Multi-ancestry meta-analysis of tobacco use disorders prioritizes novel candidate risk genes and reveals associations with numerous health outcomes

Tobacco use disorder ( TUD ) is the most prevalent substance use disorder in the world. Genetic factors influence smoking behaviors, and although strides have been made using genome-wide association studies ( GWAS ) to identify risk variants, the majority of variants identified have been for nicotine consumption, rather than TUD. We leveraged five biobanks to perform a multi-ancestral meta-analysis of TUD (derived via electronic health records, EHR ) in 898,680 individuals (739,895 European, 114,420 African American, 44,365 Latin American). 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 behaviors in children, and hundreds of medical outcomes, including HIV infection, heart disease, and pain. This work furthers our biological understanding of TUD and establishes EHR as a source of phenotypic information for studying the genetics of TUD. ### Competing Interest Statement Dr. Palmer is on the scientific advisory board of Vivid Genomics for which he receives stock options. Dr. Smoller is a member of the Scientific Advisory Board of Sensorium Therapeutics (with equity) and has received grant support from Biogen, Inc. He is PI of a collaborative study of the genetics of depression and bipolar disorder sponsored by 23andMe for which 23andMe provides analysis time as in-kind support but no payments. Dr. Kranzler is a member of advisory boards for Dicerna Pharmaceuticals, Sophrosyne Pharmaceuticals, and Enthion Pharmaceuticals; a consultant to Sobrera Pharmaceuticals; the recipient of research funding and medication supplies for an investigator-initiated study from Alkermes; a member of the American Society of Clinical Psychopharmacology's Alcohol Clinical Trials Initiative, which was supported in the last three years by Alkermes, Dicerna, Ethypharm, Lundbeck, Mitsubishi, Otsuka, and Pear Therapeutics; and with Dr Gelernter, a holder of U.S. patent 10,900,082 titled: “Genotype-guided dosing of opioid agonists,” issued 26 January 2021. The other authors declare no competing interests. ### Funding Statement MVJ, SBB, SRP and SSR were supported by funds from the California Tobacco-Related Disease Research Program (TRDRP; Grant Number T29KT0526 and T32IR5226). SBB and were also supported by P50DA037844. BP, JM and SSR were supported by NIH/NIDA DP1DA054394. ASH was supported by AA030083. TTM was supported by NHGRI T32HG010464. ECJ was supported by K01DA051759. JG was supported by VA Merit Award CX001849-01 and 5R01DA054869. DBH was supported by R01 DA042090. LKD was supported by R01 MH113362. HRK was supported by the Veterans Integrated Service Network 4 Mental Illness Research, Education and Clinical Center. RLK was supported by NIAAA K01 AA028292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The project was approved by the VUMC Institutional Review Board (IRB #160302, #172020, #190418). The project was approved by the MGBB Institutional Review Board (IRB # 2019P003696). The PMBB is approved under IRB protocol #813913. The Central VA Institutional Review Board (IRB) and site-specific IRBs approved the MVP study. The Institutional Review Board of Mayo Clinic approved this study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The full summary statistics from the meta-analyses will be available through dbGaP upon publication.