Samuel Kuperman1, Grace Chan2, John Kramer3, Leah Wetherill4, Laura Acion3, Howard J Edenberg5, Tatiana M Foroud4, John Nurnberger6, Arpana Agrawal7, Andrey Anokhin7, Andrew Brooks8, Victor Hesselbrock2, Michie Hesselbrock2, Marc Schuckit9, Jay Tischfield8, Xiangtao Liu3. 1. Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA. Electronic address: samuel-kuperman@uiowa.edu. 2. Department of Psychiatry, University of Connecticut Health Center, Farmington, CT, USA. 3. Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA. 4. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA. 5. Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA. 6. Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA. 7. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA. 8. Department of Genetics, Rutgers University, Piscataway, NJ, USA. 9. Department of Psychiatry, University of California San Diego School of Medicine, La Jolla, CA, USA.
Abstract
BACKGROUND: Survival analysis was used to explore the addition of a single nucleotide polymorphism (SNP) and covariates (sex, interview age, and ancestry) on a previously published model's ability to predict onset of drinking. A SNP variant of rs279871, in the chromosome 4 gene encoding gamma-aminobutyric acid receptor (GABRA2), was selected due to its associations with alcoholism in young adults and with behaviors that increased risk for early drinking. METHODS: A subsample of 674 adolescents (ages 14-17) participating in the Collaborative Study on the Genetics of Alcoholism (COGA) was examined using a previously derived Cox proportional hazards model containing: 1) number of non-drinking related conduct disorder (CD) symptoms, 2) membership in a high-risk alcohol-dependent (AD) family, 3) most best friends drank (MBFD), 4) Achenbach Youth Self Report (YSR) externalizing score, and 5) YSR social problems score. The above covariates along with the SNP variant of GABRA2, rs279871, were added to this model. Five new prototype models were examined. The most parsimonious model was chosen based on likelihood ratio tests and model fit statistics. RESULTS: The final model contained four of the five original predictors (YSR social problems score was no longer significant and hence dropped from subsequent models), the three covariates, and a recessive GABRA2 rs279871 TT genotype (two copies of the high-risk allele containing thymine). The model indicated that adolescents with the high-risk TT genotype were more likely to begin drinking than those without this genotype. CONCLUSIONS: The joint effect of the gene (rs279871 TT genotype) and environment (MBFD) on adolescent alcohol initiation is additive, but not interactive, after controlling for behavior problems (CD and YSR externalizing score). This suggests that the impact of the high-risk TT genotype on the onset of drinking is affected by controlling for peer drinking and does not include genotype-by-environment interactions.
BACKGROUND: Survival analysis was used to explore the addition of a single nucleotide polymorphism (SNP) and covariates (sex, interview age, and ancestry) on a previously published model's ability to predict onset of drinking. A SNP variant of rs279871, in the chromosome 4 gene encoding gamma-aminobutyric acid receptor (GABRA2), was selected due to its associations with alcoholism in young adults and with behaviors that increased risk for early drinking. METHODS: A subsample of 674 adolescents (ages 14-17) participating in the Collaborative Study on the Genetics of Alcoholism (COGA) was examined using a previously derived Cox proportional hazards model containing: 1) number of non-drinking related conduct disorder (CD) symptoms, 2) membership in a high-risk alcohol-dependent (AD) family, 3) most best friends drank (MBFD), 4) Achenbach Youth Self Report (YSR) externalizing score, and 5) YSR social problems score. The above covariates along with the SNP variant of GABRA2, rs279871, were added to this model. Five new prototype models were examined. The most parsimonious model was chosen based on likelihood ratio tests and model fit statistics. RESULTS: The final model contained four of the five original predictors (YSR social problems score was no longer significant and hence dropped from subsequent models), the three covariates, and a recessive GABRA2rs279871 TT genotype (two copies of the high-risk allele containing thymine). The model indicated that adolescents with the high-risk TT genotype were more likely to begin drinking than those without this genotype. CONCLUSIONS: The joint effect of the gene (rs279871 TT genotype) and environment (MBFD) on adolescent alcohol initiation is additive, but not interactive, after controlling for behavior problems (CD and YSR externalizing score). This suggests that the impact of the high-risk TT genotype on the onset of drinking is affected by controlling for peer drinking and does not include genotype-by-environment interactions.
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