A saturated map of common genetic variants associated with human height
Autoren
Loïc Yengo, Sailaja Vedantam, Eirini Marouli, Julia Sidorenko, Eric Bartell, Saori Sakaue, Marielisa Graff, Anders Eliasen, Yunxuan Jiang, Sridharan Raghavan, Jenkai Miao, Joshua Arias, Sarah Graham, Ronen Mukamel, Cassandra Spracklen, Xianyong Yin, Shyh-Huei Chen, Teresa Ferreira, Heather Highland, Yingjie Ji, Tugce Karaderi, Kuang Lin, Kreete Lüll, Deborah Malden, Carolina Medina-Gomez, Moara Machado, Amy Moore, Sina Rüeger, Xueling Sim, Scott Vrieze, Tarunveer Ahluwalia, Masato Akiyama, Matthew Allison, Marcus Alvarez, Mette Andersen, Alireza Ani, Vivek Appadurai, Liubov Arbeeva, Seema Bhaskar, Lawrence Bielak, Sailalitha Bollepalli, Lori Bonnycastle, Jette Bork-Jensen, Jonathan Bradfield, Yuki Bradford, Peter Braund, Jennifer Brody, Kristoffer Burgdorf, Brian 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 Choi, Ren-Hua Chung, Massimiliano Cocca, Maria Concas, Christian Couture, Gabriel Cuellar-Partida, Rebecca Danning, E. Daw, Frauke Degenhard, Graciela Delgado, Alessandro Delitala, Ayse Demirkan, Xuan Deng, Poornima Devineni, Alexander Dietl, Maria Dimitriou, Latchezar Dimitrov, Rajkumar Dorajoo, Arif Ekici, Jorgen Engmann, Zammy Fairhurst-Hunter, Aliki-Eleni Farmaki, Jessica Faul, Juan-Carlos Fernandez-Lopez, Lukas Forer, Margherita Francescatto, Sandra Freitag-Wolf, Christian Fuchsberger, Tessel Galesloot, Yan Gao, Zishan Gao, Frank Geller, Olga Giannakopoulou, Franco Giulianini, Anette Gjesing, Anuj Goel, Scott Gordon, Mathias Gorski, Jakob Grove, Xiuqing Guo, Stefan Gustafsson, Jeffrey Haessler, Thomas Hansen, Aki Havulinna, Simon Haworth, Jing He, Nancy Heard-Costa, Prashantha Hebbar, George Hindy, Yuk-Lam Ho, Edith Hofer, Elizabeth Holliday, Katrin Horn, Whitney Hornsby, Jouke-Jan Hottenga, Hongyan Huang, Jie Huang, Alicia Huerta-Chagoya, Jennifer Huffman, Yi-Jen Hung, Shaofeng Huo, Mi Hwang, Hiroyuki Iha, Daisuke Ikeda, Masato Isono, Anne Jackson, Susanne Jäger, Iris Jansen, Ingegerd Johansson, Jost Jonas, Anna Jonsson, Torben Jørgensen, Ioanna-Panagiota Kalafati, Masahiro Kanai, Stavroula Kanoni, Line Kårhus, Anuradhani Kasturiratne, Tomohiro Katsuya, Takahisa Kawaguchi, Rachel Kember, Katherine Kentistou, Han-Na Kim, Young Kim, Marcus Kleber, Maria Knol, Azra Kurbasic, Marie Lauzon, Phuong Le, Rodney Lea, Jong-Young Lee, Hampton Leonard, Shengchao Li, Xiaohui Li, Xiaoyin Li, Jingjing Liang, Honghuang Lin, Shih-Yi Lin, Jun Liu, Xueping Liu, Ken 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 McDaid, Karina Meidtner, Tori Melendez, Josep Mercader, Yuri Milaneschi, Jason Miller, Iona Millwood, Pashupati Mishra, Ruth Mitchell, Line Møllehave, Anna Morgan, Soeren Mucha, Matthias Munz, Masahiro Nakatochi, Christopher Nelson, Maria Nethander, Chu Nho, Aneta Nielsen, Ilja Nolte, Suraj Nongmaithem, Raymond Noordam, Ioanna Ntalla, Teresa Nutile, Anita Pandit, Paraskevi Christofidou, Katri Pärna, Marc Pauper, Eva Petersen, Liselotte Petersen, Niina Pitkänen, Ozren Polašek, Alaitz Poveda, Michael Preuss, Saiju Pyarajan, Laura Raffield, Hiromi Rakugi, Julia Ramirez, Asif Rasheed, Dennis Raven, Nigel Rayner, Carlos Riveros, Rebecca Rohde, Daniela Ruggiero, Sanni Ruotsalainen, Kathleen Ryan, Maria Sabater-Lleal, Richa Saxena, Markus Scholz, Anoop Sendamarai, Botong