TY - JOUR
T1 - A saturated map of common genetic variants associated with human height
AU - 23andMe Research Team
AU - VA Million Veteran Program
AU - DiscovEHR (DiscovEHR and MyCode Community Health Initiative)
AU - eMERGE (Electronic Medical Records and Genomics Network)
AU - Lifelines Cohort Study
AU - The PRACTICAL Consortium
AU - Understanding Society Scientific group
AU - Yengo, Loïc
AU - Vedantam, Sailaja
AU - Marouli, Eirini
AU - Sidorenko, Julia
AU - Bartell, Eric
AU - Sakaue, Saori
AU - Graff, Marielisa
AU - Eliasen, Anders U.
AU - Jiang, Yunxuan
AU - Raghavan, Sridharan
AU - Miao, Jenkai
AU - Arias, Joshua D.
AU - Graham, Sarah E.
AU - Mukamel, Ronen E.
AU - Spracklen, Cassandra N.
AU - Yin, Xianyong
AU - Chen, Shyh Huei
AU - Ferreira, Teresa
AU - Highland, Heather H.
AU - Ji, Yingjie
AU - Karaderi, Tugce
AU - Lin, Kuang
AU - Lüll, Kreete
AU - Malden, Deborah E.
AU - Medina-Gomez, Carolina
AU - Machado, Moara
AU - Moore, Amy
AU - Rüeger, Sina
AU - Sim, Xueling
AU - Vrieze, Scott
AU - Ahluwalia, Tarunveer S.
AU - Akiyama, Masato
AU - Allison, Matthew A.
AU - Alvarez, Marcus
AU - Andersen, Mette K.
AU - Ani, Alireza
AU - Appadurai, Vivek
AU - Arbeeva, Liubov
AU - Bhaskar, Seema
AU - Bielak, Lawrence F.
AU - Bollepalli, Sailalitha
AU - Bonnycastle, Lori L.
AU - Bork-Jensen, Jette
AU - Bradfield, Jonathan P.
AU - Bradford, Yuki
AU - Braund, Peter S.
AU - Brody, Jennifer A.
AU - Burgdorf, Kristoffer S.
AU - Cade, Brian E.
AU - Cai, Hui
AU - Cai, Qiuyin
AU - Campbell, Archie
AU - Cañadas-Garre, Marisa
AU - Catamo, Eulalia
AU - Chai, Jin Fang
AU - Chai, Xiaoran
AU - Chang, Li Ching
AU - Chang, Yi Cheng
AU - Chen, Chien Hsiun
AU - Chesi, Alessandra
AU - Choi, Seung Hoan
AU - Chung, Ren Hua
AU - Cocca, Massimiliano
AU - Concas, Maria Pina
AU - Couture, Christian
AU - Cuellar-Partida, Gabriel
AU - Danning, Rebecca
AU - Daw, E. Warwick
AU - Degenhard, Frauke
AU - Delgado, Graciela E.
AU - Delitala, Alessandro
AU - Demirkan, Ayse
AU - Deng, Xuan
AU - Devineni, Poornima
AU - Dietl, Alexander
AU - Dimitriou, Maria
AU - Dimitrov, Latchezar
AU - Dorajoo, Rajkumar
AU - Ekici, Arif B.
AU - Engmann, Jorgen E.
AU - Fairhurst-Hunter, Zammy
AU - Farmaki, Aliki Eleni
AU - Faul, Jessica D.
AU - Fernandez-Lopez, Juan Carlos
AU - Forer, Lukas
AU - Francescatto, Margherita
AU - Freitag-Wolf, Sandra
AU - Fuchsberger, Christian
AU - Galesloot, Tessel E.
AU - Gao, Yan
AU - Gao, Zishan
AU - Geller, Frank
AU - Giannakopoulou, Olga
AU - Giulianini, Franco
AU - Gjesing, Anette P.
AU - Goel, Anuj
AU - Gordon, Scott D.
AU - Gorski, Mathias
AU - Grove, Jakob
AU - Guo, Xiuqing
AU - Gustafsson, Stefan
AU - Haessler, Jeffrey
AU - Hansen, Thomas F.
