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KCNJ6 is associated with adult alcohol dependence and involved in gene × early life stress interactions in adolescent alcohol drinking.

ABSTRACT: Alcohol abuse and dependence have proven to be complex genetic traits that are influenced by environmental factors. Primate and human studies have shown that early life stress increases the propensity for alcohol abuse in later life. The reinforcing properties of alcohol are mediated by dopaminergic signaling; however, there is little evidence to indicate how stress alters alcohol reinforcement. KCNJ6 (the gene encoding G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2)) is a brain expressed potassium channel with inhibitory effects on dopaminergic tone. The properties of GIRK2 have been shown to be enhanced by the stress peptide corticotrophin-releasing hormone. Therefore, we sought to examine the role of KCNJ6 polymorphisms in adult alcohol dependence and stress-related alcohol abuse in adolescents. We selected 11 SNPs in the promoter region of KCNJ6, which were genotyped in 1152 adult alcohol dependents and 1203 controls. One SNP, rs2836016, was found to be associated with alcohol dependence (p=0.01, false discovery rate). We then assessed rs2836016 in an adolescent sample of 261 subjects, which were characterized for early life stress and adolescent hazardous drinking, defined using the Alcohol Use Disorders Identification Test (AUDIT), to examine gene-environment interactions. In the adolescent sample, the risk genotype of rs2836016 was significantly associated with increased AUDIT scores, but only in those individuals exposed to high levels of psychosocial stress in early life (p=0.01). Our findings show that KCNJ6 is associated with alcohol dependence and may moderate the effect of early psychosocial stress on risky alcohol drinking in adolescents. We have identified a candidate gene for future studies investigating a possible functional link between the response to stress and alcohol reinforcement.

SUBMITTER: Clarke TK

PROVIDER: S-EPMC3079832 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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KCNJ6 is associated with adult alcohol dependence and involved in gene × early life stress interactions in adolescent alcohol drinking.

Clarke Toni-Kim TK Laucht Manfred M Ridinger Monika M Wodarz Norbert N Rietschel Marcella M Maier Wolfgang W Lathrop Mark M Lourdusamy Anbarasu A Zimmermann Ulrich S US Desrivieres Sylvane S Schumann Gunter G

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20110209 6

Alcohol abuse and dependence have proven to be complex genetic traits that are influenced by environmental factors. Primate and human studies have shown that early life stress increases the propensity for alcohol abuse in later life. The reinforcing properties of alcohol are mediated by dopaminergic signaling; however, there is little evidence to indicate how stress alters alcohol reinforcement. KCNJ6 (the gene encoding G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2)) is a brai ...[more]

PMID: 21307845

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Project description:Adolescent alcohol abuse is associated with adverse outcomes in early adulthood, but differences in familial status and structure and household and community environments correlate with both adolescent drinking and adverse adult outcomes and may explain their association. We studied drinking-discordant twin pairs to evaluate such confounds to ask: Will between-family associations replicate in within-family comparisons?With longitudinal data from >3,000 Finnish twins, we associated drinking problems at age 18½ with 13 outcomes assessed at age 25; included were sustained substance abuse, poor health, physical symptoms, early coital debut, multiple sexual partners, life dissatisfaction, truncated education, and financial problems. We assessed associations among twins as individuals with linear regression adjusted for correlated observations; within-family analyses of discordant twin pairs followed, comparing paired means for adult outcomes among co-twins discordant for adolescent problem drinking. Defining discordance by extreme scores on self-reported problem drinking at age 18½ permitted parallel analyses of twins as individuals and discordant twin pairs. Alternate definitions of pair-wise discordance and difference score correlations across the entire twin sample yielded supplementary analyses.All individual associations were highly significant for all definitions of discordance we employed. Depending on definitions of discordance, 11 to 13 comparisons of all drinking-discordant twin pairs and 3 to 6 comparisons of discordant monozygotic (MZ) twin pairs replicated between-family associations. For most outcomes, effect size attenuated from individual-level analysis to that within discordant MZ twin pairs providing evidence of partial confounding in associations reported in earlier research. The exception was the General Health Questionnaire (GHQ); at age 25, GHQ-12 had equivalent associations with age 18½ Rutgers Alcohol Problem Index across all comparisons.Our analyses control for shared family background, and, partly or fully, for shared genes, to yield within-family replications and more compelling evidence than previously available that adolescent alcohol abuse disrupts transitions into early adulthood.

Dataset Information

KCNJ6 is associated with adult alcohol dependence and involved in gene × early life stress interactions in adolescent alcohol drinking.

Publications

KCNJ6 is associated with adult alcohol dependence and involved in gene × early life stress interactions in adolescent alcohol drinking.

Similar Datasets

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