Rare and low-frequency coding variants alter human adult height
Creators: name: Tybjaerg-Hansen, Anne
name: Helgeland, Øyvind
name: Thorsteinsdottir, Unnur
name: Boeing, Heiner
name: Balkau, Beverley
name: Nauck, Matthias
name: Liu, Dajiang J.
name: Lange, Leslie A.
name: Oksa, Heikki
name: Meidtner, Karina
name: Corley, Janie
name: Zhou, Wei
name: Zhan, Xiaowei
name: Tyrer, Jonathan P.
name: Vozzi, Diego
name: Bonnycastle, Lori L.
name: Kutalik, Zoltán
name: Wang, Feijie
name: Girotto, Giorgia
name: Bang, Lia E.
name: Hveem, Kristian
name: Rioux, John D.
name: Frayling, Timothy M.
name: Hoyng, Carel B.
name: Burt, Amber A.
name: Lind, Lars
name: Deary, Ian J.
name: Willems, Sara M.
name: Kitajima, Hidetoshi
name: Reilly, Dermot F.
name: Jørgensen, Torben
name: De Borst, Gert J.
name: Liu, Yeheng
name: Ebeling, Tapani
name: Mahajan, Anubha
name: Stirrups, Kathleen E.
name: Gustafsson, Stefan
name: Heard-Costa, Nancy L.
name: Bowden, Donald W.
name: Florez, Jose C.
name: Highland, Heather M.
name: Ulivi, Sheila
name: Owen, Katharine R.
name: Ellinor, Patrick T.
name: Boehnke, Michael
name: Benn, Marianne
name: Trompet, Stella
name: Asselbergs, Folkert W.
name: Sivapalaratnam, Suthesh
name: Kooperberg, Charles
name: La Bianca, Martina
name: Davies, Gail
name: Böger, Carsten A.
name: Jørgensen, Marit E.
name: Cox, Amanda J.
name: Kuivaniemi, Helena
name: Giedraitis, Vilmantas
name: Wood, Andrew R.
name: Den Hollander, Anneke I.
name: McCarthy, Mark I.
name: Lindström, Jaana
name: Tönjes, Anke
name: Arveiler, Dominique
name: Jhun, Min A.
name: Raitakari, Olli T.
name: Langenberg, Claudia
name: Easton, Douglas F.
name: Turcot, Valérie
name: Rotter, Jerome I.
name: Tansey, Katherine E.
name: Masca, Nicholas G.D.
name: Pedersen, Oluf
name: Keeman, Renske
name: Grarup, Niels
name: Cocca, Massimiliano
name: Robino, Antonietta
name: Kluivers, Kirsten B.
name: Kahn, René S.
name: De Bakker, Paul I.W.
name: Rauramaa, Rainer
name: Komulainen, Pirjo
name: Blüher, Matthias
name: Karaderi, Tugce
name: Alam, Dewan S.
name: Van Der Laan, Sander W.
name: Caulfield, Mark J.
name: Van Der Leij, Andries R.
name: Chowdhury, Rajiv
name: Fine, Rebecca S.
name: Tsafantakis, Emmanouil
name: Ford, Ian
name: De Denus, Simon
name: Hocking, Lynne J.
name: Chambers, John C.
name: Farmaki, Aliki-Eleni
name: Posthuma, Danielle
name: Lin, Li-An
name: Linneberg, Allan
name: Ophoff, Roel A.
name: He, Liang
name: Manning, Alisa K.
name: Tardif, Jean-Claude
name: Thompson, Deborah J.
name: Danesh, John
name: O'Connel, Jeffrey R.
name: Peissig, Peggy L.
name: Bottinger, Erwin P.
name: Hollensted, Mette
name: Wilson, James G.
name: Wu, Ying
name: Banas, Bernhard
name: Li, Jin
name: Gordon, Scott D.
name: Pasterkamp, Gerard
name: Männistö, Satu
name: Fornage, Myriam
name: Deloukas, Panos
name: Johansson, Stefan
name: Marenne, Gaëlle
name: Southam, Lorraine
name: Christensen, Cramer
name: Nelson, Christopher P.
name: Lange, Ethan M.
name: Harris, Tamara B.
name: Cook, James P.
name: Vogt, Thomas F.
name: Li, Huaixing
name: Elliott, Paul
name: Stefansson, Kari
name: Starr, John M.
