Department of Psychological Sciences, University of Missouri, Columbia, Missouri.
Renaissance Computing Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
J Stud Alcohol Drugs. 2019 Nov;80(6):585-593. doi: 10.15288/jsad.2019.80.585.
Epidemiological estimates suggest that nearly half of individuals diagnosed with alcohol use disorder will be diagnosed with another mental health disorder, with strong associations involving other externalizing disorders. Molecular genetic studies investigating the relation between alcohol use disorder and externalizing behaviors (e.g., antisocial behavior) have focused on a cluster of chromosome 4 γ-aminobutyric acid (GABA) receptor genes (GABRG1-A2-A4-B1) but have generated varying results.
The current study examined associations between common and rare variation in this region with alcohol use disorder and antisocial behavior using genetic sequencing data. Specifically, the University of California at San Francisco Family Alcoholism Sample (n = 1,610; 62% female) was used to conduct common and rare variant association tests in the GABRG1-A2-A4-B1 cluster with DSM-5 alcohol use disorder symptom counts, antisocial behavior, and a product term representing their interaction.
Gene-based analyses of rare variation resulted in a significant association between rare GABRA2 variation and the interaction term. Single-variant analysis yielded only nominally significant associations. The strongest association for alcohol use disorder (rs3756007) was located in GABRA2, the strongest association for antisocial behavior (rs11941860) was located in GABRG1, and the interaction term yielded top associations in GABRA2 (rs2119183) and the intergenic region between GABRA2 and GABRG1 (rs536599). Common and rare variant associations for the interaction remained similar when covarying for the effects of the other type of variation, suggesting that the significant rare variant signal is independent of common variant contributions.
The present study suggests that both rare and common variant associations in GABRA2 confer risk for alcohol use disorder and antisocial behaviors, indicating a potential liability toward externalizing behavior more broadly.
流行病学估计表明，近一半被诊断患有酒精使用障碍的个体将被诊断患有另一种心理健康障碍，且与其他外在障碍存在强烈关联。研究酒精使用障碍与外在行为（如反社会行为）之间关系的分子遗传研究集中在一组 4 号染色体γ-氨基丁酸（GABA）受体基因（GABRG1-A2-A4-B1）上，但结果各不相同。
本研究使用遗传测序数据，研究了该区域常见和罕见变异与酒精使用障碍和反社会行为之间的关联。具体来说，使用加利福尼亚大学旧金山分校家庭酗酒样本（n=1610；62%为女性）进行常见和罕见变体关联测试，测试该区域与 DSM-5 酒精使用障碍症状计数、反社会行为以及代表两者相互作用的乘积项之间的关联。
罕见变异的基因分析导致罕见 GABRA2 变异与相互作用项之间存在显著关联。单变异分析仅产生名义上显著的关联。酒精使用障碍最强的关联（rs3756007）位于 GABRA2，反社会行为最强的关联（rs11941860）位于 GABRG1，相互作用项在 GABRA2（rs2119183）和 GABRA2 与 GABRG1 之间的基因间区域（rs536599）产生了最强的关联。当共变量为其他类型的变异的影响时，酒精使用障碍和反社会行为的相互作用的常见和罕见变异关联仍然相似，这表明显著的罕见变异信号独立于常见变异的贡献。
本研究表明，GABRA2 中的罕见和常见变异关联均会增加酒精使用障碍和反社会行为的风险，这表明更广泛地存在外在行为的潜在倾向。
