A Saturated Map of Common Genetic Variants Associated with Human Height from 5.4 Million Individuals of Diverse Ancestries
Authors: Yengo Loic , Vedantam Sailaja , Marouli Eirini , Sidorenko Julia , Bartell Eric , Sakaue Saori , Graff Marielisa , Eliasen Anders U. , Jiang Yunxuan , Raghavan Sridharan , Miao Jenkai , Arias Joshua D. , Mukamel Ronen E. , Spracklen Cassandra N. , Yin Xianyong , Chen Shyh-Huei , Ferreira Teresa , Yingjie JI , Karedera Tugce , Lüll Kreete , Lin Kuang , Malden Deborah E. , Medina-Gomez Carolina , Machado Moara , Moore Amy , Rüeger Sina , Ahluwalia Tarunveer S. , Akiyama Masato , Allison Matthew A. , Alvarez Marcus , Andersen Mette K. , Ani Alireza , Appadurai Vivek , Arbeeva Liubov , Bhaskar Seema , Bielak Lawrence F. , Bollepalli Sailalitha , Bonnycastle Lori L. , Bork-Jensen Jette , Bradfield Jonathan P. , Bradford Yuki , Braund Peter S. , Brody Jennifer A. , Burgdorf Kristoffer S. , Cade Brian E. , Cai Hui , Cai Qiuyin , Campbell Archie , Cañadas-Garre Marisa , Catamo Eulalia , Chai Jin-Fang , Chai Xiaoran , Chang Li-Ching , Chang Yi-Cheng , Chen Chien-Hsiun , Chesi Alessandra , Choi Seung Hoan , Chung Ren-Hua , Cocca Massimiliano , Concas Maria Pina , Couture Christian , Cuellar-Partida Gabriel , Danning Rebecca , Daw E. Warwick , Degenhard Frauke , Delgado Graciela E. , Delitala Alessandro , Demirkan Ayşe , Deng Xuan , Devineni Poornima , Dietl Alexander , Dimitriou Maria , Dimitrov Latchezar , Dorajoo Rajkumar , Ekici Arif B. , Engmann Jorgen E. , Fairhurst-Hunter Zammy , Farmaki Aliki-Eleni , Faul Jessica D. , Fernandez-Lopez Juan-Carlos , Forer Lukas , Francescatto Margherita , Freitag-Wolf Sandra , Fuchsberger Christian , Galesloot Tessel E. , Gao Yan , Gao Zishan , Geller Frank , Giannakopoulou Olga , Giulianini Franco , Gjesing Anette P. , Goel Anuj , Gordon Scott D. , Gorski Mathias , Graham Sarah E. , Grove Jakob , Guo Xiuqing , Gustafsson Stefan , Haessler Jeffrey , Hansen Thomas F. , Havulinna Aki , Haworth Simon J. , He Jing , Heard-Costa Nancy , Hebbar Prashantha , Hindy George , Ho Yuk-Lam A. , Hofer Edith , Holliday Elizabeth , Horn Katrin , Hornsby Whitney E. , Hottenga Jouke-Jan , Huang Hongyan , Huang Jie , Huerta-Chagoya Alicia , Huffman Jennifer E. , Hung Yi-Jen , Huo Shaofeng , Hwang Mi Yeong , Iha Hiroyuki , Ikeda Daisuke D. , Isono Masato , Jackson Anne U. , Jäger Susanne , Jansen Iris E. , Johansson Ingegerd , Jonas Jost B. , Jonsson Anna , Jørgensen Torben , Kalafati Ioanna-Panagiota , Kanai Masahiro , Kanoni Stavroula , Kårhus Line L. , Kasturiratne Anuradhani , Katsuya Tomohiro , Kawaguchi Takahisa , Kember Rachel L. , Kentistou Katherine A. , Kim Han-Na , Kim Young Jin , Kleber Marcus E. , Knol Maria J. , Kurbasic Azra , Lauzon Marie , Le Phuong , Lea Rodney , Lee Jong-Young , Leonard Hampton L. , Li Shengchao A. , Li Xiaohui , Li Xiaoyin , Liang Jingjing , Lin Honghuang , Lin Shih-Yi , Liu Jun , Liu Xueping , Lo Ken Sin , Long Jirong , Lores-Motta Laura , Luan Jian’an , Lyssenko Valeriya , Lyytikäinen Leo-Pekka , Mahajan Anubha , Mamakou Vasiliki , Mangino Massimo , Manichaikul Ani , Marten Jonathan , Mattheisen Manuel , Mavarani Laven , McDaid Aaron F. , Meidtner Karina , Melendez Tori L. , Mercader Josep M. , Milaneschi Yuri , Miller Jason E. , Millwood Iona Y. , Mishra Pashupati P. , Mitchell Ruth E. , Møllehave Line T. , Morgan Anna , Mucha Soeren , Munz Matthias , Nakatochi Masahiro , Nelson Christopher P. , Nethander Maria , Nho Chu Won , Nielsen Aneta A. , Nolte Ilja M. , Nongmaithem Suraj S. , Noordam Raymond , Ntalla Ioanna , Nutile Teresa , Pandit Anita , Christofidou Paraskevi , Pärna Katri , Pauper Marc , Petersen Eva R. B. , Petersen Liselotte V. , Pitkänen Niina , Polašek Ozren , Poveda Alaitz , Preuss Michael H. , Pyarajan Saiju , Raffield Laura M. , Rakugi Hiromi , Ramirez Julia , Rasheed Asif , Raven Dennis , Rayner Nigel W. , Riveros Carlos , Rohde Rebecca , Ruggiero Daniela , Ruotsalainen Sanni E. , Ryan Kathleen A. , Sabater-Lleal Maria , Saxena Richa , Scholz Markus , Sendamarai Anoop , Shen Botong , Shi Jingchunzi , Shin Jae Hun , Sidore Carlo , Sim Xueling , Sitlani Colleen M. , Slieker Roderick C. , Smit Roelof A. J. , Smith Albert V. , Smith Jennifer A. , Smyth Laura J. , Southam Lorraine , Steinthorsdottir Valgerdur , Sun Liang , Takeuchi Fumihiko , Priyanka Tallapragada Divya Sri , Taylor Kent D. , Tayo Bamidele O. , Tcheandjieu Catherine , Terzikhan Natalie , Tesolin Paola , Teumer Alexander , Theusch Elizabeth , Thompson Deborah J. , Thorleifsson Gudmar , Timmers Paul R. H. J. , Trompet Stella , Turman Constance , Vaccargiu Simona , van der Laan Sander W. , van der Most Peter J. , van Klinken Jan B. , van Setten Jessica , Verma Shefali S. , Verweij Niek , Veturi Yogasudha , Wang Carol A. , Wang Chaolong , Wang Lihua , Wang Zhe , Warren Helen R. , Wei Wen Bin , Wickremasinghe Ananda R. , Wielscher Matthias , Wiggins Kerri L. , Winsvold Bendik S. , Wong Andrew , Wu Yang , Wuttke Matthias , Xia Rui , Xie Tian , Yamamoto Ken , Yang Jingyun , Yao Jie , Young Hannah , Yousri Noha A. , Yu Lei , Zeng Lingyao , Zhang Weihua , Zhang Xinyuan , Zhao Jing-Hua , Zhao Wei , Zhou Wei , Zimmermann Martina E. , Zoledziewska Magdalena , Adair Linda S. , Adams Hieab H. H. , Aguilar-Salinas Carlos A. , Al-Mulla Fahd , Arnett Donna K. , Asselbergs Folkert W. , Åsvold Bjørn Olav , Attia John , Banas Bernhard , Bandinelli Stefania , Bennett David A. , Bergler Tobias , Bharadwaj Dwaipayan , Biino Ginevra , Bisgaard Hans , Boerwinkle Eric , Böger Carsten A. , Bønnelykke Klaus , Boomsma Dorret I. , Børglum Anders D. , Borja Judith B. , Bouchard Claude , Bowden Donald W. , Brandslund Ivan , Brumpton Ben , Buring Julie E. , Caulfield Mark J. , Chambers John C. , Chandak Giriraj R. , Chanock Stephen J. , Chaturvedi Nish , Chen Yii-Der Ida , Chen Zhengming , Cheng Ching-Yu , Christophersen Ingrid E. , Ciullo Marina , Cole John W. , Collins Francis S. , Cooper Richard