Department of Psychology, University of Texas at Austin (Mallard, Grotzinger, Harden); Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam (Savage); Department of Psychiatry, Washington University School of Medicine, Saint Louis (Johnson, Anokhin, Agrawal); Department of Psychiatry (Huang, Jennings, Palmer, Sanchez-Roige) and Institute for Genomic Medicine (Palmer), University of California San Diego, La Jolla; Virginia Institute for Psychiatric and Behavioral Genetics, Richmond (Edwards); Department of Biological Psychiatry, Vrije Universiteit Amsterdam (Hottenga, Nivard, de Geus, Boomsma); Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, Tenn. (Gustavson, Davis, Sanchez-Roige); Department of Psychology, Virginia Commonwealth University, Richmond (Dick); Department of Biochemistry and Molecular Biology (Edenberg) and Department of Medical and Molecular Genetics (Lai), Indiana University School of Medicine, Indianapolis; Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City (Kramer); Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, N.Y. (Meyers, Pandey); Department of Psychiatry and Behavioral Sciences and Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tenn. (Davis); Division of Psychiatry, University of Edinburgh, Edinburgh, U.K. (Clarke).
Am J Psychiatry. 2022 Jan;179(1):58-70. doi: 10.1176/appi.ajp.2020.20091390. Epub 2021 May 14.
Genome-wide association studies (GWASs) of the Alcohol Use Disorders Identification Test (AUDIT), a 10-item screen for alcohol use disorder (AUD), have elucidated novel loci for alcohol consumption and misuse. However, these studies also revealed that GWASs can be influenced by numerous biases (e.g., measurement error, selection bias), which may have led to inconsistent genetic correlations between alcohol involvement and AUD, as well as paradoxically negative genetic correlations between alcohol involvement and psychiatric disorders and/or medical conditions. The authors used genomic structural equation modeling to elucidate the genetics of alcohol consumption and problematic consequences of alcohol use as measured by AUDIT.
To explore these unexpected differences in genetic correlations, the authors conducted the first item-level and the largest GWAS of AUDIT items (N=160,824) and applied a multivariate framework to mitigate previous biases.
The authors identified novel patterns of similarity (and dissimilarity) among the AUDIT items and found evidence of a correlated two-factor structure at the genetic level ("consumption" and "problems," r=0.80). Moreover, by applying empirically derived weights to each of the AUDIT items, the authors constructed an aggregate measure of alcohol consumption that was strongly associated with alcohol dependence (r=0.67), moderately associated with several other psychiatric disorders, and no longer positively associated with health and positive socioeconomic outcomes. Lastly, by conducting polygenic analyses in three independent cohorts that differed in their ascertainment and prevalence of AUD, the authors identified novel genetic associations between alcohol consumption, alcohol misuse, and health.
This work further emphasizes the value of AUDIT for both clinical and genetic studies of AUD and the importance of using multivariate methods to study genetic associations that are more closely related to AUD.
全基因组关联研究（GWAS）对酒精使用障碍识别测试（AUDIT）进行了研究，AUDIT 是一种用于酒精使用障碍（AUD）的 10 项筛查测试，该研究揭示了与酒精消耗和滥用有关的新基因座。然而，这些研究也表明，GWAS 可能受到许多偏差的影响（例如，测量误差、选择偏差），这可能导致酒精摄入与 AUD 之间的遗传相关性不一致，以及与精神障碍和/或医疗状况之间的遗传相关性呈负相关。作者使用基因组结构方程模型来阐明 AUDIT 测量的酒精消耗和酒精使用问题后果的遗传学。
为了探讨这些遗传相关性的意外差异，作者进行了 AUDIT 项目的第一项和最大的 GWAS（N=160824），并应用多变量框架来减轻先前的偏差。
作者在 AUDIT 项目中发现了相似性（和不相似性）的新模式，并在遗传水平上发现了相关的两因素结构的证据（“消耗”和“问题”，r=0.80）。此外，通过对 AUDIT 项目中的每一项应用经验衍生的权重，作者构建了一个酒精消耗的综合测量值，该值与酒精依赖密切相关（r=0.67），与其他几种精神障碍中度相关，与健康和积极的社会经济结果不再呈正相关。最后，通过在三个在 AUD 的发现和流行率方面存在差异的独立队列中进行多基因分析，作者确定了酒精消耗、酒精滥用和健康之间的新遗传关联。
这项工作进一步强调了 AUDIT 在 AUD 的临床和遗传研究中的价值，以及使用多变量方法研究与 AUD 更密切相关的遗传关联的重要性。
