A saturated map of common genetic variants associated with human height

Yengo, L. et al. (2022) A saturated map of common genetic variants associated with human height. Nature Communications, 610, pp. 704-712. (doi: 10.1038/s41586-022-05275-y) (PMID:36224396) (PMCID:PMC9605867)

Abstract

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10–20% (14–24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sattar, Professor Naveed and Ford, Professor Ian
• Authors: Yengo, L., Vedantam, S., Marouli, E., Sidorenko, J., Bartell, E., Sakaue, S., Graff, M., Eliasen, A. U., Jiang, Y., Raghavan, S., Miao, J., Arias, J. D., Graham, S. E., Mukamel, R. E., Spracklen, C. N., Yin, X., Chen, S.-H., Ferreira, T., Highland, H. H., Ji, Y., Karaderi, T., Lin, K., Lüll, K., Malden, D. E., Medina-Gomez, C., Machado, M., Moore, A., Rüeger, S., Sim, X., Vrieze, S., Ahluwalia, T. S., Akiyama, M., Allison, M. A., Alvarez, M., Andersen, M. K., Ani, A., Appadurai, V., Arbeeva, L., Bhaskar, S., Bielak, L. F., Bollepalli, S., Bonnycastle, L. L., Bork-Jensen, J., Bradfield, J. P., Bradford, Y., Braund, P. S., Brody, J. A., Burgdorf, K. S., Cade, B. E., Cai, H., Cai, Q., Campbell, A., Cañadas-Garre, M., Catamo, E., Chai, J.-F., Chai, X., Chang, L.-C., Chang, Y.-C., Chen, C.-H., Chesi, A., Choi, S. H., Chung, R.-H., Cocca, M., Concas, M. P., Couture, C., Cuellar-Partida, G., Danning, R., Daw, E. W., Degenhard, F., Delgado, G. E., Delitala, A., Demirkan, A., Deng, X., Devineni, P., Dietl, A., Dimitriou, M., Dimitrov, L., Dorajoo, R., Ekici, A. B., Engmann, J. E., Fairhurst-Hunter, Z., Farmaki, A.-E., Faul, J. D., Fernandez-Lopez, J.-C., Forer, L., Francescatto, M., Freitag-Wolf, S., Fuchsberger, C., Galesloot, T. E., Gao, Y., Gao, Z., Geller, F., Giannakopoulou, O., Giulianini, F., Gjesing, A. P., Goel, A., Gordon, S. D., Gorski, M., Grove, J., Guo, X., Gustafsson, S., Haessler, J., Hansen, T. F., Havulinna, A. S., Haworth, S. J., He, J., Heard-Costa, N., Hebbar, P., Hindy, G., Ho, Y.-L. A., Hofer, E., Holliday, E., Horn, K., Hornsby, W. E., Hottenga, J.-J., Huang, H., Huang, J., Huerta-Chagoya, A., Huffman, J. E., Hung, Y.-J., Huo, S., Hwang, M. Y., Iha, H., Ikeda, D. D., Isono, M., Jackson, A. U., Jäger, S., Jansen, I. E., Johansson, I., Jonas, J. B., Jonsson, A., Jørgensen, T., Kalafati, I.-P., Kanai, M., Kanoni, S., Kårhus, L. L., Kasturiratne, A., Katsuya, T., Kawaguchi, T., Kember, R. L., Kentistou, K. A., Kim, H.-N., Kim, Y. J., Kleber, M. E., Knol, M. J., Kurbasic, A., Lauzon, M., Le, P., Lea, R., Lee, J.-Y., Leonard, H. L., Li, S. A., Li, X., Li, X., Liang, J., Lin, H., Lin, S.-Y., Liu, J., Liu, X., Lo, K. S., Long, J., Lores-Motta, L., Luan, J.'a., Lyssenko, V., Lyytikäinen, L.-P., Mahajan, A., Mamakou, V., Mangino, M., Manichaikul, A., Marten, J., Mattheisen, M., Mavarani, L., McDaid, A. F., Meidtner, K., Melendez, T. L., Mercader, J. M., Milaneschi, Y., Miller, J. E., Millwood, I. Y., Mishra, P. P., Mitchell, R. E., Møllehave, L. T., Morgan, A., Mucha, S., Munz, M., Nakatochi, M., Nelson, C. P., Nethander, M., Nho, C. W., Nielsen, A. A., Nolte, I. M., Nongmaithem, S. S., Noordam, R., Ntalla, I., Nutile, T., Pandit, A., Christofidou, P., Pärna, K., Pauper, M., Petersen, E