S. , Cruz Miguel , Cucca Francesco , Cupples L. Adrienne , Cutler Michael J. , Damrauer Scott M. , Dantoft Thomas M. , Borst Gert J. de , de Groot Lisette C. P. G. M. , De Jager Philip L. , de Kleijn Dominique P. V. , de Silva H. Janaka , Dedoussis George V. , den Hollander Anneke I. , Du Shufa , Easton Douglas F. , Elders Petra J. M. , Eliassen A. Heather , Ellinor Patrick T. , Elmståhl Sölve , Erdmann Jeanette , Evans Michele K. , Fatkin Diane , Feenstra Bjarke , Feitosa Mary F. , Ferrucci Luigi , Ford Ian , Fornage Myriam , Franke Andre , Franks Paul W. , Freedman Barry I. , Gasparini Paolo , Gieger Christian , Girotto Giorgia , Goddard Michael E. , Golightly Yvonne M. , Gonzalez-Villalpando Clicerio , Gordon-Larsen Penny , Grallert Harald , Grant Struan F. A. , Grarup Niels , Griffiths Lyn , Groop Leif , Gudnason Vilmundur , Haiman Christopher , Hakonarson Hakon , Hansen Torben , Hartman Catharina A. , Hattersley Andrew T. , Hayward Caroline , Heckbert Susan R. , Heng Chew-Kiat , Hengstenberg Christian , Hewitt Alex W. , Hishigaki Haretsugu , Hoyng Carel B. , Huang Paul L. , Huang Wei , Hunt Steven C. , Hveem Kristian , Hyppönen Elina , Iacono William G. , Ichihara Sahoko , Ikram M. Arfan , Isasi Carmen R. , Jackson Rebecca D. , Jarvelin Marjo-Riitta , Jin Zi-Bing , Jöckel Karl-Heinz , Joshi Peter K. , Jousilahti Pekka , Jukema J. Wouter , Kähönen Mika , Kamatani Yoichiro , Kang Kui Dong , Kaprio Jaakko , Kardia Sharon L. R. , Karpe Fredrik , Kato Norihiro , Kee Frank , Kessler Thorsten , Khera Amit V. , Khor Chiea Chuen , Kiemeney Lambertus A. L. M. , Kim Bong-Jo , Kim Eung Kwon , Kim Hyung-Lae , Kirchhof Paulus , Kivimaki Mika , Koh Woon-Puay , Koistinen Heikki A. , Kolovou Genovefa D. , Kooner Jaspal S. , Kooperberg Charles , Köttgen Anna , Kovacs Peter , Kraaijeveld Adriaan , Kraft Peter , Krauss Ronald M. , Kumari Meena , Kutalik Zoltan , Laakso Markku , Lange Leslie A. , Langenberg Claudia , Launer Lenore J. , Marchand Loic Le , Lee Hyejin , Lee Nanette R. , Lehtimäki Terho , Li Huaixing , Li Liming , Lieb Wolfgang , Lin Xu , Lind Lars , Linneberg Allan , Liu Ching-Ti , Liu Jianjun , Loeffler Markus , London Barry , Lubitz Steven A. , Lye Stephen J. , Mackey David A. , Mägi Reedik , Magnusson Patrik K. E. , Marcus Gregory M. , Vidal Pedro Marques , Martin Nicholas G. , März Winfried , Matsuda Fumihiko , McGarrah Robert W. , McGue Matt , McKnight Amy Jayne , Medland Sarah E. , Mellström Dan , Metspalu Andres , Mitchell Braxton D. , Mitchell Paul , Mook-Kanamori Dennis O. , Morris Andrew D. , Mucci Lorelei A. , Munroe Patricia B. , Nalls Mike A. , Nazarian Saman , Nelson Amanda E. , Neville Matt J. , Newton-Cheh Christopher , Nielsen Christopher S. , Nöthen Markus M. , Ohlsson Claes , Oldehinkel Albertine J. , Orozco Lorena , Pahkala Katja , Pajukanta Päivi , Palmer Colin N. A. , Parra Esteban J. , Pattaro Cristian , Pedersen Oluf , Pennell Craig E. , Penninx Brenda W. J. H. , Perusse Louis , Peters Annette , Peyser