Phenome-Wide Association Study for Alcohol and Nicotine Risk Alleles in 26394 Women
Phenome-Wide Association Study for Alcohol and Nicotine Risk Alleles in 26394 Women
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DOI：
10.1038/npp.2016.72
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发表时间：
2016-10-01
影响因子：
7.6
通讯作者：
Gelernter, Joel
中科院分区：
文献类型：
--
作者：
Polimanti, Renato;Kranzler, Henry R.;Gelernter, Joel
为了确定与已知易患酒精和尼古丁的等位基因相关的新特征，我们在一个大型多人群队列中进行了全现象关联研究（PheWAS）。我们调查了来自妇女健康倡议的7688名非洲裔美国人、1133名亚裔美国人、14081名欧洲裔美国人和3492名西班牙裔美国人，分析了CHRNA3-CHRNA5位点、ADH1B和ALDH2等位基因与人体测量特征、饮食习惯、社会地位、心理特征、生殖史、健康状况和尼古丁/酒精使用相关的表型性状。在ADH1B跨人群荟萃分析和人群特异性分析中，我们重复了与饮酒行为的先前关联，并确定了与心理特征、社会经济地位、血管/代谢状况和生殖健康相关的多个新的全现象显著性和暗含性发现。然后，我们应用贝叶斯网络学习算法来深入了解新型ADH1B关联的因果关系：ADH1B似乎通过酒精介导和酒精独立效应影响表型性状。在2379名受试者的独立样本中，我们还复制了与社会经济地位（家庭总收入和在学校完成的最高成绩）相关的新型ADH1B关联。对于CHRNA3-CHRNA5风险等位基因，我们重复了与吸烟行为、肺癌和哮喘的关联。在高胆固醇药物使用和不信任态度方面也有新的提示性CHRNA3-CHRNA5发现。总之，酒精和烟草使用的遗传学对身心健康的潜在影响比目前认识到的要广泛。特别是，ADH1B可能是通过酒精代谢相关机制和其他酒精代谢独立机制与人类现象相关的基因。
To identify novel traits associated with alleles known to predispose to alcohol and nicotine use, we conducted a phenome-wide association study (PheWAS) in a large multi-population cohort. We investigated 7688 African-Americans, 1133 Asian-Americans, 14 081 European Americans, and 3492 Hispanic-Americans from the Women's Health Initiative, analyzing alleles at the CHRNA3-CHRNA5 locus, ADH1B,and ALDH2 with respect to phenotypic traits related to anthropometric characteristics, dietary habits, social status, psychological traits, reproductive history, health conditions, and nicotine/alcohol use. In ADH1B trans-population meta-analysis and population-specific analysis, we replicated prior associations with drinking behaviors and identified multiple novel phenome-wide significant and suggestive findings related to psychological traits, socioeconomic status, vascular/metabolic conditions, and reproductive health. We then applied Bayesian network learning algorithms to provide insight into the causative relationships of the novel ADH1B associations: ADH1B appears to affect phenotypic traits via both alcohol-mediated and alcohol-independent effects. In an independent sample of 2379 subjects, we also replicated the novel ADH1B associations related to socioeconomic status (household gross income and highest grade finished in school). For CHRNA3-CHRNA5 risk alleles, we replicated association with smoking behaviors, lung cancer, and asthma. There were also novel suggestive CHRNA3-CHRNA5 findings with respect to high-cholesterol-medication use and distrustful attitude. In conclusion, the genetics of alcohol and tobacco use potentially has broader implications on physical and mental health than is currently recognized. In particular, ADH1B may be a gene relevant for the human phenome via both alcohol metabolism-related mechanisms and other alcohol metabolism independent mechanisms.