. R. B., Petersen, L. V., Pitkänen, N., Polašek, O., Poveda, A., Preuss, M. H., Pyarajan, S., Raffield, L. M., Rakugi, H., Ramirez, J., Rasheed, A., Raven, D., Rayner, N. W., Riveros, C., Rohde, R., Ruggiero, D., Ruotsalainen, S. E., Ryan, K. A., Sabater-Lleal, M., Saxena, R., Scholz, M., Sendamarai, A., Shen, B., Shi, J., Shin, J. H., Sidore, C., Sitlani, C. M., Slieker, R. C., Smit, R. A. J., Smith, A. V., Smith, J. A., Smyth, L. J., Southam, L., Steinthorsdottir, V., Sun, L., Takeuchi, F., Tallapragada, D. S. P., Taylor, K. D., Tayo, B. O., Tcheandjieu, C., Terzikhan, N., Tesolin, P., Teumer, A., Theusch, E., Thompson, D. J., Thorleifsson, G., Timmers, P. R. H. J., Trompet, S., Turman, C., Vaccargiu, S., van der Laan, S. W., van der Most, P. J., van Klinken, J. B., van Setten, J., Verma, S. S., Verweij, N., Veturi, Y., Wang, C. A., Wang, C., Wang, L., Wang, Z., Warren, H. R., Bin Wei, W., Wickremasinghe, A. R., Wielscher, M., Wiggins, K. L., Winsvold, B. S., Wong, A., Wu, Y., Wuttke, M., Xia, R., Xie, T., Yamamoto, K., Yang, J., Yao, J., Young, H., Yousri, N. A., Yu, L., Zeng, L., Zhang, W., Zhang, X., Zhao, J.-H., Zhao, W., Zhou, W., Zimmermann, M. E., Zoledziewska, M., Adair, L. S., Adams, H. H. H., Aguilar-Salinas, C. A., Al-Mulla, F., Arnett, D. K., Asselbergs, F. W., Åsvold, B. O., Attia, J., Banas, B., Bandinelli, S., Bennett, D. A., Bergler, T., Bharadwaj, D., Biino, G., Bisgaard, H., Boerwinkle, E., Böger, C. A., Bønnelykke, K., Boomsma, D. I., Børglum, A. D., Borja, J. B., Bouchard, C., Bowden, D. W., Brandslund, I., Brumpton, B., Buring, J. E., Caulfield, M. J., Chambers, J. C., Chandak, G. R., Chanock, S. J., Chaturvedi, N., Chen, Y.-D. I., Chen, Z., Cheng, C.-Y., Christophersen, I. E., Ciullo, M., Cole, J. W., Collins, F. S., Cooper, R. S., Cruz, M., Cucca, F., Cupples, L. A., Cutler, M. J., Damrauer, S. M., Dantoft, T. M., de Borst, G. J., de Groot, L. C. P. G. M., De Jager, P. L., de Kleijn, D. P. V., Janaka de Silva, H., Dedoussis, G. V., den Hollander, A. I., Du, S., Easton, D. F., Elders, P. J. M., Eliassen, A. H., Ellinor, P. T., Elmståhl, S., Erdmann, J., Evans, M. K., Fatkin, D., Feenstra, B., Feitosa, M. F., Ferrucci, L., Ford, I., Fornage, M., Franke, A., Franks, P. W., Freedman, B. I., Gasparini, P., Gieger, C., Girotto, G., Goddard, M. E., Golightly, Y. M., Gonzalez-Villalpando, C., Gordon-Larsen, P., Grallert, H., Grant, S. F. A., Grarup, N., Griffiths, L., Gudnason, V., Haiman, C., Hakonarson, H., Hansen, T., Hartman, C. A., Hattersley, A. T., Hayward, C., Heckbert, S. R., Heng, C.-K., Hengstenberg, C., Hewitt, A. W., Hishigaki, H., Hoyng, C. B., Huang, P. L., Huang, W., Hunt, S. C., Hveem, K., Hyppönen, E., Iacono, W. G., Ichihara, S., Ikram, M. A., Isasi, C. R., Jackson, R. D., Jarvelin, M.-R., Jin, Z.-B., Jöckel, K.-H., Joshi, P. K., Jousilahti, P., Jukema, J. W., Kähönen, M., Kamatani, Y., Kang, K. D., Kaprio, J., Kardia, S. L. R., Karpe, F., Kato, N., Kee, F., Kessler, T., Khera, A. V., Khor, C. C., Kiemeney, L. A. L. M., Kim, B.-J., Kim, E. K., Kim, H.-L., Kirchhof, P., Kivimaki, M., Koh, W.