Toggle Main Menu Toggle Search

Open Access padlockePrints

Rare and low-frequency coding variants alter human adult height

Lookup NU author(s): Professor Mark Walker

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


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.


Publication metadata

Author(s): Marouli E, Graff M, Medina-Gomez C, Lo KS, Wood AR, Kjaer TR, Fine RS, Lu YC, Schurmann C, Highland HM, Rueger S, Thorleifsson G, Justice AE, Lamparter D, Stirrups KE, Turcot V, Young KL, Winkler TW, Esko T, Karaderi T, Locke AE, Masca NGD, Ng MCY, Mudgal P, Rivas MA, Vedantam S, Mahajan A, Guo XQ, Abecasis G, Aben KK, Adair LS, Alam DS, Albrecht E, Allin KH, Allison M, Amouyel P, Appel EV, Arveiler D, Asselbergs FW, Auer PL, Balkau B, Banas B, Bang LE, Benn M, Bergmann S, Bielak LF, Bluher M, Boeing H, Boerwinkle E, Boger CA, Bonnycastle LL, Bork-Jensen J, Bots ML, Bottinger EP, Bowden DW, Brandslund I, Breen G, Brilliant MH, Broer L, Burt AA, Butterworth AS, Carey DJ, Caulfield MJ, Chambers JC, Chasman DI, Chen YDI, Chowdhury R, Christensen C, Chu AY, Cocca M, Collins FS, Cook JP, Corley J, Galbany JC, Cox AJ, Cuellar-Partida G, Danesh J, Davies G, de Bakker PIW, de Borst GJ, de Denus S, de Groot MCH, de Mutsert R, Deary IJ, Dedoussis G, Demerath EW, den Hollander AI, Dennis JG, Di Angelantonio E, Drenos F, Du MM, Dunning AM, Easton DF, Ebeling T, Edwards TL, Ellinor PT, Elliott P, Evangelou E, Farmaki AE, Faul JD, Feitosa MF, Feng S, Ferrannini E, Ferrario MM, Ferrieres J, Florez JC, Ford I, Fornage M, Franks PW, Frikke-Schmidt R, Galesloot TE, Gan W, Gandin I, Gasparini P, Giedraitis V, Giri A, Girotto G, Gordon SD, Gordon-Larsen P, Gorski M, Grarup N, Grove ML, Gudnason V, Gustafsson S, Hansen T, Harris KM, Harris TB, Hattersley AT, Hayward C, He L, Heid IM, Heikkila K, Helgeland O, Hernesniemi J, Hewitt AW, Hocking LJ, Hollensted M, Holmen OL, Hovingh GK, Howson JMM, Hoyng CB, Huang PL, Hveem K, Ikram MA, Ingelsson E, Jackson AU, Jansson JH, Jarvik GP, Jensen GB, Jhun MA, Jia YC, Jiang XJ, Johansson S, Jorgensen ME, Jorgensen T, Jousilahti P, Jukema JW, Kahali B, Kahn RS, Kahonen M, Kamstrup PR, Kanoni S, Kaprio J, Karaleftheri M, Kardia SLR, Karpe F, Kee F, Keeman R, Kiemeney LA, Kitajima H, Kluivers KB, Kocher T, Komulainen P, Kontto J, Kooner JS, Kooperberg C, Kovacs P, Kriebel J, Kuivaniemi H, Kury S, Kuusisto J, La Bianca M, Laakso M, Lakka TA, Lange EM, Lange LA, Langefeld CD, Langenberg C, Larson EB, Lee IT, Lehtimaki T, Lewis CE, Li HX, Li J, Li-Gao R, Lin HH, Lin LA, Lin X, Lind L, Lindstrom J, Linneberg A, Liu YH, Liu YM, Lophatananon A, Luan J, Lubitz SA, Lyytikainen LP, Mackey DA, Madden PAF, Manning AK, Mannisto S, Marenne G, Marten J, Martin NG, Mazul AL, Meidtner K, Metspalu A, Mitchell P, Mohlke