohol effects scores than individuals homozygous for the common allele at each SNP (P = 0.0060, P = 0.0035, P = 0.0045, P = 0.0043, P = 0.0037 and P = 0.0061, respectively). Haplotype effects of block 1 showed concordant results with SNPs in this block (P = 0.0492 and P = 0.0150 for haplotypes 1 and 4, respectively). The minor alleles for several of these SNPs have previously been associated with AD. Our findings provide further evidence that variation within GABRA2 is associated with attenuated negative responses to alcohol, a known risk factor for vulnerability to alcohol use disorders.
Timeline of events during the Alcohol Challenge Session. At time 0, placebo was administered, using blinding procedures. Three equal doses of alcohol were then administered at 45-min intervals; subjects had 10 minutes to finish each drink. Subjective assessments were obtained at baseline, following each drink, and at 45-minute intervals for the remainder of the session. BAC depicts times at which alcohol concentration was measured.
Blood alcohol concentration achieved over time during the Alcohol Challenge Session. Values reflect mean (SE) time course of blood alcohol level during the alcohol sensitivity session. P denotes time of placebo drink. A denotes times of alcohol drinks.
A. Visual Analog Drug Effect Questionnaire (VAS) “Negative” effects responses to acute alcohol administration by GABRA2 SNP rs279858. Values reflect unadjusted means (SE). P denotes time of placebo drink. A denotes times of alcohol drinks. Subjects homozygous (n= 14) or heterozygous (n=31) for the minor allele, C, reported on average a lower mean change from baseline “Negative” effects than those homozygous for the common allele (n=23) (p=0.0060).B. Visual Analog Drug Effect Questionnaire (VAS) “Negative” effects responses to acute alcohol administration by GABRA2 SNP rs279836. Values reflect unadjusted means (SE). P denotes time of placebo drink. A denotes times of alcohol drinks. Subjects homozygous (n= 14) or heterozygous (n=33) for the minor allele, A, reported on average a lower mean change from baseline “Negative” effects than those homozygous for the common allele (n=21) (p=0.0061).
Pattern of linkage disequilibrium (LD) within the tagging SNPs genotyped across the Chromosome 4 region that contains GABRA2 in the Caucasian population. The numbers on the top correspond to each SNP’s rs number as named in Table 1. Each number in the diamonds represents LD (D′) values for the respective SNP pairs. ◆, Absolute LD (D′=1); 95, D′: 0.95 between SNPs 3 and 13.
Visual Analog Drug Effect Questionnaire (VAS) “Negative” effects responses to acute alcohol administration by Haplotype block1, haplotype 1, GTGGTACCTCTTAGCAGC (B1,H1). Values reflect unadjusted means (SE). P denotes time of placebo drink. A denotes times of alcohol drinks. Subjects who were carriers of one or two copies of B1,H1, predominantly a minor allele haplotype (n=24), reported on average significantly lower mean change from baseline alcohol “Negative” effects (which is the sum of “Bad, Dislike and Worst” effects responses) than non-carriers (n=28) (p=0.0492).