AU - Havulinna, Aki S.
AU - Haworth, Simon J.
AU - He, Jing
AU - Heard-Costa, Nancy
AU - Hebbar, Prashantha
AU - Hindy, George
AU - Ho, Yuk Lam A.
AU - Hofer, Edith
AU - Holliday, Elizabeth
AU - Horn, Katrin
AU - Hornsby, Whitney E.
AU - Hottenga, Jouke Jan
AU - Huang, Hongyan
AU - Huang, Jie
AU - Huerta-Chagoya, Alicia
AU - Huffman, Jennifer E.
AU - Hung, Yi Jen
AU - Huo, Shaofeng
AU - Hwang, Mi Yeong
AU - Iha, Hiroyuki
AU - Ikeda, Daisuke D.
AU - Isono, Masato
AU - Jackson, Anne U.
AU - Jäger, Susanne
AU - Jansen, Iris E.
AU - Johansson, Ingegerd
AU - Jonas, Jost B.
AU - Jonsson, Anna
AU - Jørgensen, Torben
AU - Kalafati, Ioanna Panagiota
AU - Kanai, Masahiro
AU - Kanoni, Stavroula
AU - Kårhus, Line L.
AU - Kasturiratne, Anuradhani
AU - Katsuya, Tomohiro
AU - Kawaguchi, Takahisa
AU - Kember, Rachel L.
AU - Kentistou, Katherine A.
AU - Kim, Han Na
AU - Kim, Young Jin
AU - Kleber, Marcus E.
AU - Knol, Maria J.
AU - Kurbasic, Azra
AU - Lauzon, Marie
AU - Le, Phuong
AU - Lea, Rodney
AU - Lee, Jong Young
AU - Leonard, Hampton L.
AU - Li, Shengchao A.
AU - Li, Xiaohui
AU - Li, Xiaoyin
AU - Liang, Jingjing
AU - Lin, Honghuang
AU - Lin, Shih Yi
AU - Liu, Jun
AU - Liu, Xueping
AU - Lo, Ken Sin
AU - Long, Jirong
AU - Lores-Motta, Laura
AU - Luan, Jian’an
AU - Lyssenko, Valeriya
AU - Lyytikäinen, Leo Pekka
AU - Mahajan, Anubha
AU - Mamakou, Vasiliki
AU - Mangino, Massimo
AU - Manichaikul, Ani
AU - Marten, Jonathan
AU - Mattheisen, Manuel
AU - Mavarani, Laven
AU - McDaid, Aaron F.
AU - Meidtner, Karina
AU - Melendez, Tori L.
AU - Mercader, Josep M.
AU - Milaneschi, Yuri
AU - Miller, Jason E.
AU - Millwood, Iona Y.
AU - Mishra, Pashupati P.
AU - Mitchell, Ruth E.
AU - Møllehave, Line T.
AU - Morgan, Anna
AU - Mucha, Soeren
AU - Munz, Matthias
AU - Nakatochi, Masahiro
AU - Nelson, Christopher P.
AU - Nethander, Maria
AU - Nho, Chu Won
AU - Nielsen, Aneta A.
AU - Nolte, Ilja M.
AU - Nongmaithem, Suraj S.
AU - Noordam, Raymond
AU - Ntalla, Ioanna
AU - Nutile, Teresa
AU - Pandit, Anita
AU - Christofidou, Paraskevi
AU - Province, Michael A.
AU - Rao, Dabeeru C.
AU - Locke, Adam E.
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/10/27
Y1 - 2022/10/27
N2 - 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 sizes1. 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 panel2) 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.
AB - 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 sizes1. 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 panel2) 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.
UR - http://www.scopus.com/inward/record.url?scp=85139748621&partnerID=8YFLogxK
U2 - 10.1038/s41586-022-05275-y
DO - 10.1038/s41586-022-05275-y
M3 - Article
C2 - 36224396
AN - SCOPUS:85139748621
SN - 0028-0836
VL - 610
SP - 704
EP - 712
JO - Nature
JF - Nature
IS - 7933
ER -