Rare and Low-Frequency Coding Variants Alter Human Adult Height

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Citation

Marouli, Eirini; Graff, Mariaelisa; Medina-Gomez, Carolina; Lo, Ken Sin; Wood, Andrew R.; Kjaer, Troels R.; Fine, Rebecca S.; Lu, Yingchang; Schurmann, Claudia; & Highland, Heather M., et al. (2017). Rare and Low-Frequency Coding Variants Alter Human Adult Height. Nature, 542(7640), 186-190. PMCID: PMC5302847

Abstract

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

URL

http://dx.doi.org/10.1038/nature21039

Reference Type

Journal Article

Year Published

2017

Journal Title

Nature

Author(s)

Marouli, Eirini
Graff, Mariaelisa
Medina-Gomez, Carolina
Lo, Ken Sin
Wood, Andrew R.
Kjaer, Troels R.
Fine, Rebecca S.
Lu, Yingchang
Schurmann, Claudia
Highland, Heather M.
Rueger, Sina
Thorleifsson, Gudmar
Justice, Anne E.
Lamparter, David
Stirrups, Kathleen E.
Turcot, Valerie
Young, Kristin L.
Winkler, Thomas W.
Esko, Tonu
Karaderi, Tugce
Locke, Adam E.
Masca, Nicholas G. D.
Ng, Maggie C. Y.
Mudgal, Poorva
Rivas, Manuel A.
Vedantam, Sailaja
Mahajan, Anubha
Guo, Xiuqing
Abecasis, Gonçalo R.
Aben, Katja K.
Adair, Linda S.
Alam, Dewan S.
Albrecht, Eva
Allin, Kristine H.
Allison, Matthew A.
Amouyel, Philippe
Appel, Emil V. R.
Arveiler, Dominique
Asselbergs, Folkert W.
Auer, Paul L.
Balkau, Beverley
Banas, Bernhard
Bang, Lia E.
Benn, Marianne
Bergmann, Sven
Bielak, Lawrence F.
Bluher, Matthias
Boeing, Heiner
Boerwinkle, Eric A.
Boger, Carsten A.
Bonnycastle, Lori L.
Bork-Jensen, Jette
Bots, Michiel L.
Bottinger, Erwin P.
Bowden, Donald W.
Brandslund, Ivan
Breen, Gerome
Brilliant, Murray H.
Broer, Linda
Burt, Amber A.
Butterworth, Adam S.
Carey, David J.
Caulfield, Mark J.
Chambers, John C.
Chasman, Daniel I.
Chen, Yii-Der Ida
Chowdhury, Rajiv
Christensen, Cramer
Chu, Audrey Y.
Cocca, Massimiliano
Collins, Francis S.
Cook, James P.
Corley, Janie
Galbany, Jordi Corominas
Cox, Amanda J.
Cuellar-Partida, Gabriel
Danesh, John
Davies, Gail
de Bakker, Paul I. W.
de Borst, Gert J.
de Denus, Simon
de Groot, Mark C. H.
de Mutsert, Renee
Deary, Ian J.
Dedoussis, George
Demerath, Ellen W.
den Hollander, Anneke I.
Dennis, Joe G.
Di Angelantonio, Emanuele
Drenos, Fotios
Du, Mengmeng
Dunning, Alison M.
Easton, Douglas F.
Ebeling, Tapani
Edwards, Todd L.
Ellinor, Patrick T.
Elliott, Paul
Evangelou, Evangelos
Farmaki, Aliki-Eleni
Faul, Jessica D.
Feitosa, Mary F.
Feng, Shuang
Ferrannini, Ele
Ferrario, Marco M.
Ferrieres, Jean
Florez, Jose C.
Ford, Ian
Fornage, Myriam
Franks, Paul W.
Frikke-Schmidt, Ruth
Galesloot, Tessel E.
Gan, Wei
Gandin, Ilaria
Gasparini, Paolo
Giedraitis, Vilmantas
Giri, Ayush
Girotto, Giorgia
Gordon, Scott D.
Gordon-Larsen, Penny
Gorski, Mathias
Grarup, Niels
Grove, Megan L.
Gudnason, Vilmundur G.
Gustafsson, Stefan
Hansen, Torben
Harris, Kathleen Mullan
Harris, Tamara B.
Hattersley, Andrew T.
Hayward, Caroline
He, Liang
Heid, Iris M.
Heikkila, Kauko
Helgeland, Oyvind
Hernesniemi, Jussi
Hewitt, Alex W.
Hocking, Lynne J.
Hollensted, Mette
Holmen, Oddgeir L.
Hovingh, G. Kees
Howson, Joanna M. M.
Hoyng, Carel B.
Huang, Paul L.
Hveem, Kristian
Ikram, M. Arfan
Ingelsson, Erik
Jackson, Anne U.
Jansson, Jan-Hakan
Jarvik, Gail P.
Jensen, Gorm B.
Jhun, Min A.
Jia, Yucheng
Jiang, Xuejuan
Johansson, Stefan
Jorgensen, Marit E.
Jorgensen, Torben
Jousilahti, Pekka
Jukema, J. Wouter
Kahali, Bratati
Kahn, Rene S.
Kahonen, Mika
Kamstrup, Pia R.
Kanoni, Stavroula
Kaprio, Jaakko
Karaleftheri, Maria
Kardia, Sharon L. R.
Karpe, Fredrik
Kee, Frank
Keeman, Renske
Kiemeney, Lambertus A.
Kitajima, Hidetoshi
Kluivers, Kirsten B.
Kocher, Thomas
Komulainen, Pirjo
Kontto, Jukka