| # | Section | Preview |
|---|---|---|
| 20 | Subjects and Methods — Genotyping Procedures — Genotyping for population markers | City, CA) at 94°C for 12 minutes followed by 40 cycles of 94°C for 30 sec., 55°C for 30 sec.,… |
| 21 | Subjects and Methods — Statistical Analysis | Summary values for demographic characteristics are expressed as means (SD) for continuous variables… |
| 22 | Subjects and Methods — Statistical Analysis — Population substructure | The population analysis software Structure 2.3.3 (developed by J. Pritchard from University of… |
| 23 | Subjects and Methods — Statistical Analysis — Population substructure | We conducted two different sets of analyses to assess the effect of genotype and haplotypes on the… |
| 24 | Subjects and Methods — Statistical Analysis — Population substructure | In addition, we evaluated if the placebo drink was believable for participants. We observed that the… |
| 25 | Subjects and Methods — Statistical Analysis — A. Individual SNP analysis | The linear mixed effects model included a contrast for genotype differences as a major predictor,… |
| 26 | Subjects and Methods — Statistical Analysis — Determining significance level for individual SNP analysis | The conventional alpha or Type I error level to declare a finding significant (p<0.05) was corrected… |
| 27 | Subjects and Methods — Statistical Analysis — B. Haplotype analysis | Given that our sample was predominantly Caucasian (see Table 2), the haplotype analysis was limited… |
| 28 | Subjects and Methods — Statistical Analysis — B.1. Reconstruction of haplotypes in the study cohort (Caucasian population) | The program Haploview (v4.2) was used to delineate haplotype blocks (Barrett et al., 2005).… |
| 29 | Subjects and Methods — Statistical Analysis — B.1. Reconstruction of haplotypes in the study cohort (Caucasian population) | All association analyses were performed using the SAS software, version 9.2 (SAS Institute Inc,… |
| 30 | Results — 1. Demographics | Demographic characteristics for the participants who underwent the alcohol challenge are presented… |
| 31 | Results — 2. Blood alcohol level | As shown in Figure 2, a range of BAC levels obtained over time captured both the ascending and… |
| 32 | Results — 3. Individual SNPs effects on Subjective Responses to Alcohol — 3. A. Visual Analog Drug Effect Questionnaire (VAS) | During the alcohol challenge session, subjects with one or two copies of the minor alleles for the… |
| 33 | Results — 3. Individual SNPs effects on Subjective Responses to Alcohol — 3. A. Visual Analog Drug Effect Questionnaire (VAS) | p=0.0045). rs279826: Negative effects score was lower in carriers of the minor allele, G, than in… |
| 34 | Results — 3. Individual SNPs effects on Subjective Responses to Alcohol — 3. A. Visual Analog Drug Effect Questionnaire (VAS) | We did not observe significant association of individual SNPs with alcohol’s positive and… |
| 35 | Results — 4. Haplotype block structure in the Caucasian cohort | Two main haplotype blocks were observed (Figure 4). The first haplotype block includes SNPs… |
| 36 | Results — 5. Haplotype effects on Subjective Responses to Alcohol — 5. A. Block 1: intergenic region 5′ GABRG1-3′ GABRA2 and GABRA2 region — 5. A.1. Visual Analog Drug Effect Questionnaire (VAS) | Carriers of one or two copies of block 1, haplotype 1, GTGGTACCTCTTAGCAGC, had significantly lower… |
| 37 | Results — 5. Haplotype effects on Subjective Responses to Alcohol — 5. A. Block 1: intergenic region 5′ GABRG1-3′ GABRA2 and GABRA2 region — 5. A.2. Biphasic Alcohol Effects Scale (BAES) | Carriers of one or two copies of block 1, haplotype 3, ACTATGTTGTTATAATAT, had significantly higher… |
| 38 | Results — 5. Haplotype effects on Subjective Responses to Alcohol — 5. A. Block 1: intergenic region 5′ GABRG1-3′ GABRA2 and GABRA2 region — 5. A.3. Subjective High Assessment Scale (SHAS) | Carriers of one or two copies of block 1, haplotype 4, ACGATGTTGTTATAATAT, had significantly lower… |
