Publication

Rare and low-frequency coding variants alter human adult height

Nature. 2017 Feb 9;542(7640):186-190. doi: 10.1038/nature21039. Epub 2017 Feb 1.

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.

Authors

Marouli E1, Graff M2, Medina-Gomez C3,4, Lo KS5, Wood AR6, Kjaer TR7, Fine RS8,9,10, Lu Y11,12,13, Schurmann C12,13, Highland HM2,14, Rüeger S15,16, Thorleifsson G17, Justice AE2, Lamparter D16,18, Stirrups KE1,19, Turcot V5, Young KL2, Winkler TW20, Esko T8,10,21, Karaderi T22, Locke AE23,24, Masca NG25,26, Ng MC27,28, Mudgal P27, Rivas MA8,29, Vedantam S8,9,10, Mahajan A22, Guo X30, Abecasis G23, Aben KK31,32, Adair LS33, Alam DS34, Albrecht E35, Allin KH36, Allison M37, Amouyel P38,39,40, Appel EV36, Arveiler D41,42, Asselbergs FW43,44,45, Auer PL46, Balkau B47, Banas B48, Bang LE49, Benn M50,51, Bergmann S16,18, Bielak LF52, Blüher M53,54, Boeing H55, Boerwinkle E56,57, Böger CA48, Bonnycastle LL58, Bork-Jensen J36, Bots ML59, Bottinger EP12, Bowden DW27,28,60, Brandslund I61,62, Breen G63, Brilliant MH64, Broer L4, Burt AA65, Butterworth AS66,67, Carey DJ68, Caulfield MJ1,69, Chambers JC70,71,72, Chasman DI8,73,74,75, Chen YI30, Chowdhury R66, Christensen C76, Chu AY74,77, Cocca M78, Collins FS58, Cook JP79, Corley J80,81, Galbany JC82, Cox AJ27,28,83, Cuellar-Partida G84,85, Danesh J66,67,86,87, Davies G80,81, de Bakker PI59,88, de Borst GJ89, de Denus S5,90, de Groot MC91,92, de Mutsert R93, Deary IJ80,81, Dedoussis G94, Demerath EW95, den Hollander AI96, Dennis JG97, Di Angelantonio E66,67, Drenos F98,99, Du M100,101, Dunning AM102, Easton DF97,102, Ebeling T103,104, Edwards TL105, Ellinor PT106,107, Elliott P108, Evangelou E71,109, Farmaki AE94, Faul JD110, Feitosa MF111, Feng S23, Ferrannini E112,113, Ferrario MM114, Ferrieres J115, Florez JC106,107,116, Ford I117, Fornage M118, Franks PW119,120,121, Frikke-Schmidt R51,122, Galesloot TE32, Gan W22, Gandin I123, Gasparini P123,124, Giedraitis V125, Giri A105, Girotto G123,124, Gordon SD85, Gordon-Larsen P126,127, Gorski M20,48, Grarup N36, Grove ML56, Gudnason V128,129, Gustafsson S130, Hansen T36, Harris KM126,131, Harris TB132, Hattersley AT133, Hayward C134, He L135,136, Heid IM20,35, Heikkilä K136,137, Helgeland Ø138,139, Hernesniemi J140,141,142, Hewitt AW143,144,145, Hocking LJ146,147, Hollensted M36, Holmen OL148, Hovingh GK149, Howson JM66, Hoyng CB96, Huang PL106, Hveem K150, Ikram MA3,151,152, Ingelsson E130,153, Jackson AU23, Jansson JH154,155, Jarvik GP65,156, Jensen GB157, Jhun MA52, Jia Y30, Jiang X158,159, Johansson S139,160, Jørgensen ME161,162, Jørgensen T51,163,164, Jousilahti P165, Jukema JW166,167, Kahali B168,169,170, Kahn RS171, Kähönen M172, Kamstrup PR50, Kanoni S1, Kaprio J136,137,165, Karaleftheri M173, Kardia SL52, Karpe F174,175, Kee F176, Keeman R177, Kiemeney LA32, Kitajima H22, Kluivers KB32, Kocher T178, Komulainen P179, Kontto J165, Kooner JS70,72,180, Kooperberg C181, Kovacs P53, Kriebel J182,183,184, Kuivaniemi H68,185, Küry S186, Kuusisto J187, La Bianca M188, Laakso M187, Lakka TA179,189, Lange EM190, Lange LA190, Langefeld CD191, Langenberg