Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

Surendran, P. et al. (2020) Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals. Nature Genetics, 52(12), pp. 1314-1332. (doi: 10.1038/s41588-020-00713-x) (PMID:33230300) (PMCID:PMC7610439)

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Abstract

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10−8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.

Item Type:Articles
Additional Information:A correction to this article is available at https://doi.org/10.1038/s41588-021-00832-z.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Young, Dr Robin and Padmanabhan, Professor Sandosh and Dominiczak, Professor Anna and Sattar, Professor Naveed and Ford, Professor Ian and Connell, Professor John
Authors: Surendran, P., Feofanova, E. V., Lahrouchi, N., Ntalla, I., Karthikeyan, S., Cook, J., Chen, L., Mifsud, B., Yao, C., Kraja, A. T., Cartwright, J. H., Hellwege, J. N., Giri, A., Tragante, V., Thorleifsson, G., Liu, D. J., Prins, B. P., Stewart, I. D., Cabrera, C. P., Eales, J. M., Akbarov, A., Auer, P. L., Bielak, L. F., Bis, J. C., Braithwaite, V. S., Brody, J. A., Daw, E. W., Warren, H. R., Drenos, F., Fallgaard Nielsen, S., Faul, J. D., Fauman, E. B., Fava, C., Ferreira, T., Foley, C. N., Franceschini, N., Gao, H., Giannakopoulou, O., Giulianini, F., Gudbjartsson, D. F., Guo, X., Harris, S. E., Havulinna, A. S., Helgadottir, A., Huffman, J. E., Hwang, S.-J., Kanoni, S., Kontto, J., Larson, M. G., Li-Gao, R., Lindström, J., Lotta, L. A., Lu, Y., Luan, J.'a., Mahajan, A., Malerba, G., Masca, N. G.D., Mei, H., Menni, C., Mook-Kanamori, D. O., Mosen-Ansorena, D., Müller-Nurasyid, M., Paré, G., Paul, D. S., Perola, M., Poveda, A., Rauramaa, R., Richard, M., Richardson, T. G., Sepúlveda, N., Sim, X., Smith, A. V., Smith, J. A., Staley, J. R., Stanáková, A., Sulem, P., Thériault, S., Thorsteinsdottir, U., Trompet, S., Varga, T. V., Velez Edwards, D. R., Veronesi, G., Weiss, S., Willems, S. M., Yao, J., Young, R., Yu, B., Zhang, W., Zhao, J.-H., Zhao, W., Zhao, W., Evangelou, E., Aeschbacher, S., Asllanaj, E., Blankenberg, S., Bonnycastle, L. L., Bork-Jensen, J., Brandslund, I., Braund, P. S., Burgess, S., Cho, K., Christensen, C., Connell, J., de Mutsert, R., Dominiczak, A. F., Dörr, M., Eiriksdottir, G., Farmaki, A.-E., Gaziano, J. M., Grarup, N., Grove-Gaona, M. L., Hallmans, G., Hansen, T., Have, C. T., Heiss, G., Jørgensen, M. E., Jousilahti, P., Kajantie, E., Kamat, M., Käräjämäki, A., Karpe, F., Koistinen, H. A., Kovesdy, C. P., Kuulasmaa, K., Laatikainen, T., Lannfelt, L., Lee, I.-T., Lee, W.-J., LifeLines Cohort Study, , Linneberg, A., Martin, L. W., Moitry, M., Nadkarni, G., Neville, M., Palmer, C. N.A., Papanicolaou, G. J., Pedersen, O., Peters, J., Poulter, N., Rasheed, A., Rasmussen, K. L., Rayner, N. W., Mägi, R., Renström, F., Rettig, R., Rossouw, J., Schreiner, P. J., Sever, P. J., Sigurdsson, E. L., Skaaby, T., Sun, Y. V., Sundstrom, J., Thorgeirsson, G., Tõnu, E., Trabetti, E., Tsao, P. S., Tuomi, T., Turner, S. T., Tzoulaki, I., Vaartjes, I., Vergnaud, A.-C., Willer, C. J., Wilson, P. W.F., Witte, D. R., Yonova-Doing, E., Zhang, H., Aliya, N., Almgren, P., Amouyel, P., Asselbergs, F. W., Barnes, M. R., Blakemore, A. I., Boehnke, M., Bots, M. L., Bottinger, E. P., Buring, J. E., Chambers, J. C., Ida Chen, Y.-D., Chowdhury, R., Conen, D., Correa, A., Davey Smith, G., de Boer, R. A., Deary, I. J., Dedoussis, G., Deloukas, P., Di Angelantonio, E., Elliott, P., EPIC-CVD, , EPIC-InterAct, , Felix, S. B., Ferrières, J., Ford, I., Fornage, M., Franks, P. W., Franks, S., Frossard, P., Gambaro, G., Gaunt, T. R., Groop, L., Gudnason, V., Harris, T. B., Hayward, C., Hennig, B. J., Herzig, K.-H., Ingelsson, E., Tuomilehto, J., Jarvelin, M.-R., Jukema, J. W., Kardia, S. L.R., Kee, F., Kooner, J. S., Kooperberg, C., Launer, L. J., Lind, L., Loos, R. J.F., Majumder, A. a. S., Laakso, M., McCarthy, M. I., Melander, O., Mohlke, K. L., Murray, A. D., Nordestgaard, B. G., Orho-Melander, M., Packard, C. J., Padmanabhan, S., Palmas, W., Polasek, O., Porteous, D. J., Prentice, A. M., Province, M. A., Relton, C. L., Rice, K., Ridker, P. M., Rolandsson, O., Rosendaal, F. R., Rotter, J. I., Rudan, I., Salomaa, V., Samani, N. J., Sattar, N., H-H Sheu, W., Smith, B. H., Soranzo, N., Spector, T. D., Starr, J. M., Sylvain, S., Taylor, K. D., Lakka, T. A., Timpson, N. J., Tobin, M. D., Understanding Society Scientific Group, , van der Harst, P., van der Meer, P., Ramachandran, V. S., Verweij, N., Virtamo, J., Völker, U., Weir, D. R., Zeggini, E., Charchar, F. J., Million Veteran Program, , Wareham, N. J., Langenberg, C., Tomaszewski, M., Butterworth, A. S., Caulfield, M. J., Danesh, J., Edwards, T. L., Holm, H., Hung, A. M., Lindgren, C. M., Liu, C., Manning, A. K., Morris, A. P., Morrison, A. C., O'Donnell, C., Psaty, B. M., Saleheen, D., Stefansson, K., Boerwinkle, E., Chasman, D. I., Levy, D., Newton-Cheh, C., Munroe, P. B., and Howson, J. M.M.
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 Genetics
Publisher:Nature Research
ISSN:1061-4036
ISSN (Online):1546-1718
Published Online:23 November 2020
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Nature Genetics 52(12): 1314-1332
Publisher Policy:Reproduced in accordance with the publisher copyright policy
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