Patricia A. , Porteous David J. , Posthuma Danielle , Power Chris , Pramstaller Peter P. , Province Michael A. , Qi Qibin , Qu Jia , Rader Daniel J. , Raitakari Olli T. , Ralhan Sarju , Rallidis Loukianos S. , Rao Dabeeru C. , Redline Susan , Reilly Dermot F. , Reiner Alexander P. , Rhee Sang Youl , Ridker Paul M. , Rienstra Michiel , Ripatti Samuli , Ritchie Marylyn D. , Roden Dan M. , Rosendaal Frits R. , Rotter Jerome I. , Rudan Igor , Rutters Femke , Sabanayagam Charumathi , Saleheen Danish , Salomaa Veikko , Samani Nilesh J. , Sanghera Dharambir K. , Sattar Naveed , Schmidt Börge , Schmidt Helena , Schmidt Reinhold , Schulze Matthias B. , Schunkert Heribert , Scott Laura J. , Scott Rodney J. , Sever Peter , Shiroma Eric J. , Shoemaker M. Benjamin , Shu Xiao-Ou , Simonsick Eleanor M. , Sims Mario , Singh Jai Rup , Singleton Andrew B. , Sinner Moritz F. , Smith J. Gustav , Snieder Harold , Spector Tim D. , Stampfer Meir J. , Stark Klaus J. , Strachan David P. , t Hart Leen M. , Tabara Yasuharu , Tang Hua , Tardif Jean-Claude , Thanaraj Thangavel A. , Timpson Nicholas J. , Tönjes Anke , Tremblay Angelo , Tuomi Tiinamaija , Tuomilehto Jaakko , Tusié-Luna Maria-Teresa , Uitterlinden Andre G. , van Dam Rob M. , van der Harst Pim , Van der Velde Nathalie , van Duijn Cornelia M. , van Schoor Natasja , Vitart Veronique , Völker Uwe , Vollenweider Peter , Völzke Henry , Vrieze Scott , Wacher-Rodarte Niels H. , Walker Mark , Wang Ya Xing , Wareham Nicholas J. , Watanabe Richard M. , Watkins Hugh , Weir David R. , Werge Thomas M. , Widen Elisabeth , Wilkens Lynne R. , Willemsen Gonneke , Willett Walter C. , Wilson James F. , Wong Tien-Yin , Woo Jeong-Taek , Wright Alan F. , Wu Jer-Yuarn , Xu Huichun , Yajnik Chittaranjan S. , Yokota Mitsuhiro , Yuan Jian-Min , Zeggini Eleftheria , Zemel Babette S. , Zheng Wei , Zhu Xiaofeng , Zmuda Joseph M. , Zonderman Alan B. , Zwart John-Anker ,   23andMe Research Team,   VA Million Veteran Program,   DiscovEHR (DiscovEHR and MyCode Community Health Initiative),   eMERGE (Electronic Medical Records and Genomics Network),   Lifelines Cohort Study,   Regeneron Genetics Center,   The PRACTICAL Consortium,   Understanding Society Scientific Group, Chasman Daniel I. , Cho Yoon Shin , Heid Iris M. , McCarthy Mark I. , Ng Maggie C. Y. , O’Donnell Christopher J. , Rivadeneira Fernando , Thorsteinsdottir Unnur , Sun Yan V. , Tai E. Shyong , Boehnke Michael , Deloukas Panos , Justice Anne E. , Lindgren Cecilia M. , Loos Ruth J. F. , Mohlke Karen L. , North Kari E. , Stefansson Kari , Walters Robin G. , Winkler Thomas W. , Young Kristin L. , Loh Po-Ru , Yang Jian , Esko Tõnu , Assimes Themistocles L. , Auton Adam , Abecasis Goncalo R. , Willer Cristen J. , Locke Adam E. , Berndt Sonja I. , Lettre Guillaume , Frayling Timothy M. , Okada Yukinori , Wood Andrew R. , Visscher Peter M. , Hirschhorn Joel N. 
Published: January 2022

ABSTRACTCommon 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.