name: Gudnason, Vilmundur
name: Ferrannini, Ele
name: Varga, Tibor V.
name: Laakso, Markku
name: Sapkota, Yadav
name: Reiner, Alex P.
name: Lehtimäki, Terho
name: Polasek, Ozren
name: Vestergaard, Henrik
name: Padmanabhan, Sandosh
name: Stringham, Heather M.
name: Kontto, Jukka
name: Marten, Jonathan
name: Scott, Robert A.
name: Jensen, Gorm B.
name: Allison, Matthew
name: Zhao, Wei
name: Kocher, Thomas
name: Pirie, Ailith
name: Nielsen, Sune F.
name: Palmer, Colin N.A.
name: Young, Robin
name: Lu, Yingchang
name: Gordon-Larsen, Penny
name: Jarvik, Gail P.
name: Samani, Nilesh J.
name: Heid, Iris M.
name: Kahali, Bratati
name: Auer, Paul L.
name: North, Kari E.
name: Sandow, Kevin
name: Pattie, Alison
name: Kaprio, Jaakko
name: Giri, Ayush
name: Smith, Albert Vernon
name: Gorski, Mathias
name: Schurmann, Claudia
name: Stumvoll, Michael
name: Surendran, Praveen
name: Lin, Xu
name: Martin, Nicholas G.
name: Metspalu, Andres
name: Ng, Maggie C.Y.
name: Feng, Shuang
name: De Groot, Mark C.H.
name: Brandslund, Ivan
name: Galesloot, Tessel E.
name: Adair, Linda S.
name: Feitosa, Mary F.
name: Nordestgaard, Børge G.
name: Zheng, He
name: Kriebel, Jennifer
name: Hattersley, Andrew T.
name: Gasparini, Paolo
name: Mitchell, Paul
name: Neville, Matt
name: Rivadeneira, Fernando
name: Spector, Timothy D.
name: Packard, Chris J.
name: Howson, Joanna M.M.
name: Hewitt, Alex W.
name: Faul, Jessica D.
name: Chasman, Daniel I.
name: Van Schoor, Natasja M.
name: Vermeulen, Sita H.
name: Wessel, Jennifer
name: Perola, Markus
name: Holmen, Oddgeir L.
name: Rivas, Manuel A.
name: Schreiner, Pamela J.
name: Boerwinkle, Eric
name: Steinthorsdottir, Valgerdur
name: Loohuis, Loes M. Olde
name: Albrecht, Eva
name: Lamparter, David
name: Munroe, Patricia B.
name: Varma, Rohit
name: Van Duijn, Cornelia M.
name: Yaghootkar, Hanieh
name: Hayward, Caroline
name: Guo, Xiuqing
name: Locke, Adam E.
name: Lee, I-Te
name: Grove, Megan L.
name: Abecasis, Goncalo
name: Kardia, Sharon L.R.
name: Franks, Paul W.
name: Kooner, Jaspal S.
name: Hovingh, G Kees
name: Nalls, Mike A.
name: Rasheed, Asif
name: Kähönen, Mika
name: Willer, Cristen J.
name: Teumer, Alexander
name: Speliotes, Elizabeth K.
name: Morris, Andrew P.
name: Lyytikäinen, Leo-Pekka
name: Njølstad, Pål R.
name: Mazul, Angela L.
name: Zhang, Weihua
name: Walker, Mark
name: Woods, Michael O.
name: Witte, Daniel R.
name: Bots, Michiel L.
name: Cuellar-Partida, Gabriel
name: Yao, Pang
name: Galbany, Jordi Corominas
name: Dennis, Joe G.
name: Dedoussis, George
name: Müller-Nurasyid, Martina
name: Chu, Audrey Y.
name: Young, Kristin L.
name: Brilliant, Murray H.
name: Drenos, Fotios
name: Huang, Paul L.
name: Harris, Kathleen Mullan
name: Yao, Jie
name: Renström, Frida
name: Borecki, Ingrid B.
name: Kamstrup, Pia R.
name: Demerath, Ellen W.
name: Rolandsson, Olov
name: Ferrieres, Jean
name: Gandin, Ilaria
name: Larson, Eric B.
name: Evangelou, Evangelos
name: Dunning, Alison M.
name: Wareham, Nicholas J.