| 39 | Results — 5. Haplotype effects on Subjective Responses to Alcohol — 5. B. Block 2: GABRA2 region — 5. A.1. Visual Analog Drug Effect Questionnaire (VAS) | Carriers of one or two copies of block 2, haplotype 1, GT, had significantly higher mean alcohol… |
| Name | Type |
|---|---|
| 3′-GABRA2 polymorphisms local | variant |
| 6-FAM | drug |
| ABI 7900HT Sequence Detection System local | drug |
| ACGATGTTGTTATAATAT local | variant |
| ACKR1 local | gene |
| ACTATGTTGTTATAATAT local | variant |
| age | phenotype |
| alcohol | phenotype |
| Alcohol challenge participants local | cohort |
| alcohol dependence | phenotype |
| Alcohol_dependence | phenotype |
| alcohol High effects local | phenotype |
| alcoholized beverage local | drug |
| Alcohol Negative Effects local | phenotype |
| Alcohol Negative effects score local | phenotype |
| Alcohol sedative effects local | phenotype |
| alcohol sensitivity | phenotype |
| Alcohol Use Disorder | phenotype |
| alcohol use disorders | phenotype |
| Alzheimer's disease | phenotype |
| antidepressants | drug |
| antipsychotics | drug |
| appetite suppressants local | drug |
| AUD | phenotype |
| BAC | phenotype |
| BAC levels local | phenotype |
| Bad Effects | phenotype |
| Baltimore Healthy Young Adult Cohort local | cohort |
| benzodiazepines | drug |
| BEST local | phenotype |
| Biphasic Alcohol Effects Scale (BAES) | phenotype |
| block 1 | variant |
| block1_haplotype4 local | variant |
| Block1_Haplotype4 local | variant |
| Block2_Haplotype1 local | variant |
| block 2 haplotype 1 GT local | variant |
| blood alcohol concentration | phenotype |
| blood alcohol level | phenotype |
| Blood alcohol level (BAC) local | phenotype |
| blood ethanol concentration | phenotype |
| Breath alcohol level | phenotype |
| Caucasian | cohort |
| Caucasian participants | cohort |
| Caucasian subsample local | cohort |
| cigarettes | phenotype |
| Collaborative Study on the Genetics of Alcoholism (COGA) | cohort |
| Custom TaqMan® SNP Genotyping Assay local | drug |
| D10S1786 local | variant |
| D10S197 local | variant |
| D11S935 local | variant |
| D12S352 local | variant |
| D15S1002 local | variant |
| D16S3017 local | variant |
| D17S799 local | variant |
| D1S196 local | variant |
| D1S252 local | variant |
| D1S2628 local | variant |
| D22S274 local | variant |
| D2S162 local | variant |
| D2S319 local | variant |
| D5S407 local | variant |
| D5S410 local | variant |
| D6S1610 local | variant |
| D7S2469 local | variant |
| D7S640 local | variant |
| D7S657 local | variant |
| D8S1827 local | variant |
| D8S272 local | variant |
| D9S175 local | variant |
| demographic characteristics local | cohort |
| DISLIKE local | phenotype |
| dNTPs | drug |
| dopaminergic medications local | drug |
| drinking | phenotype |
| drug dependence | phenotype |
| Drunk or Intoxicated local | phenotype |
| DSM-IV | phenotype |
| EEG β power local | phenotype |
| ethanol consumption | phenotype |
| GABA | phenotype |
| GABAA receptor | drug |
| GABAB receptor | drug |
| GABAergic function local | phenotype |
| GABRA2 | gene |
| Gabrg1 | gene |
| genetic ancestry proportion local | phenotype |
| genetic variants | cohort |
| genotype differences local | variant |
| genotype group local | cohort |
| glucocorticoids | drug |
| GOOD effects local | phenotype |
| GTGGTACCTCTTAGCAGC local | variant |
| haplotype | variant |
| Haplotype 1 local | variant |
| Haplotype 4 local | variant |
| Haplotypes in GABRA2 local | variant |
| Healthy social drinkers local | cohort |
| heavy drinking | phenotype |
| heavy/hazardous drinking local | phenotype |
| high | phenotype |
| International Hapmap Project | cohort |
| Intoxicated effects local | phenotype |
| Italian sample local | cohort |
| Johns Hopkins General Clinical Research Unit local | cohort |
| Kool-Aid local | drug |
| LIKE local | phenotype |
| limbic regions | anatomy |
| lower negative responses to alcohol local | phenotype |
