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These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries\n                    <jats:sup>5<\/jats:sup>\n                    . Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. 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M.H.C. has received grant funding from GSK and Bayer, and speaking or consulting fees from AstraZeneca, Illumina and Genentech. R.T.-S. is a former employee and current shareholder of GSK and is currently a non-executive member of the ENA Respiratory board of directors. She reports personal fees from Teva, Immunomet, Vocalis Health and ENA Respiratory (until January 2021). D.A.S. is the founder and chief scientific officer of Eleven P15, a company focused on the early diagnosis of treatment of pulmonary fibrosis. J.B.N. and E.J. are employed by Regeneron Pharmaceuticals, Inc. The spouse of C.J.W. is employed by Regeneron Pharmaceuticals, Inc. L.J.B. is listed as an inventor on Issued U.S. Patent 8080371 \u2018Markers for addiction\u2019, covering the use of certain single-nucleotide polymorphisms in determining the diagnosis, prognosis and treatment of addiction. The 23andMe Research Team, including J.S. and S.S.S., are employees of 23andMe, Inc., and hold stock and\/or stock options in 23andMe. T.E.T., D.F.G., H.S., G.B. and K.\u00a0Stefansson are employees of deCODE genetics\/AMGEN. M.\u00a0Moll received grant support from Bayer. A.W.B. is listed as a co-inventor on a U.S. patent application \u2018Biosignature discovery for substance use disorder using statistical learning\u2019 assigned to BioRealm, LLC, and serves as a scientific advisor and consultant to BioRealm, LLC. All other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}