Rare and low-frequency coding variants alter human adult height

Publication

Rare and low-frequency coding variants alter human adult height

Journal Paper/Review - Feb 1, 2017

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

Citation

Ntalla I, Peissig P, Peloso G, Pennell C, Perola M, Perry J, Perry J, Person T, Pirie A, Polasek O, Pedersen O, Pattie A, Patel A, O'Connel J, Oksa H, Loohuis L, Ophoff R, Owen K, Packard C, Padmanabhan S, Palmer C, Pasterkamp G, Posthuma D, Raitakari O, Saleheen D, Salomaa V, Samani N, Sandow K, Sapkota Y, Sattar N, Schmidt M, Schreiner P, Schulze M, Ruth K, Rudan I, Rolandsson O, Rasheed A, Rauramaa R, Reilly D, Reiner A, Renström F, Ridker P, Rioux J, Robertson N, Robino A, Scott R, Nordestgaard B, Langefeld C, Lindström J, Linneberg A, Liu Y, Liu Y, Lophatananon A, Luan J, Lubitz S, Lyytikäinen L, Mackey D, Lind L, Lin X, Lin L, Langenberg C, Larson E, Lee I, Lehtimäki T, Lewis C, Li H, Li J, Li-Gao R, Lin H, Madden P, Manning A, Morris A, Müller-Nurasyid M, Munroe P, Nalls M, Nauck M, Nelson C, Neville M, Nielsen S, Nikus K, Morris A, Morgan A, Mook-Kanamori D, Männistö S, Marenne G, Marten J, Martin N, Mazul A, Meidtner K, Metspalu A, Mitchell P, Mohlke K, Njølstad P, Walker M, Yaghootkar H, Yao J, Yao P, Yerges-Armstrong L, Young R, Zeggini E, Zhan X, Zhang W, Zhao J, Wu Y, Woods M, Witte D, Wang F, Wang C, Wang S, Wang Y, Wareham N, Warren H, Wessel J, Willems S, Wilson J, Zhao W, Zheng H, Pers T, Lindgren C, Oxvig C, Kutalik Z, Rivadeneira F, Loos R, Frayling T, Hirschhorn J, Deloukas P, Heard-Costa N, North K, Liu D, Zhou W, Rotter J, Boehnke M, Kathiresan S, McCarthy M, Willer C, Stefansson K, Borecki I, Lettre G, Vozzi D, Segura-Lepe M, Stumvoll M, Surendran P, 't Hart L, Tansey K, Tardif J, Taylor K, Teumer A, Thompson D, Thorsteinsdottir U, Stringham H, Steinthorsdottir V, Starr J, Shah S, Sim X, Sivapalaratnam S, Small K, Smith A, Smith J, Southam L, Spector T, Speliotes E, Thuesen B, Tönjes A, van Schoor N, van Setten J, Varbo A, Varga T, Varma R, Edwards D, Vermeulen S, Vestergaard H, Vitart V, van Duijn C, Van Der Leij A, van der Laan S, Tromp G, Trompet S, Tsafantakis E, Tuomilehto J, Tybjaerg-Hansen A, Tyrer J, Uher R, Uitterlinden A, Ulivi S, Vogt T, Boeing H, Butterworth A, Carey D, Caulfield M, Chambers J, Chasman D, Chen Y, Chowdhury R, Christensen C, Chu A, Burt A, Broer L, Brilliant M, Boerwinkle E, Böger C, Bonnycastle L, Bork-Jensen J, Bots M, Bottinger E, Bowden D, Brandslund I, Breen G, Cocca M, Collins F, Deary I, Dedoussis G, Demerath E, den Hollander A, Dennis J, Di Angelantonio E, Drenos F, Du M, Dunning A, de Mutsert R, de Groot M, de Denus S, Cook J, Corley J, Galbany J, Cox A, Cuellar-Partida G, Danesh J, Davies G, de Bakker P, de Borst G, Easton D, Blüher M, Marouli E, Lamparter D, Stirrups K, Turcot V, Young K, Winkler T, Esko T, Karaderi T, Locke A, Masca N, Justice A, Thorleifsson G, Rüeger S, Graff M, Medina-Gomez C, Lo K, Wood A, Kjaer T, Fine R, Lu Y, Schurmann C, Highland H, Ng M, Mudgal P, Appel E, Arveiler D, Asselbergs F, Auer P, Balkau B, Banas B, Bang L, Benn M, Bergmann S, Amouyel P, Allison M, Allin K, Rivas M, Vedantam S, Mahajan A, Guo X, Abecasis G, Aben K, Adair L, Alam D, Albrecht E, Bielak L, Hoyng C, Jørgensen M, Jørgensen T, Jousilahti P, Jukema J, Kahali B, Kahn R, Kähönen M, Kamstrup P, Kanoni S, Johansson S, Jiang X, Jia Y, Huang P, Hveem K, Ikram M, Ingelsson E, Jackson A, Jansson J, Jarvik G, Jensen G, Jhun M, Kaprio J, Karaleftheri M, Kovacs P, Kriebel J, Kuivaniemi H, Küry S, Kuusisto J, La Bianca M, Laakso M, Lakka T, Lange E, Kooperberg C, Kooner J, Kontto J, Kardia S, Karpe F, Kee F, Keeman R, Kiemeney L, Kitajima H, Kluivers K, Kocher T, Komulainen P, Lange L, Howson J, Ebeling T, Ford I, Fornage M, Franks P, Frikke-Schmidt R, Galesloot T, Gan W, Gandin I, Gasparini P, Giedraitis V, Florez J, Ferrieres J, Ferrario M, Edwards T, Ellinor P, Elliott P, Evangelou E, Farmaki A, Faul J, Feitosa M, Feng S, Ferrannini E, Giri A, Girotto G, He L, Heid I, Heikkilä K, Helgeland Ø, Hernesniemi J, Hewitt A, Hocking L, Hollensted M, Holmen O, Hayward C, Hattersley A, Harris T, Gordon S, Gordon-Larsen P, Gorski M, Grarup N, Grove M, Gudnason V, Gustafsson S, Hansen T, Harris K, Hovingh G. Rare and low-frequency coding variants alter human adult height. Nature 2017; 542:186-190.

Type

Journal Paper/Review (English)

Journal

Nature 2017; 542

Publication Date

Feb 1, 2017

Issn Electronic

1476-4687

Pages

186-190

Brief description/objective

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.