Kuperman Samuel, Chan Grace, Kramer John, Wetherill Leah, Acion Laura, Edenberg Howard J, Foroud Tatiana M, Nurnberger John, Agrawal Arpana, Anokhin Andrey, Brooks Andrew, Hesselbrock Victor, Hesselbrock Michie, Schuckit Marc, Tischfield Jay, Liu Xiangtao
Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
Department of Psychiatry, University of Connecticut Health Center, Farmington, CT, USA.
Alcohol. 2017 Sep;63:1-8. doi: 10.1016/j.alcohol.2017.03.003. Epub 2017 Jun 28.
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.
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.
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.
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.
生存分析用于探究单核苷酸多态性（SNP）及协变量（性别、访谈年龄和血统）对先前发表模型预测饮酒起始能力的影响。位于4号染色体上编码γ-氨基丁酸受体（GABRA2）的基因中的rs279871 SNP变体被选中，因为它与青少年酒精中毒以及增加早期饮酒风险的行为有关。
使用先前推导的Cox比例风险模型对参与酒精中毒遗传学合作研究（COGA）的674名青少年（14 - 17岁）的子样本进行检查，该模型包含：1）与饮酒无关的品行障碍（CD）症状数量，2）高危酒精依赖（AD）家族成员身份，3）大多数最好的朋友饮酒（MBFD），4）阿肯巴克青少年自我报告（YSR）外化得分，以及5）YSR社会问题得分。将上述协变量以及GABRA2的SNP变体rs279871添加到该模型中。检查了五个新的原型模型。根据似然比检验和模型拟合统计选择最简约的模型。
最终模型包含五个原始预测因子中的四个（YSR社会问题得分不再显著，因此从后续模型中剔除）、三个协变量以及隐性GABRA2 rs279871 TT基因型（包含胸腺嘧啶的高危等位基因的两个拷贝）。该模型表明，具有高危TT基因型的青少年比没有这种基因型的青少年更有可能开始饮酒。
在控制行为问题（CD和YSR外化得分）后，基因（rs279871 TT基因型）和环境（MBFD）对青少年饮酒起始的联合效应是相加的，但不是交互的。这表明高危TT基因型对饮酒起始的影响受控制同伴饮酒的影响，且不包括基因 - 环境交互作用。