KL, Mook-Kanamori DO, Morgan A, Morris AD, Morris AP, Muller-Nurasyid M, Munroe PB, Nalls MA, Nauck M, Nelson CP, Nelson CP, Neville M, Nielsen SF, Nikus K, Njolstad PR, Nordestgaard BG, Ntalla I, O'Connel JR, Oksa H, Loohuis LMO, Ophoff RA, Owen KR, Packard CJ, Padmanabhan S, Palmer CNA, Pasterkamp G, Patel AP, Pattie A, Pedersen O, Peissig PL, Peloso GM, Pennell CE, Perola M, Perry JA, Perry JRB, Person TN, Pirie A, Polasek O, Posthuma D, Raitakari OT, Rasheed A, Rauramaa R, Reilly DF, Reiner AP, Renstrom F, Ridker PM, Rioux JD, Robertson N, Robino A, Rolandsson O, Rudan I, Ruth KS, Saleheen D, Salomaa V, Samani NJ, Sandow K, Sapkota Y, Sattar N, Schmidt MK, Schreiner PJ, Schulze MB, Scott RA, Segura-Lepe MP, Shah S, Sim XL, Sivapalaratnam S, Small KS, Smith AV, Smith JA, Southam L, Spector TD, Speliotes EK, Starr JM, Steinthorsdottir V, Stringham HM, Stumvoll M, Surendran P, 't Hart LM, Tansey KE, Tardif JC, Taylor KD, Teumer A, Thompson DJ, Thorsteinsdottir U, Thuesen BH, Tonjes A, Tromp G, Trompet S, Tsafantakis E, Tuomilehto J, Tybjaerg-Hansen A, Tyrer JP, Uher R, Uitterlinden AG, Ulivi S, van der Laan SW, Van Der Leij AR, van Duijn CM, van Schoor NM, van Setten J, Varbo A, Varga TV, Varma R, Edwards DRV, Vermeulen SH, Vestergaard H, Vitart V, Vogt TF, Vozzi D, Walker M, Wang FJ, Wang CA, Wang S, Wang YQ, Wareham NJ, Warren HR, Wessel J, Willems SM, Wilson JG, Witte DR, Woods MO, Wu Y, Yaghootkar H, Yao J, Yao P, Yerges-Armstrong LM, Young R, Zeggini E, Zhan XW, Zhang WH, Zhao JH, Zhao W, Zhao W, Zheng H, Zhou W, Rotter JI, Boehnke M, Kathiresan S, McCarthy MI, Willer CJ, Stefansson K, Borecki IB, Liu DJ, North KE, Heard-Costa NL, Pers TH, Lindgren CM, Oxvig C, Kutalik Z, Rivadeneira F, Loos RJF, Frayling TM, Hirschhorn JN, Deloukas P, Lettre G, EPIC-InterAct Consortium, EPIC-CVD Consortium, CHD Exome Consortium, ExomeBP Consortium, T2D-Genes Consortium, GoT2D Genes Consortium, Global Lipids Genetics Consortium, ReproGen Consortium, MAGIC Investigators

Publication type: Article

Publication status: Published

Journal: Nature

Year: 2017

Volume: 542

Issue: 7640

Pages: 186-190

Print publication date: 09/02/2017

Online publication date: 01/02/2017

Acceptance date: 04/12/2016

ISSN (print): 0028-0836

ISSN (electronic): 1476-4687

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/nature21039

DOI: 10.1038/nature21039


Altmetrics

Altmetrics provided by Altmetric


Funding

Funder referenceFunder name
2014105Doris Duke Charitable Foundation
HHSN268201100046CNHLBI NIH HHS
K99 HL130580NHLBI NIH HHS
HHSN268201300046CNHLBI NIH HHS
K23 HL114724NHLBI NIH HHS
N01 HC095159NHLBI NIH HHS
R01 DK075787NIDDK NIH HHS
R01 DK089256NIDDK NIH HHS
P30 DK063491NIDDK NIH HHS
UL1 TR001881NCATS NIH HHS
UL1 TR000124NCATS NIH HHS

Share