A saturated map of common genetic variants associated with human height

著者: 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 E. Graham, Ronen E. Mukamel, Cassandra N. Spracklen, Xianyong Yin, Shyh‐Huei Chen, Teresa Ferreira, Heather H Highland, Yingjie Ji, Tugce Karaderi, Kuang Lin, Kreete Lüll, Deborah E. Malden, Carolina Medina‐Gómez, Moara Machado, Amy Moore, Sina Rüeger, Xueling Sim, Scott Vrieze, Tarunveer S. Ahluwalia, Masato Akiyama, Matthew 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 Sølvsten 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 Cuéllar-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 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, Jakob Grove, Xiuqing Guo, Stefan Gustafsson, Jeffrey Haessler, Thomas Folkmann Hansen, Aki S. Havulinna, Simon Haworth, Jing He, Nancy L. 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 E. Huffman, Yi‐Jen Hung, Shaofeng Huo, Mi Yeong Hwang, Hiroyuki Iha, Daisuke D. Ikeda, Masato Isono, Anne Jackson, Susanne Jäger, Iris E. Jansen, Ingegerd Johansson, Jost B. Jonas, Anna Jonsson, Torben Jørgensen, Ioanna Panagiota Kalafati, Masahiro Kanai, Stavroula Kanoni, Line Lund 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, Rod A. 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 Lorés‐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 Aleksandra Nielsen, Ilja M. Nolte, Suraj S. Nongmaithem, Raymond Noordam, Ιωάννα Ντάλλα, Teresa Nutile, Anita Pandit, Paraskevi Christofidou, Katri Pärna, Marc Pauper, Annette Peters, Liselotte Petersen, Niina Pitkänen, Ozren Polašek, Alaitz Poveda, Michael Preuß, Saiju Pyarajan, Laura M. Raffield, Hiromi Rakugi, Julia Ramírez, Asif Rasheed, Dennis Raven, Nigel W. Rayner, Carlos Riveros, Rebecca Rohde, Daniela Ruggiero, Sanni Ruotsalainen, Kathleen A. Ryan, Maria Sabater‐Lleal, Richa Saxena, Markus Scholz, Anoop K. Sendamarai, Botong Shen, Jingchunzi Shi, Jae Hun Shin, Carlo Sidore, Colleen M. Sitlani, Roderick C. Slieker, Roelof A. J. Smit, Albert V. Smith, Jennifer A. Smith, Laura J. Smyth, Lorraine Southam, Valgerður Steinthórsdóttir, 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, Guðmar Þorleifsson, 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, Jinghua Zhao, Wei Zhao, Wei Zhou, Martina E. Zimmermann, Magdalena Żołędziewska, 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 Meinertz Dantoft, Gert J. de Borst, C.P.G.M. de Groot, Philip L. De Jager, Dominique P.V. de Kleijn, H Janaka de Silva, George 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, André Franke, Paul W. Franks, Barry I. Freedman, Paolo Gasparini, Christian Gieger, Giorgia Girotto, Michael E. Goddard, Yvonne M. Golightly, Clicerio González‐Villalpando, Penny Gordon‐Larsen, Harald Grallert, Struan F.A. Grant, Niels Grarup, Lyn R. Griffiths, Vilmundur Guðnason, Christopher A. Haiman, Håkon Håkonarson, 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 Järvelin, 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. Kiemeney, Bong-Jo Kim, Eung Kweon Kim, Hyung‐Lae Kim, Paulus Kirchhof, Mika Kivimäki, Woon‐Puay Koh, Heikki A. Koistinen, Genovefa Kolovou, Jaspal S. Kooner, Charles Kooperberg, Anna Köttgen, Péter Kovács, Adriaan O. Kraaijeveld, Peter Kraft, Ronald M. Krauss, Meena Kumari, Zoltán Kutalik, Markku Laakso, Leslie A. Lange, Claudia Langenberg, Lenore J. Launer, Loı̈c Le Marchand, Hyejin Lee, Sang Lee, Terho Lehtimäki, Huaixing Li, Liming Li, Wolfgang Lieb, Lin Xu, 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 Sivert Nielsen, Markus M. Nöthen, 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 Përusse, Annette Peters, Patricia A. Peyser, David J. Porteous, Daniëlle Posthuma, Chris Power, Peter P. Pramstaller, Michael A. Province, Qibin Qi, Jia Qu, Daniel J. Rader, Olli T. Raitakari, Sarju Ralhan, Lοukianos S. Rallidis, D. C. Rao, Susan Redline, Dermot F. Reilly, Alex 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 B. Singleton, Moritz F. Sinner, J. G. Smith, Harold Snieder, Tim D. Spector, Meir J. Stampfer, Klaus Stark, David P. Strachan, Leen M. ‘t Hart, Yasuharu Tabara, Hua Tang, Jean‐Claude Tardif, Thangavel Alphonse Thanaraj, Nicholas J. Timpson, Anke Tönjes, Angelo Tremblay, Tiinamaija Tuomi, Jaakko Tuomilehto, Maria-Teresa Tusié-Luna, André G. Uitterlinden, Rob M. van Dam, Pim van der Harst, Nathalie van der Velde, Cornelia M. van Duijn, Natasja M. van Schoor, Véronique Vitart, Uwe Völker, Péter Vollenweider, Henry Völzke, Niels Wacher-Rodarte, Mark Walker, Ya Xing Wang, Nicholas J. Wareham, Richard M. Watanabe, Hugh Watkins, David R. Weir, Thomas Werge, Elisabeth Widén, 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, Gabriel Cuellar Partida, VA Million Veteran Program, Yan V. Sun, DiscovEHR (DiscovEHR and MyCode Community Health Initiative), Damien Croteau-Chonka, Lifelines Cohort Study, Judith M. Vonk, Stephen Chanock, Loic Le Marchand, 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 A. 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 Walters, Thomas W Winkler, Kristin L. Young, Po‐Ru Loh, Jian Yang, Tõnu Esko, Themistocles L. Assimes, Adam Auton, Goncalo Abecasis, Cristen J. Willer, Adam E. Locke, Sonja I Berndt, Guillaume Lettre, Timothy M Frayling, Yukinori Okada, Andrew R Wood, Peter M. Visscher, Joel N. Hirschhorn - Nature 2022 被引用: 921

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.