name: Lakka, Timo A.
name: Lettre, Guillaume
name: Bergmann, Sven
name: Kiemeney, Lambertus A.
name: Person, Thomas N.
name: Ferrario, Marco M.
name: Pennell, Craig E.
name: Marouli, Eirini
name: Loos, Ruth J.F.
name: Thuesen, Betina H.
name: Broer, Linda
name: Pers, Tune H.
name: Kuusisto, Johanna
name: Smith, Jennifer A.
name: Patel, Aniruddh P.
name: Jousilahti, Pekka
name: Tuomilehto, Jaakko
name: Wang, Carol A.
name: Jia, Yucheng
name: Li-Gao, Ruifang
name: Heikkilä, Kauko
name: Karaleftheri, Maria
name: Thorleifsson, Gudmar
name: De Mutsert, Renée
name: Velez Edwards, Digna R.
name: Hart't, Leen M.
name: Ikram, M Arfan
name: Allin, Kristine H.
name: Appel, Emil V.
name: Ntalla, Ioanna
name: Yerges-Armstrong, Laura M.
name: Mook-Kanamori, Dennis O.
name: Edwards, Todd L.
name: Lo, Ken Sin
name: Carey, David J.
name: Lubitz, Steven A.
name: Kanoni, Stavroula
name: Sattar, Naveed
name: Kovacs, Peter
name: Vedantam, Sailaja
name: Van Setten, Jessica
name: Graff, Mariaelisa
name: Hirschhorn, Joel N.
name: Sim, Xueling
name: Gan, Wei
name: Nikus, Kjell
name: Butterworth, Adam S.
name: Salomaa, Veikko
name: Wang, Yiqin
name: Hernesniemi, Jussi
name: Oxvig, Claus
name: Bork-Jensen, Jette
name: Esko, Tõnu
name: Tromp, Gerard
name: Medina-Gomez, Carolina
name: Winkler, Thomas W.
name: Aben, Katja K.
name: Peloso, Gina M.
name: Frikke-Schmidt, Ruth
name: Langefeld, Carl D.
name: Di Angelantonio, Emanuele
name: Hansen, Torben
name: Chen, Yii-Der Ida
name: Justice, Anne E.
name: Saleheen, Danish
name: Uitterlinden, André G.
name: Jiang, Xuejuan
name: Wang, Shuai
name: Jackson, Anne U.
name: Uher, Rudolf
name: Zhao, Jing Hua
name: Bielak, Lawrence F.
name: Luan, Jian'an
name: Segura-Lepe, Marcelo P.
name: Lin, Honghuang
name: Ruth, Katherine S.
name: Mohlke, Karen L.
name: Vitart, Veronique
name: Shah, Svati
name: Kathiresan, Sekar
name: Collins, Francis S.
name: Warren, Helen R.
name: Jukema, J Wouter
name: Robertson, Neil
name: Madden, Pamela A.F.
name: Taylor, Kent D.
name: Mudgal, Poorva
name: Lindgren, Cecilia M.
name: Karpe, Fredrik
name: Ingelsson, Erik
name: Rudan, Igor
name: Kee, Frank
name: Perry, John R.B.
name: Zeggini, Eleftheria
name: Rüeger, Sina
name: Liu, Yongmei
name: Perry, James A.
name: MacKey, David A.
name: Schulze, Matthias B.
name: Small, Kerrin S.
name: Amouyel, Philippe
name: Varbo, Anette
name: Küry, Sébastien
name: Breen, Gerome
name: Morgan, Anna
name: Du, Mengmeng
name: Jansson, Jan-Håkan
name: Ridker, Paul M.
name: Kjaer, Troels R.
name: Lewis, Cora E.
name: Schmidt, Marjanka K.
name: Lophatananon, Artitaya
name: Morris, Andrew D.
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2017

description: Height is a highly heritable, classic polygenic trait with ∼700 common associated variants identified so far through genome-wide association studies. Here, we report 83 height-associated coding variants with lower minor allele frequencies (range of 0.1-4.8%) and effects of up to 2 cm/allele (e.g. in IHH, STC2, AR and CRISPLD2), >10 times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (+1-2 cm/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 mutated in monogenic growth disorders and highlight new biological candidates (e.g. ADAMTS3, IL11RA, NOX4) and pathways (e.g. proteoglycan/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.