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

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

Posted 10 Jan 2022
bioRxiv DOI: 10.1101/2022.01.07.475305

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.

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