A Saturated Map of Common Genetic Variants Associated with Human Height from 5.4 Million Individuals of Diverse Ancestries

Common SNPs are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes. Here we show, using GWAS data from 5.4 million individuals of diverse ancestries, that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a median size of ~90 kb, covering ~21% of the genome. The density of independent associations varies across the genome and the regions of elevated density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs account for 40% of phenotypic variance in European ancestry populations but only ~10%-20% in other ancestries. Effect sizes, associated regions, and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely explained by linkage disequilibrium and allele frequency differences within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than needed to implicate causal genes and variants. Overall, this study, the largest GWAS to date, provides an unprecedented saturated map of specific genomic regions containing the vast majority of common height-associated variants. ### Competing Interest Statement Yu.J. is employed by and hold stock or stock options in 23andMe, Inc. T.S.A. is a shareholder in Zealand Pharma A/S and Novo Nordisk A/S. G.C-P is an employee of 23andMe Inc. M.E.K. is employed by SYNLAB Holding Deutschland GmbH. H.L.L. receives support from a consulting contract between Data Tecnica International and the National Institute on Aging (NIA), National Institutes of Health (NIH). As of January 2020, A.Mah. is an employee of Genentech, and a holder of Roche stock. I.N. is an employee and stock owner of Gilead Sciences; this work was conducted before employment by Gilead Sciences. Ji.S. is employed by and hold stock or stock options in 23andMe, Inc. Ca.S. is an employee of Regeneron, Inc. Va.S. is employed by deCODE Genetics/Amgen inc. Since completing the work contributed to this paper, D.J.T. has left the University of Cambridge and is now employed by Genomics plc. G.T. is employed by deCODE Genetics/Amgen inc. H.B. has consultant arrangements with Chiesi Pharmaceuticals and Boehringer Ingelheim. M.J.Ca. is Chief Scientist for Genomics England, a UK Government company. M.J.Cu. has served on Advisory Board or Consulted for Biosense Webster, Janssen Scientific Affairs and Johnson & Johnson. S.M.D. receives research support from RenalytixAI and personal consulting fees from Calico Labs, outside the scope of the current research. P.T.E. receives sponsored research support from Bayer AG and IBM Health, and he has served on advisory boards or consulted for Bayer AG, Quest Diagnostics, MyoKardia and Novartis. P.Ki. has received suppport from several drug and device companies active in atrial fibrillation, and has received honoraria from several such companies in the past, but not in the last three years. P.Ki. is listed as inventor on two patents held by University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). G.D.K. has given talks, attended conferences and participated in trials sponsored by Amgen, MSD, Lilly, Vianex, Sanofi, and have also accepted travel support to conferences from Amgen, Sanofi, MSD and Elpen. S.A.Lu. receives sponsored research support from Bristol Myers Squibb / Pfizer, Bayer AG, Boehringer Ingelheim, Fitbit, and IBM, and has consulted for Bristol Myers Squibb / Pfizer, Bayer AG, and Blackstone Life Sciences. W.M. reports grants and personal fees from AMGEN, BASF, Sanofi, Siemens Diagnostics, Aegerion Pharmaceuticals, Astrazeneca, Danone Research, Numares, Pfizer, Hoffmann LaRoche: personal fees from MSD, Alexion; grants from Abbott Diagnostics, all outside the submitted work. W.M. is employed with Synlab Holding Deutschland GmbH. M.A.N. receives support from a consulting contract between Data Tecnica International and the National Institute on Aging (NIA), National Institutes of Health (NIH). S.N. is a scientific advisor to Circle software, ADAS software, CardioSolv, and ImriCor and recieves grant support from Biosense Webster, ADAS software, and ImriCor. Her.S. has received honoraria for consulting from AstraZeneca, MSD/Merck, Daiichi, Servier, Amgen and Takeda Pharma. He has further received honoraria for lectures and/or chairs from AstraZeneca, BayerVital, BRAHMS, Daiichi, Medtronic, Novartis, Sanofi and Servier. P.S. has received research awards from Pfizer Inc. 23andMe Research team are employed by and hold stock or stock options in 23andMe, Inc. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. M.I.McC. has served on advisory panels for Pfizer, NovoNordisk and Zoe Global, has received honoraria from Merck, Pfizer, Novo Nordisk and Eli Lilly, and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. As of June 2019, MMcC is an employee of Genentech, and a holder of Roche stock. C.J.O. is a current employee of Novartis Institute of Biomedical Research. U.T. is employed by deCODE Genetics/Amgen inc. K.S. is employed by deCODE Genetics/Amgen inc. Ad.A. is employed by and hold stock or stock options in 23andMe, Inc. C.J.W.'s spouse is employed by Regeneron. A.E.L. is currently employed by and holds stock in Regeneron Pharmaceuticals, Inc. J.N.H. holds equity in Camp4 Therapeutics.