基于两个人群队列的酒精使用障碍识别测试（AUDIT）全基因组关联研究的荟萃分析。
Genome-Wide Association Study Meta-Analysis of the Alcohol Use Disorders Identification Test (AUDIT) in Two Population-Based Cohorts.
机构信息
From the Department of Psychiatry and the Institute for Genomic Medicine, University of California San Diego, La Jolla; 23andMe, Inc., Mountain View, Calif.; the Division of Psychiatry, the Department of Psychology, and the Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, U.K.; the Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis; and the Translational Research Laboratories, Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia.
出版信息
Am J Psychiatry. 2019 Feb 1;176(2):107-118. doi: 10.1176/appi.ajp.2018.18040369. Epub 2018 Oct 19.
OBJECTIVE
Alcohol use disorders are common conditions that have enormous social and economic consequences. Genome-wide association analyses were performed to identify genetic variants associated with a proxy measure of alcohol consumption and alcohol misuse and to explore the shared genetic basis between these measures and other substance use, psychiatric, and behavioral traits.
METHOD
This study used quantitative measures from the Alcohol Use Disorders Identification Test (AUDIT) from two population-based cohorts of European ancestry (UK Biobank [N=121,604] and 23andMe [N=20,328]) and performed a genome-wide association study (GWAS) meta-analysis. Two additional GWAS analyses were performed, a GWAS for AUDIT scores on items 1-3, which focus on consumption (AUDIT-C), and for scores on items 4-10, which focus on the problematic consequences of drinking (AUDIT-P).
RESULTS
The GWAS meta-analysis of AUDIT total score identified 10 associated risk loci. Novel associations localized to genes including JCAD and SLC39A13; this study also replicated previously identified signals in the genes ADH1B, ADH1C, KLB, and GCKR. The dimensions of AUDIT showed positive genetic correlations with alcohol consumption (r=0.76-0.92) and DSM-IV alcohol dependence (r=0.33-0.63). AUDIT-P and AUDIT-C scores showed significantly different patterns of association across a number of traits, including psychiatric disorders. AUDIT-P score was significantly positively genetically correlated with schizophrenia (r=0.22), major depressive disorder (r=0.26), and attention deficit hyperactivity disorder (r=0.23), whereas AUDIT-C score was significantly negatively genetically correlated with major depressive disorder (r=-0.24) and ADHD (r=-0.10). This study also used the AUDIT data in the UK Biobank to identify thresholds for dichotomizing AUDIT total score that optimize genetic correlations with DSM-IV alcohol dependence. Coding individuals with AUDIT total scores ≤4 as control subjects and those with scores ≥12 as case subjects produced a significant high genetic correlation with DSM-IV alcohol dependence (r=0.82) while retaining most subjects.
CONCLUSIONS
AUDIT scores ascertained in population-based cohorts can be used to explore the genetic basis of both alcohol consumption and alcohol use disorders.
目的
酒精使用障碍是常见病症，会产生巨大的社会和经济后果。本研究进行全基因组关联分析，以确定与酒精摄入和酒精使用障碍的替代测量值相关的遗传变异，并探讨这些测量值与其他物质使用、精神疾病和行为特征之间的共同遗传基础。
方法
本研究使用来自两个欧洲血统的基于人群的队列（英国生物库[N=121604]和 23andMe[N=20328]）的酒精使用障碍识别测试（AUDIT）的定量测量值，并进行全基因组关联研究（GWAS）荟萃分析。还进行了另外两项 GWAS 分析，一项是 AUDIT 总分项目 1-3（主要关注消费）的 GWAS，另一项是 AUDIT 总分项目 4-10（主要关注饮酒的不良后果）的 GWAS。
结果
AUDIT 总分的 GWAS 荟萃分析确定了 10 个相关风险位点。新的关联定位于包括 JCAD 和 SLC39A13 在内的基因；本研究还在 ADH1B、ADH1C、KLB 和 GCKR 基因中复制了先前确定的信号。AUDIT 的各个维度与酒精摄入量（r=0.76-0.92）和 DSM-IV 酒精依赖（r=0.33-0.63）呈正遗传相关。AUDIT-P 和 AUDIT-C 评分在包括精神疾病在内的许多特征上表现出明显不同的关联模式。AUDIT-P 评分与精神分裂症（r=0.22）、重度抑郁症（r=0.26）和注意力缺陷多动障碍（r=0.23）呈显著正遗传相关，而 AUDIT-C 评分与重度抑郁症（r=-0.24）和 ADHD（r=-0.10）呈显著负遗传相关。本研究还使用英国生物库中的 AUDIT 数据确定了将 AUDIT 总分二分法以优化与 DSM-IV 酒精依赖的遗传相关性的阈值。将 AUDIT 总分≤4 的个体编码为对照，将得分≥12 的个体编码为病例，与 DSM-IV 酒精依赖产生显著的高遗传相关性（r=0.82），同时保留了大多数个体。
结论
基于人群的队列中确定的 AUDIT 评分可用于探索酒精摄入和酒精使用障碍的遗传基础。
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