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

Marouli, E. et al. (2017) Rare and low-frequency coding variants alter human adult height. Nature, 542(7640), pp. 186-190. (doi:10.1038/nature21039) (PMID:28146470)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Padmanabhan, Professor Sandosh and Young, Dr Robin and Packard, Professor Chris and Sattar, Professor Naveed and Ford, Professor Ian
Authors: Marouli, E., Graff, M., Medina-Gomez, C., Lo, K. S., Wood, A. R., Kjaer, T. R., Fine, R. S., Lu, Y., Schurmann, C., Highland, H. M., Rüeger, S., Thorleifsson, G., Justice, A. E., Lamparter, D., Stirrups, K. E., Turcot, V., Young, K. L., Winkler, T. W., Esko, T., Karaderi, T., Locke, A. E., Masca, N. G.D., Ng, M. C.Y., Mudgal, P., Rivas, M. A., Vedantam, S., Mahajan, A., Guo, X., Abecasis, G., Aben, K. K., Adair, L. S., Alam, D. S., Albrecht, E., Allin, K. H., Allison, M., Amouyel, P., Appel, E. V., Arveiler, D., Asselbergs, F. W., Auer, P. L., Balkau, B., Banas, B., Bang, L. E., Benn, M., Bergmann, S., Bielak, L. F., Blüher, M., Boeing, H., Boerwinkle, E., Böger, C. A., Bonnycastle, L. L., Bork-Jensen, J., Bots, M. L., Bottinger, E. P., Bowden, D. W., Brandslund, I., Breen, G., Brilliant, M. H., Broer, L., Burt, A. A., Butterworth, A. S., Carey, D. J., Caulfield, M. J., Chambers, J. C., Chasman, D. I., Chen, Y.-D. I., Chowdhury, R., Christensen, C., Chu, A. Y., Cocca, M., Collins, F. S., Cook, J. P., Corley, J., Galbany, J. C., Cox, A. J., Cuellar-Partida, G., Danesh, J., Davies, G., de Bakker, P. I.W., de Borst, G. J., de Denus, S., de Groot, M. C.H., de Mutsert, R., Deary, I. J., Dedoussis, G., Demerath, E. W., den Hollander, A. I., Dennis, J. G., Di Angelantonio, E., Drenos, F., Du, M., Dunning, A. M., Easton, D. F., Ebeling, T., Edwards, T. L., Ellinor, P. T., Elliott, P., Evangelou, E., Farmaki, A.-E., Faul, J. D., Feitosa, M. F., Feng, S., Ferrannini, E., Ferrario, M. M., Ferrieres, J., Florez, J. C., Ford, I., Fornage, M., Franks, P. W., Frikke-Schmidt, R., Galesloot, T. E., Gan, W., Gandin, I., Gasparini, P., Giedraitis, V., Giri, A., Girotto, G., Gordon, S. D., Gordon-Larsen, P., Gorski, M., Grarup, N., Grove, M. L., Gudnason, V., Gustafsson, S., Hansen, T., Harris, K. M., Harris, T. B., Hattersley, A. T., Hayward, C., He, L., Heid, I. M., Heikkilä, K., Helgeland, Ø., Hernesniemi, J., Hewitt, A. W., Hocking, L. J., Hollensted, M., Holmen, O. L., Hovingh, G. K., Howson, J. M.M., Hoyng, C. B., Huang, P. L., Hveem, K., Ikram, M. A., Ingelsson, E., Jackson, A. U., Jansson, J.-H., Jarvik, G. P., Jensen, G. B., Jhun, M. A., Jia, Y., Jiang, X., Johansson, S., Jørgensen, M. E., Jørgensen, T., Jousilahti, P., Jukema, J. W., Kahali, B., Kahn, R. S., Kähönen, M., Kamstrup, P. R., Kanoni, S., Kaprio, J., Karaleftheri, M., Kardia, S. L.R., Karpe, F., Kee, F., Keeman, R., Kiemeney, L. A., Kitajima, H., Kluivers, K. B., Kocher, T., Komulainen, P., Kontto, J., Kooner, J. S., Kooperberg, C., Kovacs, P., Kriebel, J., Kuivaniemi, H., Küry, S., Kuusisto, J., La Bianca, M., Laakso, M., Lakka, T. A., Lange, E. M., Lange, L. A., Langefeld, C. D., Langenberg, C., Larson, E. B., Lee, I.