| Low level of overall response to alcohol local | phenotype |
| low level of response | phenotype |
| Master Mix local | drug |
| medication | drug |
| MgCl2 | drug |
| Negative alcohol effects local | phenotype |
| Negative effects local | phenotype |
| Negative effects of alcohol local | phenotype |
| Negative effects score local | phenotype |
| opioid | drug |
| outcome of interest local | phenotype |
| participants | cohort |
| PET® local | drug |
| placebo beverage | drug |
| Positive alcohol effects local | phenotype |
| Positive and stimulant effects local | phenotype |
| Positive effects local | phenotype |
| Positive_Effects_of_Alcohol local | phenotype |
| psychoactive medications local | drug |
| rs279826 | variant |
| rs279828 local | variant |
| rs279836 | variant |
| rs279844 local | variant |
| rs279845 | variant |
| rs279858 | variant |
| rs2814778 | variant |
| SDS v2.1 software local | drug |
| sedative effects | phenotype |
| sedatives | drug |
| serious medical conditions local | phenotype |
| sex | phenotype |
| SHAS High local | phenotype |
| SHAS subjective response scores local | phenotype |
| SNP | cohort |
| SNPs in 3′GABRA2-5′GABRG1 intergenic region local | variant |
| SNPs in GABRA2 local | variant |
| stimulant effects | drug |
| Stimulant_Effects_of_Alcohol local | phenotype |
| stimulation | phenotype |
| study cohort | cohort |
| Subjective High Assessment Scale (SHAS) | phenotype |
| Subjective_High_Effects_of_Alcohol local | phenotype |
| subjective measurements local | phenotype |
| Taq Gold polymerase local | drug |
| TaqMan® Pre-Designed SNP Genotyping Assays local | drug |
| VIC | drug |
| Visual Analog Drug Effect Questionnaire local | phenotype |
| WORST local | phenotype |
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External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Association Between GABRG2 and Self-Rating of the Effects of Alcohol in a French Young Adult Sample. | Moe JS et al. | — | 2025 | → |
| Genomic factors associated with substance use disorder relapse: A critical review. | Al-Marzooqi N et al. | — | 2024 | → |
| FACTORS CONTRIBUTING TO THE ESCALATION OF ALCOHOL CONSUMPTION. | Bowen MT et al. | — | 2022 | → |
| GABA<sub>A</sub> subunit single nucleotide polymorphisms show sex-specific association to alcohol consumption and mental distress in a Norwegian population-based sample. | Moe JS et al. | — | 2022 | → |
| Sex differences in GABA<sub>A</sub> receptor subunit transcript expression are mediated by genotype in subjects with alcohol-related cirrhosis of the liver. | Ashton MK et al. | — | 2022 | → |
| The effects of oral and vaporized cannabis alone, and in combination with alcohol, on driving performance using the STISIM driving simulator: A two-part, double-blind, double-dummy, placebo-controlled, randomized crossover clinical laboratory protocol. | Zamarripa CA et al. | — | 2022 | → |
| History of regular nonmedical sedative and/or alcohol use differentiates substance-use patterns and consequences among chronic heroin users. | Moses TEH et al. | — | 2019 | → |
| Identification of a functional non-coding variant in the GABA<sub>A</sub> receptor α2 subunit of the C57BL/6J mouse reference genome: Major implications for neuroscience research | Mulligan MK et al. | — | 2019 | — |
| Identification of a Functional Non-coding Variant in the GABA <sub><i>A</i></sub> Receptor α2 Subunit of the C57BL/6J Mouse Reference Genome: Major Implications for Neuroscience Research. | Mulligan MK et al. | — | 2019 | → |
| A Critical Review of Methods and Results in the Search for Genetic Contributors to Alcohol Sensitivity. | Schuckit MA | — | 2018 | → |
| GABA<sub>A</sub> receptor polymorphisms in alcohol use disorder in the GWAS era. | Koulentaki M et al. | — | 2018 | → |
| GABA<sub>A</sub> Receptor Subtype Mechanisms and the Abuse-Related Effects of Ethanol: Genetic and Pharmacological Evidence. | Chandler CM et al. | — | 2018 | → |