Shen, Jingchunzi Shi, Jae Shin, Carlo Sidore, Colleen Sitlani, Roderick Slieker, Roelof Smit, Albert Smith, Jennifer Smith, Laura Smyth, Lorraine Southam, Valgerdur Steinthorsdottir, Liang Sun, Fumihiko Takeuchi, Divya Tallapragada, Kent Taylor, Bamidele Tayo, Catherine Tcheandjieu, Natalie Terzikhan, Paola Tesolin, Alexander Teumer, Elizabeth Theusch, Deborah Thompson, Gudmar Thorleifsson, Timmers, Paul R H J, Stella Trompet, Constance Turman, Simona Vaccargiu, van der Laan, Sander W, van der Most, Peter J, Jan van Klinken, Jessica van Setten, Shefali Verma, Niek Verweij, Yogasudha Veturi, Carol Wang, Chaolong Wang, Lihua Wang, Zhe Wang, Helen Warren, Wen Bin Wei, Ananda Wickremasinghe, Matthias Wielscher, Kerri Wiggins, Bendik Winsvold, Andrew Wong, Yang Wu, Matthias Wuttke, Rui Xia, Tian Xie, Ken Yamamoto, Jingyun Yang, Jie Yao, Hannah Young, Noha Yousri, Lei Yu, Lingyao Zeng, Weihua Zhang, Xinyuan Zhang, Jing-Hua Zhao, Wei Zhao, Wei Zhou, Martina Zimmermann, Magdalena Zoledziewska, Linda Adair, Hieab Adams, Carlos Aguilar-Salinas, Fahd Al-Mulla, Donna Arnett, Folkert Asselbergs, Bjørn Åsvold, John Attia, Bernhard Banas, Stefania Bandinelli, David Bennett, Tobias Bergler, Dwaipayan Bharadwaj, Ginevra Biino, Hans Bisgaard, Eric Boerwinkle, Carsten Böger, Klaus Bønnelykke, Dorret Boomsma, Anders Børglum, Judith Borja, Claude Bouchard, Donald Bowden, Ivan Brandslund, Ben Brumpton, Julie Buring, Mark Caulfield, John Chambers, Giriraj Chandak, Stephen Chanock, Nish Chaturvedi, Yii-Der Chen, Zhengming Chen, Ching-Yu Cheng, Ingrid Christophersen, Marina Ciullo, John Cole, Francis Collins, Richard Cooper, Miguel Cruz, Francesco Cucca, L. Cupples, Michael Cutler, Scott Damrauer, Thomas Dantoft, Gert Borst, de Groot, Lisette C P G M, Philip Jager, de Kleijn, Dominique P V, H. Janaka de Silva, George Dedoussis, Anneke Hollander, Shufa Du, Douglas Easton, Petra Elders, A. Eliassen, Patrick Ellinor, Sölve Elmståhl, Jeanette Erdmann, Michele Evans, Diane Fatkin, Bjarke Feenstra, Mary Feitosa, Luigi Ferrucci, Ian Ford, Myriam Fornage, Andre Franke, Paul Franks, Barry Freedman, Paolo Gasparini, Christian Gieger, Giorgia Girotto, Michael Goddard, Yvonne Golightly, Clicerio Gonzalez-Villalpando, Penny Gordon-Larsen, Harald Grallert, Struan Grant, Niels Grarup, Lyn Griffiths, Vilmundur Gudnason, Christopher Haiman, Hakon Hakonarson, Torben Hansen, Catharina Hartman, Andrew Hattersley, Caroline Hayward, Susan Heckbert, Chew-Kiat Heng, Christian Hengstenberg, Alex Hewitt, Haretsugu Hishigaki, Carel Hoyng, Paul Huang, Wei Huang, Steven Hunt, Kristian Hveem, Elina Hyppönen, William Iacono, Sahoko Ichihara, M. Ikram, Carmen Isasi, Rebecca Jackson, Marjo-Riitta Jarvelin, Zi-Bing Jin, Karl-Heinz Jöckel, Peter Joshi, Pekka Jousilahti, J. Jukema, Mika Kähönen, Yoichiro Kamatani, Kui Kang, Jaakko Kaprio, Sharon Kardia, Fredrik Karpe, Norihiro Kato, Frank Kee, Thorsten Kessler, Amit Khera, Chiea Khor, Kiemeney, Lambertus A L M, Bong-Jo Kim, Eung Kim, Hyung-Lae Kim, Paulus Kirchhof, Mika Kivimaki, Woon-Puay Koh, Heikki Koistinen, Genovefa Kolovou, Jaspal Kooner, Charles Kooperberg, Anna Köttgen, Peter Kovacs, Adriaan Kraaijeveld, Peter Kraft, Ronald Krauss, Meena Kumari, Zoltan Kutalik, Markku Laakso, Leslie Lange, Claudia Langenberg, Lenore Launer, Loic Le Marchand, Hyejin Lee, Nanette Lee, Terho