-T., Lehtimäki, T., Lewis, C. E., 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.'a., Lubitz, S. A., Lyytikäinen, L.-P., Mackey, D. A., Madden, P. A.F., Manning, A. K., Männistö, S., Marenne, G., Marten, J., Martin, N. G., Mazul, A. L., Meidtner, K., Metspalu, A., Mitchell, P., Mohlke, K. L., Mook-Kanamori, D. O., Morgan, A., Morris, A. D., Morris, A. P., Müller-Nurasyid, M., Munroe, P. B., Nalls, M. A., Nauck, M., Nelson, C. P., Neville, M., Nielsen, S. F., Nikus, K., Njølstad, P. R., Nordestgaard, B. G., Ntalla, I., O'Connel, J. R., Oksa, H., Loohuis, L. M. O., Ophoff, R. A., Owen, K. R., Packard, C. J., Padmanabhan, S., Palmer, C. N.A., Pasterkamp, G., Patel, A. P., Pattie, A., Pedersen, O., Peissig, P. L., Peloso, G. M., Pennell, C. E., Perola, M., Perry, J. A., Perry, J. R.B., Person, T. N., Pirie, A., Polasek, O., Posthuma, D., Raitakari, O. T., Rasheed, A., Rauramaa, R., Reilly, D. F., Reiner, A. P., Renström, F., Ridker, P. M., Rioux, J. D., Robertson, N., Robino, A., Rolandsson, O., Rudan, I., Ruth, K. S., Saleheen, D., Salomaa, V., Samani, N. J., Sandow, K., Sapkota, Y., Sattar, N., Schmidt, M. K., Schreiner, P. J., Schulze, M. B., Scott, R. A., Segura-Lepe, M. P., Shah, S., Sim, X., Sivapalaratnam, S., Small, K. S., Smith, A. V., Smith, J. A., Southam, L., Spector, T. D., Speliotes, E. K., Starr, J. M., Steinthorsdottir, V., Stringham, H. M., Stumvoll, M., Surendran, P., 't Hart, L. M., Tansey, K. E., Tardif, J.-C., Taylor, K. D., Teumer, A., Thompson, D. J., Thorsteinsdottir, U., Thuesen, B. H., Tönjes, A., Tromp, G., Trompet, S., Tsafantakis, E., Tuomilehto, J., Tybjaerg-Hansen, A., Tyrer, J. P., Uher, R., Uitterlinden, A. G., Ulivi, S., van der Laan, S. W., Van Der Leij, A. R., van Duijn, C. M., van Schoor, N. M., van Setten, J., Varbo, A., Varga, T. V., Varma, R., Velez Edwards, D. R., Vermeulen, S. H., Vestergaard, H., Vitart, V., Vogt, T. F., Vozzi, D., Walker, M., Wang, F., Wang, C. A., Wang, S., Wang, Y., Wareham, N. J., Warren, H. R., Wessel, J., Willems, S. M., Wilson, J. G., Witte, D. R., Woods, M. O., Wu, Y., Yaghootkar, H., Yao, J., Yao, P., Yerges-Armstrong, L. M., Young, R., Zeggini, E., Zhan, X., Zhang, W., Zhao, J. H., Zhao, W., Zhao, W., Zheng, H., Zhou, W., Rotter, J. I., Boehnke, M., Kathiresan, S., McCarthy, M. I., Willer, C. J., Stefansson, K., Borecki, I. B., Liu, D. J., North, K. E., Heard-Costa, N. L., Pers, T. H., Lindgren, C. M., Oxvig, C., Kutalik, Z., Rivadeneira, F., Loos, R. J.F., Frayling, T. M., Hirschhorn, J. N., Deloukas, P., and Lettre, G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Robertson Centre
Journal Name:Nature
Publisher:Nature Publishing Group
ISSN:0028-0836
ISSN (Online):1476-4687
Published Online:01 February 2017
Copyright Holders:Copyright © 2017 Macmillan Publishers Limited, part of Springer Nature
First Published:First published in Nature 542(7640): 186-190
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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