Rare and low-frequency coding variants alter human adult height.

TitleRare and low-frequency coding variants alter human adult height.
Publication TypeJournal Article
Year of Publication2017
AuthorsMarouli, E, Graff, M, Medina-Gomez, C, Lo, KSin, Wood, AR, Kjaer, TR, Fine, RS, Lu, Y, Schurmann, C, Highland, HM, Rüeger, S, Thorleifsson, G, Justice, AE, Lamparter, D, Stirrups, KE, Turcot, V, Young, KL, Winkler, TW, Esko, T, Karaderi, T, Locke, AE, Masca, NGD, C Y Ng, M, Mudgal, P, Rivas, MA, Vedantam, S, Mahajan, A, Guo, X, Abecasis, GR, Aben, KK, Adair, LS, Alam, DS, Albrecht, E, Allin, KH, Allison, MA, Amouyel, P, Appel, EV, Arveiler, D, Asselbergs, FW, Auer, PL, Balkau, B, Banas, B, Bang, LE, Benn, M, Bergmann, S, Bielak, LF, Blüher, M, Boeing, H, Boerwinkle, E, Böger, 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, Y-DI, Chowdhury, R, Christensen, C, Chu, AY, Cocca, M, Collins, FS, Cook, JP, Corley, J, Galbany, JCorominas, 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, Hollander, AI den, Dennis, JG, Di Angelantonio, E, Drenos, F, Du, M, Dunning, AM, Easton, DF, Ebeling, T, Edwards, TL, Ellinor, PT, Elliott, P, Evangelou, E, Farmaki, A-E, Faul, JD, Feitosa, MF, Feng, S, Ferrannini, E, Ferrario, MM, Ferrières, J, Florez, JC, Ford, I, Fornage, M, Franks, PW, Frikke-Schmidt, R, Galesloot, TE, Gan, W, Gandin, I, Gasparini, PP, Giedraitis, V, Giri, A, Girotto, GG, Gordon, SD, Gordon-Larsen, P, Gorski, M, Grarup, N, Grove, ML, Gudnason, V, Gustafsson, S, Hansen, T, Harris, KMullan, Harris, TB, Hattersley, AT, Hayward, C, He, L, Heid, IM, Heikkilä, K, Helgeland, Ø, Hernesniemi, J, Hewitt, AW, Hocking, LJ, Hollensted, M, Holmen, OL, G Hovingh, K, Howson, JMM, Hoyng, CB, Huang, PL, Hveem, K, Ikram, MArfan, Ingelsson, E, Jackson, AU, Jansson, J-H, Jarvik, GP, Jensen, GB, Jhun, MA, Jia, Y, Jiang, X, Johansson, S, Jørgensen, ME, Jørgensen, T, Jousilahti, P, J Jukema, W, Kahali, B, Kahn, RS, Kähönen, 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, Küry, S, Kuusisto, J, La Bianca, M, Laakso, M, Lakka, TA, Lange, EM, Lange, LA, Langefeld, CD, Langenberg, C, Larson, EB, Lee, I-T, Lehtimäki, T, Lewis, CE, Li, H, Li, J, Li-Gao, R, Lin, H, Lin, L-A, Lin, X, Lind, L, Lindström, J, Linneberg, A, Liu, Y, Liu, Y, Lophatananon, A, Luan, J'an, Lubitz, SA, Lyytikäinen, L-P, Mackey, DA, Madden, PAF, Manning, AK, Männistö, 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, Müller-Nurasyid, M, Munroe, PB, Nalls, MA, Nauck, M, Nelson, CP, Neville, M, Nielsen, SF, Nikus, K, Njølstad, PR, Nordestgaard, BG, Ntalla, I, O'Connel, JR, Oksa, H, Loohuis, LMOlde, 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, NR, 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, SH, Sim, X, Sivapalaratnam, S, Small, KS, Smith, AVernon, Smith, JA, Southam, L, Spector, TD, Speliotes, EK, Starr, JM, Steinthorsdottir, V, Stringham, HM, Stumvoll, M, Surendran, P, Hart, LM 't, Tansey, KE, Tardif, J-C, Taylor, KD, Teumer, A, Thompson, DJ, Thorsteinsdottir, U, Thuesen, BH, Tönjes, 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, DRVelez, Vermeulen, SH, Vestergaard, H, Vitart, V, Vogt, TF, Vozzi, D, Walker, M, Wang, F, Wang, CA, Wang, S, Wang, Y, 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, X, Zhang, W, Zhao, JHua, 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, Hirschhron, JN, Deloukas, P, Lettre, G
Corporate AuthorsEPIC-InterAct Consortium, CHD Exome+ Consortium, ExomeBP Consortium, T2D-GENES Consortium, GoT2D Genes Consortium, Global Lipids Genetics Consortium, ReproGen Consortium, MAGIC Investigators
JournalNature
Volume542
Issue7640
Pagination186-190
Date Published2017 Feb 09
ISSN Number1476-4687
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.

