A saturated map of common genetic variants associated with human height

Yengo, Loic and Vedantam, Sailaja and Marouli, Eirini and Sidorenko, Julia and Bartell, Eric and Sakaue, Saori and Graff, Marielisa and Eliasen, Anders U. and Jiang, Yunxuan and Raghavan, Sridharan and Miao, Jenkai and Arias, Joshua D. and Graham, Sarah E. and Mukamel, Ronen E. and Spracklen, Cassandra N. and Yin, Xianyong and Chen, Shyh-Huei and Ferreira, Teresa and Highland, Heather H. and Ji, Yingjie and Karaderi, Tugce and Lin, Kuang and Lull, Kreete and Malden, Deborah E. and Medina-Gomez, Carolina and Machado, Moara and Moore, Amy and Rueger, Sina and Sim, Xueling and Vrieze, Scott and Ahluwalia, Tarunveer S. and Akiyama, Masato and Allison, Matthew A. and Alvarez, Marcus and Andersen, Mette K. and Ani, Alireza and Appadurai, Vivek and Arbeeva, Liubov and Bhaskar, Seema and Bielak, Lawrence F. and Bollepalli, Sailalitha and Bonnycastle, Lori L. and Bork-Jensen, Jette and Bradfield, Jonathan P. and Bradford, Yuki and Braund, Peter S. and Brody, Jennifer A. and Burgdorf, Kristoffer S. and Cade, Brian E. and Cai, Hui and Cai, Qiuyin and Campbell, Archie and Canadas-Garre, Marisa and Catamo, Eulalia and Chai, Jin-Fang and Chai, Xiaoran and Chang, Li-Ching and Chang, Yi-Cheng and Chen, Chien-Hsiun and Chesi, Alessandra and Choi, Seung Hoan and Chung, Ren-Hua and Cocca, Massimiliano and Concas, Maria Pina and Couture, Christian and Cuellar-Partida, Gabriel and Danning, Rebecca and Daw, E. Warwick and Degenhard, Frauke and Delgado, Graciela E. and Delitala, Alessandro and Demirkan, Ayse and Deng, Xuan and Devineni, Poornima and Dietl, Alexander and Dimitriou, Maria and Dimitrov, Latchezar and Dorajoo, Rajkumar and Ekici, Arif B. and Engmann, Jorgen E. and Fairhurst-Hunter, Zammy and Farmaki, Aliki-Eleni and Faul, Jessica D. and Fernandez-Lopez, Juan-Carlos and Forer, Lukas and Francescatto, Margherita and Freitag-Wolf, Sandra and Fuchsberger, Christian and Galesloot, Tessel E. and Gao, Yan and Gao, Zishan and Geller, Frank and Giannakopoulou, Olga and Giulianini, Franco and Gjesing, Anette P. and Goel, Anuj and Gordon, Scott D. and Gorski, Mathias and Grove, Jakob and Guo, Xiuqing and Gustafsson, Stefan and Haessler, Jeffrey and Hansen, Thomas F. and Havulinna, Aki S. and Haworth, Simon J. and He, Jing and Heard-Costa, Nancy and Hebbar, Prashantha and Hindy, George and Ho, Yuk-Lam A. and Hofer, Edith and Holliday, Elizabeth and Horn, Katrin and Hornsby, Whitney E. and Hottenga, Jouke-Jan and Huang, Hongyan and Huang, Jie and Huerta-Chagoya, Alicia and Huffman, Jennifer E. and Hung, Yi-Jen and Huo, Shaofeng and Hwang, Mi Yeong and Iha, Hiroyuki and Ikeda, Daisuke D. and Isono, Masato and Jackson, Anne U. and Jager, Susanne and Jansen, Iris E. and Johansson, Ingegerd and Jonas, Jost B. and Jonsson, Anna and Jorgensen, Torben and Kalafati, Ioanna-Panagiota and Kanai, Masahiro and Kanoni, Stavroula and Karhus, Line L. and Kasturiratne, Anuradhani and Katsuya, Tomohiro and Kawaguchi, Takahisa and Kember, Rachel L. and Kentistou, Katherine A. and Kim, Han-Na and Kim, Young Jin and Kleber, Marcus E. and Knol, Maria J. and Kurbasic, Azra and Lauzon, Marie and Le, Phuong and Lea, Rodney and Lee, Jong-Young and Leonard, Hampton L. and Li, Shengchao A. and Li, Xiaohui and Li, Xiaoyin and Liang, Jingjing and Lin, Honghuang and Lin, Shih-Yi and Liu, Jun and Liu, Xueping and Lo, Ken Sin and Long, Jirong and Lores-Motta, Laura and Luan, Jian'an and Lyssenko, Valeriya and Lyytikainen, Leo-Pekka and Mahajan, Anubha and Mamakou, Vasiliki and Mangino, Massimo and Manichaikul, Ani and Marten, Jonathan and Mattheisen, Manuel and Mavarani, Laven and McDaid, Aaron F. and Meidtner, Karina and Melendez, Tori L. and Mercader, Josep M. and Milaneschi, Yuri and Miller, Jason E. and Millwood, Iona Y. and Mishra, Pashupati P. and Mitchell, Ruth E. and Mollehave, Line T. and Morgan, Anna and Mucha, Soeren and Munz, Matthias and Nakatochi, Masahiro and Nelson, Christopher P. and Nethander, Maria and Nho, Chu Won and Nielsen, Aneta A. and Nolte, Ilja M. and Nongmaithem, Suraj S. and Noordam, Raymond and Ntalla, Ioanna and Nutile, Teresa and Pandit, Anita and Christofidou, Paraskevi and Parna, Katri and Pauper, Marc and Petersen, Eva R. 