Impulsiveness and insula activation during reward anticipation are associated with genetic variants in GABRA2 in a family sample enriched for alcoholism.
paper
Cited
Public
- Authors
- Villafuerte, S; Heitzeg, M M; Foley, S; Yau, W-Y Wendy; Majczenko, K; Zubieta, J-K; Zucker, R A; Burmeister, M
- Year
- 2012
- Journal
- Molecular psychiatry
- PMID
- 21483437
- DOI
- 10.1038/mp.2011.33
- PMCID
- PMC3166450
Genetic factors, externalizing personality traits such as impulsivity, and brain processing of salient stimuli all can affect individual risk for alcoholism. One of very few confirmed genetic association findings differentiating alcoholics from non-alcoholics is with variants in the inhibitory Ξ³-amino butyric acid Ξ±2 receptor subunit (GABRA2) gene. Here we report the association of two of these GABRA2 variants with measures of alcohol symptoms, impulsivity and with insula cortex activation during anticipation of reward or loss using functional magnetic resonance imaging (fMRI). In a sample of 173 families (449 subjects), 129 of whom had at least one member diagnosed with alcohol dependence or abuse, carriers for the G allele in two single-nucleotide polymorphisms (SNPs) and haplotypes were more likely to have alcohol dependence symptoms (rs279858, P=0.01; rs279826, P=0.05; haplotype, P=0.02) and higher NEO Personality Inventory-Revised (NEO-PI-R) Impulsiveness scores (rs279858, P=0.016; rs279826, P=0.012; haplotype, P=0.032) with a stronger effect in women (rs279858, P=0.011; rs279826, P=0.002; haplotype, P=0.006), all P-values are corrected for family history and age. A subset of offspring from these families (n=44, 20 females), genotyped for GABRA2, participated in an fMRI study using a monetary incentive delay task. Increased insula activation during reward (r(2)=0.4; P=0.026) and loss (r(2)=0.38; P=0.039) anticipation was correlated with NEO-PI-R Impulsiveness and further associated with the GG genotype for both SNPs (P's<0.04). Our results suggest that GABRA2 genetic variation is associated with Impulsiveness through variation of insula activity responses, here evidenced during anticipatory responses.
A schematic illustration of the monetary incentive delay task performed by subjects in the fMRI scanner.
LLM interpretation
This is a schematic diagram illustrating the timeline and sequence of the monetary incentive delay task. The process flows from left to right through four stages: a "Cue" (Don't Lose, Win, or No Money), "Fixation/Anticipation," a "Target Button variable" (square, circle, or triangle), and a "Feedback variable." Each stage is labeled with its corresponding duration in milliseconds, totaling 5950 ms for a complete trial.
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21β36 of 36
| Name | Type |
|---|---|
| A-A haplotype local | variant |
| Adolescent and young adult offspring local | cohort |
| age | phenotype |
| alcohol | phenotype |
| alcohol abuse | phenotype |
| alcohol dependence | phenotype |
| alcohol dependence symptom percentage local | phenotype |
| Alcohol Dependence Symptoms | phenotype |
| Alcoholic symptomatology local | phenotype |
| alcoholism | phenotype |
| Alcohol Problems | phenotype |
| Alcohol-related measures local | phenotype |
| alcohol-related outcomes | phenotype |
| alcohol-related phenotypes | phenotype |
| alcohol sensitivity | phenotype |
| Alcohol Use Disorder | phenotype |
| American Drinking Practices Survey local | cohort |
| Anticipation of aversive exposure local | phenotype |
| anxiety | phenotype |
| anxiety-like behavior | phenotype |
| Applied Biosystems | drug |
| AUD | phenotype |
| axis I disorder | phenotype |
| biased decision-making local | phenotype |
| brain networks | anatomy |
| Centrally active medications local | drug |
| Childhood conduct disorder symptoms local | phenotype |
| children of alcoholics | cohort |
| Children of alcoholics (COA) local | cohort |
| Children of Alcoholics (COA) local | cohort |
| Collaborative Study on the Genetics of Alcoholism (COGA) | cohort |
| Community-recruited families local | cohort |
| conduct disorder | phenotype |
| Control families | cohort |
| controls | cohort |
| cortex | anatomy |
| craving | phenotype |
| cue-induced urges local | phenotype |
| drug | drug |
| drug dependence | phenotype |
| drugs | drug |
| EEG-Ξ² local | phenotype |
| EEG Ξ² frequency band local | phenotype |
| Externalizing risk behavior for AUD local | phenotype |
| family history positive | phenotype |
| GABA | phenotype |
| GABAA receptor | drug |
| GABRA2 | gene |
| GABRA2 A allele local | variant |
| GABRA2 A-carrier local | variant |
| GABRA2 G allele local | variant |
| GABRA2 GG genotype local | variant |
| GABRA2 G-G haplotype local | variant |
| GABRA2 haplotype A local | variant |
| GABRA2 haplotype G local | variant |
| GABRA2 SNP1 local | variant |
| GABRA2 SNP2 local | variant |
| G allele (GABRA2) local | variant |
| G-G haplotype local | variant |
| haplotype | variant |
| illicit drug dependence | phenotype |
| Impulsiveness (NEO-PI-R) local | phenotype |
| Impulsiveness-related traits local | phenotype |
| impulsivity | phenotype |
| Increased EEG-Ξ² activity local | phenotype |
| insula | anatomy |
| lack of perseverance | phenotype |
| lack of premeditation | phenotype |
| Large sample local | cohort |
| Legal complications local | phenotype |
| limbic regions | anatomy |
| loss | phenotype |
| loss anticipation | phenotype |
| Michigan Longitudinal Study | cohort |
| MLS offspring local | cohort |
| negative affect component local | phenotype |
| Neurological illness local | phenotype |
| neuroticism | phenotype |
| neutral incentive local | phenotype |
| NIDA Survey 1978 local | cohort |
| novelty seeking | phenotype |
| offspring | cohort |
| parents | cohort |
| participants | cohort |
| Plain Indians alcoholics local | cohort |
| problem alcohol consumption local | phenotype |
| progesterone | drug |
| psychological distress | phenotype |
| psychosis | phenotype |
| Rash action local | phenotype |
| reaction time | phenotype |
| relapse | phenotype |
| reward | phenotype |
| reward anticipation | phenotype |
| Risk families local | cohort |
| rs279826 | variant |
| rs279826 A allele local | variant |
| rs279826 G allele local | variant |
| rs279858 | variant |
| rs279858 A allele local | variant |
| rs279858 G allele local | variant |
| schizophrenia | phenotype |
| sex | phenotype |
| Social complications local | phenotype |
| stress | phenotype |
| study cohort | cohort |
| subjective pleasure local | phenotype |
| Subset of samples local | cohort |
| success rate | phenotype |
| TaqMan assay | drug |
| tolerance | phenotype |
| uncertain risk and reward local | phenotype |
| University of Michigan Medical School Institutional Review Board local | cohort |
| Urge local | phenotype |
| urgency | phenotype |
| Urine drug screen local | drug |
| V.A. Medical Center Research Questionnaire for Alcoholics local | cohort |
| whole brain | anatomy |
| withdrawal | phenotype |
| young adult children of alcoholics (COA) local | cohort |
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