DOI10.1038/nature21039
User Guide Notes

http://www.ncbi.nlm.nih.gov/pubmed/28146470?dopt=Abstract

Alternate JournalNature
Citation Key8886
PubMed ID28146470
PubMed Central IDPMC5302847
Grant ListK99 HL130580 / HL / NHLBI NIH HHS / United States
DP3 DK108220 / DK / NIDDK NIH HHS / United States
MC_UU_12013/3 / MRC_ / Medical Research Council / United Kingdom
R01 HL127564 / HL / NHLBI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
MR/M501633/2 / MRC_ / Medical Research Council / United Kingdom
U01 DK062370 / DK / NIDDK NIH HHS / United States
MR/K006584/1 / MRC_ / Medical Research Council / United Kingdom
BB/F019394/1 / BB_ / Biotechnology and Biological Sciences Research Council / United Kingdom
K23 HL114724 / HL / NHLBI NIH HHS / United States
R01 DK093757 / DK / NIDDK NIH HHS / United States
U01 HG007417 / HG / NHGRI NIH HHS / United States
R01 DK106621 / DK / NIDDK NIH HHS / United States
MR/K002414/1 / MRC_ / Medical Research Council / United Kingdom
U01 HG008657 / HG / NHGRI NIH HHS / United States
SP/13/2/30111 / BHF_ / British Heart Foundation / United Kingdom
G0700931 / MRC_ / Medical Research Council / United Kingdom
RG/08/014/24067 / BHF_ / British Heart Foundation / United Kingdom
KL2 TR001109 / TR / NCATS NIH HHS / United States
HHSN268201100046C / HL / NHLBI NIH HHS / United States
R01 DK072193 / DK / NIDDK NIH HHS / United States
MR/L01632X/1 / MRC_ / Medical Research Council / United Kingdom
R35 HL135824 / HL / NHLBI NIH HHS / United States
R01 DK075787 / DK / NIDDK NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
R01 EY022310 / EY / NEI NIH HHS / United States
MR/L01341X/1 / MRC_ / Medical Research Council / United Kingdom
MR/K026992/1 / MRC_ / Medical Research Council / United Kingdom
MR/L003120/1 / MRC_ / Medical Research Council / United Kingdom
S10 OD018522 / OD / NIH HHS / United States
G0601966 / MRC_ / Medical Research Council / United Kingdom
MC_UU_12015/1 / MRC_ / Medical Research Council / United Kingdom
R01 HL119443 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
MC_UU_12015/2 / MRC_ / Medical Research Council / United Kingdom
MC_PC_15018 / MRC_ / Medical Research Council / United Kingdom
MC_PC_U127561128 / MRC_ / Medical Research Council / United Kingdom
UM1 CA182913 / CA / NCI NIH HHS / United States
T32 GM096911 / GM / NIGMS NIH HHS / United States
R01 DK107904 / DK / NIDDK NIH HHS / United States
R01 DK089256 / DK / NIDDK NIH HHS / United States
P30 DK020572 / DK / NIDDK NIH HHS / United States
G0700704 / MRC_ / Medical Research Council / United Kingdom
RG/14/5/30893 / BHF_ / British Heart Foundation / United Kingdom
MR/K007017/1 / MRC_ / Medical Research Council / United Kingdom
HHSN268201300046C / HL / NHLBI NIH HHS / United States
R01 HD057194 / HD / NICHD NIH HHS / United States
068545/Z/02 / WT_ / Wellcome Trust / United Kingdom
MC_PC_13040 / MRC_ / Medical Research Council / United Kingdom
R01 HL117078 / HL / NHLBI NIH HHS / United States
UL1 TR001881 / TR / NCATS NIH HHS / United States
2014105 / DDCF / Doris Duke Charitable Foundation / United States
P2C HD050924 / HD / NICHD NIH HHS / United States
T32 HL007055 / HL / NHLBI NIH HHS / United States
G0600237 / MRC_ / Medical Research Council / United Kingdom
N01 HC095159 / HC / NHLBI NIH HHS / United States
G9815508 / MRC_ / Medical Research Council / United Kingdom
R01 MH090553 / MH / NIMH NIH HHS / United States
MR/M501633/1 / MRC_ / Medical Research Council / United Kingdom