Tobacco use disorder (TUD) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviours and although strides have been made using genome-wide association studies to identify risk variants, most variants identified have been for nicotine consumption, rather than TUD. Here we leveraged four US biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records) in 653,790 individuals (495,005 European, 114,420 African American and 44,365 Latin American) and data from UK Biobank (n_combined = 898,680). We identified 88 independent risk loci; integration with functional genomic tools uncovered 461 potential risk genes, primarily expressed in the brain. TUD was genetically correlated with smoking and psychiatric traits from traditionally ascertained cohorts, externalizing behaviours in children and hundreds of medical outcomes, including HIV infection, heart disease and pain. This work furthers our biological understanding of TUD and establishes electronic health records as a source of phenotypic information for studying the genetics of TUD.

烟草使用障碍（TUD）是世界上最普遍的物质使用障碍。遗传因素影响吸烟行为，尽管使用全基因组关联研究来识别风险变异已取得了长足的进步，但大多数已识别的变异都是与尼古丁消耗有关，而不是 TUD。在这里，我们利用四个美国生物样本库对 653,790 人（495,005 名欧洲人、114,420 名非裔美国人和 44,365 名拉丁美洲人）的 TUD（通过电子健康记录得出）和来自英国生物样本库的数据（n_合计 = 898,680）进行多祖先荟萃分析。 。我们确定了 88 个独立风险位点；与功能基因组工具的整合发现了 461 个潜在风险基因，主要在大脑中表达。 TUD 与传统确定的人群的吸烟和精神特征、儿童的外化行为以及数百种医疗结果（包括艾滋病毒感染、心脏病和疼痛）存在遗传相关性。这项工作加深了我们对 TUD 的生物学理解，并建立了电子健康记录作为研究 TUD 遗传学的表型信息来源。