Lehtimäki, Huaixing Li, Liming Li, Wolfgang Lieb, Xu Lin, Lars Lind, Allan Linneberg, Ching-Ti Liu, Jianjun Liu, Markus Loeffler, Barry London, Steven Lubitz, Stephen Lye, David Mackey, Reedik Mägi, Patrik Magnusson, Gregory Marcus, Pedro Vidal, Nicholas Martin, Winfried März, Fumihiko Matsuda, Robert McGarrah, Matt McGue, Amy McKnight, Sarah Medland, Dan Mellström, Andres Metspalu, Braxton Mitchell, Paul Mitchell, Dennis Mook-Kanamori, Andrew Morris, Lorelei Mucci, Patricia Munroe, Mike Nalls, Saman Nazarian, Amanda Nelson, Matt Neville, Christopher Newton-Cheh, Christopher Nielsen, Markus Nöthen, Claes Ohlsson, Albertine Oldehinkel, Lorena Orozco, Katja Pahkala, Päivi Pajukanta, Colin Palmer, Esteban Parra, Cristian Pattaro, Oluf Pedersen, Craig Pennell, Penninx, Brenda W J H, Louis Perusse, Annette Peters, Patricia Peyser, David Porteous, Danielle Posthuma, Chris Power, Peter Pramstaller, Michael Province, Qibin Qi, Jia Qu, Daniel Rader, Olli Raitakari, Sarju Ralhan, Loukianos Rallidis, Dabeeru Rao, Susan Redline, Dermot Reilly, Alexander Reiner, Sang Rhee, Paul Ridker, Michiel Rienstra, Samuli Ripatti, Marylyn Ritchie, Dan Roden, Frits Rosendaal, Jerome Rotter, Igor Rudan, Femke Rutters, Charumathi Sabanayagam, Danish Saleheen, Veikko Salomaa, Nilesh Samani, Dharambir Sanghera, Naveed Sattar, Börge Schmidt, Helena Schmidt, Reinhold Schmidt, Matthias Schulze, Heribert Schunkert, Laura Scott, Rodney Scott, Peter Sever, Eric Shiroma, M. Shoemaker, Xiao-Ou Shu, Eleanor Simonsick, Mario Sims, Jai Singh, Andrew Singleton, Moritz Sinner, J. Smith, Harold Snieder, Tim Spector, Meir Stampfer, Klaus Stark, David Strachan, Leen Hart, Yasuharu Tabara, Hua Tang, Jean-Claude Tardif, Thangavel Thanaraj, Nicholas Timpson, Anke Tönjes, Angelo Tremblay, Tiinamaija Tuomi, Jaakko Tuomilehto, Maria-Teresa Tusié-Luna, Andre Uitterlinden, Rob van Dam, van der Harst, Pim, Nathalie van der Velde, Cornelia van Duijn, Natasja van Schoor, Veronique Vitart, Uwe Völker, Peter Vollenweider, Henry Völzke, Niels Wacher-Rodarte, Mark Walker, Ya Wang, Nicholas Wareham, Richard Watanabe, Hugh Watkins, David Weir, Thomas Werge, Elisabeth Widen, Lynne Wilkens, Gonneke Willemsen, Walter Willett, James Wilson, Tien-Yin Wong, Jeong-Taek Woo, Alan Wright, Jer-Yuarn Wu, Huichun Xu, Chittaranjan Yajnik, Mitsuhiro Yokota, Jian-Min Yuan, Eleftheria Zeggini, Babette Zemel, Wei Zheng, Xiaofeng Zhu, Joseph Zmuda, Alan Zonderman, John-Anker Zwart, Daniel Chasman, Yoon Cho, Iris Heid, Mark McCarthy, Maggie Ng, Christopher O'Donnell, Fernando Rivadeneira, Unnur Thorsteinsdottir, Yan Sun, E. Tai, Michael Boehnke, Panos Deloukas, Anne Justice, Cecilia Lindgren, Ruth Loos, Karen Mohlke, Kari North, Kari Stefansson, Robin Walters, Thomas Winkler, Kristin Young, Po-Ru Loh, Jian Yang, Tõnu Esko, Themistocles Assimes, Adam Auton, Goncalo Abecasis, Cristen Willer, Adam Locke, Sonja Berndt, Guillaume Lettre, Timothy Frayling, Yukinori Okada, Andrew Wood, Peter Visscher, Joel Hirschhorn
Abstract
Common single-nucleotide polymorphisms (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(1). Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show 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 mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel(2)) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.