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M. and Kim, Bong-Jo and Kim, Eung Kweon and Kim, Hyung-Lae and Kirchhof, Paulus and Kivimaki, Mika and Koh, Woon-Puay and Koistinen, Heikki A. and Kolovou, Genovefa D. and Kooner, Jaspal S. and Kooperberg, Charles and Kottgen, Anna and Kovacs, Peter and Kraaijeveld, Adriaan and Kraft, Peter and Krauss, Ronald M. and Kumari, Meena and Kutalik, Zoltan and Laakso, Markku and Lange, Leslie A. and Langenberg, Claudia and Launer, Lenore J. and Le Marchand, Loic and Lee, Hyejin and Lee, Nanette R. and Lehtimaki, Terho and Li, Huaixing and Li, Liming and Lieb, Wolfgang and Lin, Xu and Lind, Lars and Linneberg, Allan and Liu, Ching-Ti and Liu, Jianjun and Loeffler, Markus and London, Barry and Lubitz, Steven A. and Lye, Stephen J. and Mackey, David A. and Magi, Reedik and Magnusson, Patrik K. 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Gustav and Snieder, Harold and Spector, Tim D. and Stampfer, Meir J. and Stark, Klaus J. and Strachan, David P. and t' Hart, Leen M. and Tabara, Yasuharu and Tang, Hua and Tardif, Jean-Claude and Thanaraj, Thangavel A. and Timpson, Nicholas J. and Tonjes, Anke and Tremblay, Angelo and Tuomi, Tiinamaija and Tuomilehto, Jaakko and Tusie-Luna, Maria-Teresa and Uitterlinden, Andre G. and van Dam, Rob M. and van der Harst, Pim and Van der Velde, Nathalie and van Duijn, Cornelia M. and van Schoor, Natasja M. and Vitart, Veronique and Volker, Uwe and Vollenweider, Peter and Volzke, Henry and Wacher-Rodarte, Niels H. and Walker, Mark and Wang, Ya Xing and Wareham, Nicholas J. and Watanabe, Richard M. and Watkins, Hugh and Weir, David R. and Werge, Thomas M. and Widen, Elisabeth and Wilkens, Lynne R. and Willemsen, Gonneke and Willett, Walter C. and Wilson, James F. and Wong, Tien-Yin and Woo, Jeong-Taek and Wright, Alan F. and Wu, Jer-Yuarn and Xu, Huichun and Yajnik, Chittaranjan S. and Yokota, Mitsuhiro and Yuan, Jian-Min and Zeggini, Eleftheria and Zemel, Babette S. and Zheng, Wei and Zhu, Xiaofeng and Zmuda, Joseph M. and Zonderman, Alan B. and Zwart, John-Anker and Chasman, Daniel and Cho, Yoon Shin and Heid, Iris M. and McCarthy, Mark and Ng, Maggie C. Y. and O'Donnell, Christopher J. and Rivadeneira, Fernando and Thorsteinsdottir, Unnur and Sun, Yan and Tai, E. Shyong and Boehnke, Michael and Deloukas, Panos and Justice, Anne E. and Lindgren, Cecilia M. and Loos, Ruth J. F. and Mohlke, Karen L. and North, Kari E. and Stefansson, Kari and Walters, Robin G. and Winkler, Thomas W. and Young, Kristin L. and Loh, Po-Ru and Yang, Jian and Esko, Tonu and Assimes, Themistocles L. and Auton, Adam and Abecasis, Goncalo R. and Willer, Cristen J. and Locke, Adam E. and Berndt, Sonja and Lettre, Guillaume and Frayling, Timothy M. and Okada, Yukinori and Wood, Andrew R. and Visscher, Peter M. and Hirschhorn, Joel N. (2022) A saturated map of common genetic variants associated with human height. NATURE, 610 (7933). 704-+. ISSN 0028-0836, 1476-4687

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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. A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

Item Type:	Article
Uncontrolled Keywords:	GENOME-WIDE ASSOCIATION; UK BIOBANK; RARE; HERITABILITY; GWAS; ARCHITECTURE; IMPUTATION; RESOURCE; REVEALS; SCORES;
Subjects:	600 Technology > 610 Medical sciences Medicine
Divisions:	Medicine > Lehrstuhl für Innere Medizin II Medicine > Abteilung für Nephrologie Medicine > Institut für Epidemiologie und Präventivmedizin > Lehrstuhl für Genetische Epidemiologie
Depositing User:	Dr. Gernot Deinzer
Date Deposited:	19 Sep 2023 06:22
Last Modified:	19 Sep 2023 06:22
URI:	https://pred.uni-regensburg.de/id/eprint/58862

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