| GABRA2, alcohol, and illicit drug use: An event-level model of genetic risk for polysubstance use. | Mallard TT et al. | — | 2018 | → |
| Post-GWAS in Psychiatric Genetics: A Developmental Perspective on the "Other" Next Steps. | Dick DM et al. | — | 2018 | → |
| PROSPER Intervention Effects on Adolescents' Alcohol Misuse Vary by GABRA2 Genotype and Age. | Russell MA et al. | — | 2018 | → |
| Sex and β-Endorphin Influence the Effects of Ethanol on Limbic <i>Gabra2</i> Expression in a Mouse Binge Drinking Model. | Rhinehart EM et al. | — | 2018 | → |
| GABA<sub>A</sub> receptor subtype involvement in addictive behaviour. | Stephens DN et al. | — | 2017 | → |
| GRIK1 and GABRA2 Variants Have Distinct Effects on the Dose-Related Subjective Response to Intravenous Alcohol in Healthy Social Drinkers. | Yang BZ et al. | — | 2017 | → |
| Independent and Interactive Effects of OPRM1 and DAT1 Polymorphisms on Alcohol Consumption and Subjective Responses in Social Drinkers. | Weerts EM et al. | — | 2017 | → |
| Network analysis of the genomic basis of the placebo effect. | Wang RS et al. | — | 2017 | → |
| Promising pharmacogenetic targets for treating alcohol use disorder: evidence from preclinical models. | Rinker JA et al. | — | 2017 | → |
| Alcohol-Induced Stimulation Mediates the Effect of a GABRA2 SNP on Alcohol Self-Administrated among Alcohol-Dependent Individuals. | Boyd SJ et al. | — | 2016 | → |
| Mechanisms in the relation between GABRA2 and adolescent externalizing problems. | Wang FL et al. | — | 2016 | → |
| Subjective Response to Alcohol as a Research Domain Criterion. | Ray LA et al. | — | 2016 | → |
| Adaptation of Subjective Responses to Alcohol is Affected by an Interaction of GABRA2 Genotype and Recent Drinking. | Kosobud AE et al. | — | 2015 | → |
| Deletion of the Wolfram syndrome-related gene Wfs1 results in increased sensitivity to ethanol in female mice. | Raud S et al. | — | 2015 | → |
| Endophenotypes for Alcohol Use Disorder: An Update on the Field. | Salvatore JE et al. | — | 2015 | → |
| Role of <i>gabra2</i>, GABA<sub>A</sub> receptor alpha-2 subunit, in CNS development. | Gonzalez-Nunez V | — | 2015 | → |
| Subjective response as a consideration in the pharmacogenetics of alcoholism treatment. | Roche DJ et al. | — | 2015 | → |
| The pharmacogenetics of alcohol use disorder. | Jones JD et al. | — | 2015 | → |
| α2-containing GABA(A) receptors: a requirement for midazolam-escalated aggression and social approach in mice. | Newman EL et al. | — | 2015 | → |
| A GABRA2 variant is associated with increased stimulation and 'high' following alcohol administration. | Arias AJ et al. | — | 2014 | → |
| Dutasteride reduces alcohol's sedative effects in men in a human laboratory setting and reduces drinking in the natural environment. | Covault J et al. | — | 2014 | → |
| GABAergic contributions to alcohol responsivity during adolescence: insights from preclinical and clinical studies. | Silveri MM | — | 2014 | → |
| Genetic influences on response to alcohol and response to pharmacotherapies for alcoholism. | Enoch MA | — | 2014 | → |
| The Genetics, Neurogenetics and Pharmacogenetics of Addiction. | Demers CH et al. | — | 2014 | → |
| Effects of family history of alcohol dependence on the subjective response to alcohol using the intravenous alcohol clamp. | Kerfoot K et al. | — | 2013 | → |
| Effects of the benzodiazepine GABAA α1-preferring ligand, 3-propoxy-β-carboline hydrochloride (3-PBC), on alcohol seeking and self-administration in baboons. | Kaminski BJ et al. | — | 2013 | → |
| Ethanol-induced alterations of amino acids measured by in vivo microdialysis in rats: a meta-analysis. | Fliegel S et al. | — | 2013 | → |
| Impulsiveness mediates the association between GABRA2 SNPs and lifetime alcohol problems. | Villafuerte S et al. | — | 2013 | → |
| Linking GABA(A) receptor subunits to alcohol-induced conditioned taste aversion and recovery from acute alcohol intoxication. | Blednov YA et al. | — | 2013 | → |