-P., Koistinen, H. A., Kolovou, G. D., Kooner, J. S., Kooperberg, C., Köttgen, A., Kovacs, P., Kraaijeveld, A., Kraft, P., Krauss, R. M., Kumari, M., Kutalik, Z., Laakso, M., Lange, L. A., Langenberg, C., Launer, L. J., Le Marchand, L., Lee, H., Lee, N. R., Lehtimäki, T., Li, H., Li, L., Lieb, W., Lin, X., Lind, L., Linneberg, A., Liu, C.-T., Liu, J., Loeffler, M., London, B., Lubitz, S. A., Lye, S. J., Mackey, D. A., Mägi, R., Magnusson, P. K. E., Marcus, G. M., Vidal, P. M., Martin, N. G., März, W., Matsuda, F., McGarrah, R. W., McGue, M., McKnight, A. J., Medland, S. E., Mellström, D., Metspalu, A., Mitchell, B. D., Mitchell, P., Mook-Kanamori, D. O., Morris, A. D., Mucci, L. A., Munroe, P. B., Nalls, M. A., Nazarian, S., Nelson, A. E., Neville, M. J., Newton-Cheh, C., Nielsen, C. S., Nöthen, M. M., Ohlsson, C., Oldehinkel, A. J., Orozco, L., Pahkala, K., Pajukanta, P., Palmer, C. N. A., Parra, E. J., Pattaro, C., Pedersen, O., Pennell, C. E., Penninx, B. W. J. H., Perusse, L., Peters, A., Peyser, P. A., Porteous, D. J., Posthuma, D., Power, C., Pramstaller, P. P., Province, M. A., Qi, Q., Qu, J., Rader, D. J., Raitakari, O. T., Ralhan, S., Rallidis, L. S., Rao, D. C., Redline, S., Reilly, D. F., Reiner, A. P., Rhee, S. Y., Ridker, P. M., Rienstra, M., Ripatti, S., Ritchie, M. D., Roden, D. M., Rosendaal, F. R., Rotter, J. I., Rudan, I., Rutters, F., Sabanayagam, C., Saleheen, D., Salomaa, V., Samani, N. J., Sanghera, D. K., Sattar, N., Schmidt, B., Schmidt, H., Schmidt, R., Schulze, M. B., Schunkert, H., Scott, L. J., Scott, R. J., Sever, P., Shiroma, E. J., Shoemaker, M. B., Shu, X.-O., Simonsick, E. M., Sims, M., Singh, J. R., Singleton, A. B., Sinner, M. F., Smith, J. G., Snieder, H., Spector, T. D., Stampfer, M. J., Stark, K. J., Strachan, D. P., 't Hart, L. M., Tabara, Y., Tang, H., Tardif, J.-C., Thanaraj, T. A., Timpson, N. J., Tönjes, A., Tremblay, A., Tuomi, T., Tuomilehto, J., Tusié-Luna, M.-T., Uitterlinden, A. G., van Dam, R. M., van der Harst, P., Van der Velde, N., van Duijn, C. M., van Schoor, N. M., Vitart, V., Völker, U., Vollenweider, P., Völzke, H., Wacher-Rodarte, N. H., Walker, M., Wang, Y. X., Wareham, N. J., Watanabe, R. M., Watkins, H., Weir, D. R., Werge, T. M., Widen, E., Wilkens, L. R., Willemsen, G., Willett, W. C., Wilson, J. F., Wong, T.-Y., Woo, J.-T., Wright, A. F., Wu, J.-Y., Xu, H., Yajnik, C. S., Yokota, M., Yuan, J.-M., Zeggini, E., Zemel, B. S., Zheng, W., Zhu, X., Zmuda, J. M., Zonderman, A. B., Zwart, J.-A., Chasman, D. I., Cho, Y. S., Heid, I. M., McCarthy, M. I., Ng, M. C. Y., O'Donnell, C. J., Rivadeneira, F., Thorsteinsdottir, U., Sun, Y. V., Tai, E. S., Boehnke, M., Deloukas, P., Justice, A. E., Lindgren, C. M., Loos, R. J. F., Mohlke, K. L., North, K. E., Stefansson, K., Walters, R. G., Winkler, T. W., Young, K. L., Loh, P.-R., Yang, J., Esko, T., Assimes, T. L., Auton, A., Abecasis, G. R., Willer, C. J., Locke, A. E., Berndt, S. I., Lettre, G., Frayling, T. M., Okada, Y., Wood, A. R., Visscher, P. M., and Hirschhorn, J. N.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Robertson Centre
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 1476-4687
• Published Online: 12 October 2022
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Nature 610(7933): 704-712
• Publisher Policy: Reproduced under a Creative Commons License