C192, Larson EB65,193,194, Lee IT195,196,197, Lehtimäki T141,142, Lewis CE198, Li H199, Li J200, Li-Gao R93, Lin H201, Lin LA118, Lin X199, Lind L202, Lindström J165, Linneberg A51,164,203, Liu Y30, Liu Y204, Lophatananon A205, Luan J192, Lubitz SA106,107, Lyytikäinen LP141,142, Mackey DA144, Madden PA206, Manning AK106,107,116, Männistö S165, Marenne G86, Marten J134, Martin NG85, Mazul AL2, Meidtner K182,207, Metspalu A21, Mitchell P208, Mohlke KL190, Mook-Kanamori DO93,209, Morgan A123, Morris AD210, Morris AP22,79, Müller-Nurasyid M35,211,212, Munroe PB1,69, Nalls MA213, Nauck M214,215, Nelson CP25,26, Neville M174,175, Nielsen SF50,51, Nikus K216, Njølstad PR138,139, Nordestgaard BG50,51, Ntalla I1, O'Connel JR217, Oksa H218, Loohuis LM219, Ophoff RA171,219, Owen KR174,175, Packard CJ117, Padmanabhan S117, Palmer CN220, Pasterkamp G221,222, Patel AP8,75,106, Pattie A81, Pedersen O36, Peissig PL64, Peloso GM106,107, Pennell CE223, Perola M165,224,225, Perry JA217, Perry JR192, Person TN64, Pirie A102, Polasek O210,226, Posthuma D227,228, Raitakari OT229,230, Rasheed A231, Rauramaa R179,232, Reilly DF233, Reiner AP181,234, Renström F119,235, Ridker PM74,75,236, Rioux JD5,237, Robertson N22,174, Robino A188, Rolandsson O154,238, Rudan I210, Ruth KS6, Saleheen D231,239, Salomaa V165, Samani NJ25,26, Sandow K30, Sapkota Y85, Sattar N117, Schmidt MK177, Schreiner PJ240, Schulze MB182,207, Scott RA192, Segura-Lepe MP71, Shah S241, Sim X23,242, Sivapalaratnam S106,243,244, Small KS245, Smith AV128,129, Smith JA52, Southam L22,86, Spector TD245, Speliotes EK168,169,170, Starr JM80,246, Steinthorsdottir V17, Stringham HM23, Stumvoll M53,54, Surendran P66, 't Hart LM247,248,249, Tansey KE250,251, Tardif JC5,237, Taylor KD30, Teumer A252, Thompson DJ97, Thorsteinsdottir U17,128, Thuesen BH164, Tönjes A253, Tromp G68,254, Trompet S166,255, Tsafantakis E256, Tuomilehto J165,257,258,259, Tybjaerg-Hansen A51,122, Tyrer JP102, Uher R260, Uitterlinden AG3,4, Ulivi S188, van der Laan SW222, Van Der Leij AR261, van Duijn CM3, van Schoor NM247, van Setten J43, Varbo A50,51, Varga TV119, Varma R159, Edwards DR262, Vermeulen SH32, Vestergaard H36, Vitart V134, Vogt TF263, Vozzi D124, Walker M264, Wang F199, Wang CA223, Wang S265, Wang Y199, Wareham NJ192, Warren HR1,69, Wessel J266, Willems SM192, Wilson JG267, Witte DR268,269, Woods MO270, Wu Y190, Yaghootkar H6, Yao J30, Yao P199, Yerges-Armstrong LM217,271, Young R66,117, Zeggini E86, Zhan X272, Zhang W70,71, Zhao JH192, Zhao W239, Zhao W52, Zheng H199, Zhou W168,169; EPIC-InterAct Consortium; CHD Exome+ Consortium; ExomeBP Consortium; T2D-Genes Consortium; GoT2D Genes Consortium; Global Lipids Genetics Consortium; ReproGen Consortium; MAGIC Investigators, Rotter JI30, Boehnke M23, Kathiresan S8,75,106, McCarthy MI22,174,175, Willer CJ168,169,273, Stefansson K17,128, Borecki IB111, Liu DJ274, North KE275, Heard-Costa NL77,276, Pers TH36,277, Lindgren CM22,278, Oxvig C7, Kutalik Z15,16, Rivadeneira F3,4, Loos RJ12,13,279, Frayling TM6, Hirschhorn JN8,10,280, Deloukas P1,281, Lettre G5,237.

Institute Authors

Adam E. Locke, Ph.D.