Kooner, Jaspal Singh S.
Kooperberg, Charles L.
Kovacs, Peter
Kriebel, Jennifer
Kuivaniemi, Helena
Kury, Sebastien
Kuusisto, Johanna
La Bianca, Martina
Laakso, Markku
Lakka, Timo A.
Lange, Ethan M.
Lange, Leslie A.
Langefeld, Carl D.
Langenberg, Claudia
Larson, Eric B.
Lee, I-Te
Lehtimaki, Terho
Lewis, Cora E.
Li, Huaixing
Li, Jin
Li-Gao, Ruifang
Lin, Honghuang
Lin, Li-An
Lin, Xu
Lind, Lars
Lindstrom, Jaana
Linneberg, Allan
Liu, Yeheng
Liu, Yongmei
Lophatananon, Artitaya
Luan, Jian'an
Lubitz, Steven A.
Lyytikainen, Leo-Pekka
Mackey, David A.
Madden, Pamela A. F.
Manning, Alisa K.
Mannisto, Satu
Marenne, Gaelle
Marten, Jonathan
Martin, Nicholas G.
Mazul, Angela L.
Meidtner, Karina
Metspalu, Andres
Mitchell, Paul
Mohlke, Karen L.
Mook-Kanamori, Dennis O.
Morgan, Anna
Morris, Andrew D.
Morris, Andrew P.
Muller-Nurasyid, Martina
Munroe, Patricia B.
Nalls, Mike A.
Nauck, Matthias
Nelson, Christopher P.
Neville, Matt
Nielsen, Sune F.
Nikus, Kjell
Njolstad, Pal R.
Nordestgaard, Borge G.
Ntalla, Ioanna
O'Connell, Jeffrey R.
Oksa, Heikki
Loohuis, Loes M. Olde
Ophoff, Roel A.
Owen, Katharine R.
Packard, Chris J.
Padmanabhan, Sandosh
Palmer, Colin N. A.
Pasterkamp, Gerard
Patel, Aniruddh P.
Pattie, Alison
Pedersen, Oluf
Peissig, Peggy L.
Peloso, Gina M.
Pennell, Craig E.
Perola, Markus
Perry, James A.
Perry, John R. B.
Person, Thomas N.
Pirie, Ailith
Polasek, Ozren
Posthuma, Danielle
Raitakari, Olli T.
Rasheed, Asif
Rauramaa, Rainer
Reilly, Dermot F.
Reiner, Alexander P.
Renström, Frida
Ridker, Paul M.
Rioux, John D.
Robertson, Neil R.
Robino, Antonietta
Rolandsson, Olov
Rudan, Igor
Ruth, Katherine S.
Saleheen, Danish
Salomaa, Veikko
Samani, Nilesh J.
Sandow, Kevin
Sapkota, Yadav
Sattar, Naveed
Schmidt, Marjanka K.
Schreiner, Pamela J.
Schulze, Matthias B.
Scott, Robert A.
Segura-Lepe, Marcelo P.
Shah, Svati H.
Sim, Xueling
Sivapalaratnam, Suthesh
Small, Kerrin S.
Smith, Albert V.
Smith, Jennifer A.
Southam, Lorraine
Spector, Timothy D.
Speliotes, Elizabeth K.
Starr, John M.
Steinthorsdottir, Valgerdur
Stringham, Heather M.
Stumvoll, Michael
Surendran, Praveen
't Hart, Leen M.
Tansey, Katherine E.
Tardif, Jean-Claude
Taylor, Kent D.
Teumer, Alexander
Thompson, Deborah J.
Thorsteinsdottir, Unnur
Thuesen, Betina H.
Tonjes, Anke
Tromp, Gerard
Trompet, Stella
Tsafantakis, Emmanouil
Tuomilehto, Jaakko
Tybjaerg-Hansen, Anne
Tyrer, Jonathan P.
Uher, Rudolf
Uitterlinden, Andre G.
Ulivi, Sheila
van der Laan, Sander W.
Van Der Leij, Andries R.
van Duijn, Cornelia M.
van Schoor, Natasja M.
van Setten, Jessica
Varbo, Anette
Varga, Tibor V.
Varma, Rohit
Edwards, Digna R. Velez
Vermeulen, Sita H.
Vestergaard, Henrik
Vitart, Veronique
Vogt, Thomas F.
Vozzi, Diego
Walker, Mark
Wang, Feijie
Wang, Carol A.
Wang, Shuai
Wang, Yiqin
Wareham, Nicholas J.
Warren, Helen R.
Wessel, Jennifer
Willems, Sara M.
Wilson, James G.
Witte, Daniel R.
Woods, Michael O.
Wu, Ying
Yaghootkar, Hanieh
Yao, Jie
Yao, Pang
Yerges-Armstrong, Laura M.
Young, Robin D.
Zeggini, Eleftheria
Zhan, Xiaowei
Zhang, Weihua
Zhao, Jing Hua
Zhao, Wei
Zheng, He
Zhou, Wei
EPIC-InterAct Consortium,
CHD Exome+ Consortium,
ExomeBP Consortium,
T2D-Genes Consortium,
GoT2D Genes Consortium,
Global Lipids Genetics Consortium,
ReproGen Consortium,
MAGIC Investigators,
Rotter, Jerome I.
Boehnke, Michael
Kathiresan, Sekar
McCarthy, Mark I.
Willer, Cristen J.
Stefansson, Kari
Borecki, Ingrid B.
Liu, Dajiang J.
North, Kari E.
Heard-Costa, Nancy L.
Pers, Tune H.
Lindgren, Cecilia M.
Oxvig, Claus
Kutalik, Zoltan
Rivadeneira, Fernando
Loos, Ruth J. F.
Frayling, Timothy M.
Hirschhorn, Joel N.
Deloukas, Panos
Lettre, Guillaume

PMCID

PMC5302847

ORCiD

Gordon-Larsen - 0000-0001-5322-4188