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).
| 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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