Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci

Tragante, V. et al. (2014) Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci. American Journal of Human Genetics, 94(3), pp. 349-360. (doi:10.1016/j.ajhg.2013.12.016)

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Abstract

Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ∼50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10−7) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Hastie, Dr Claire and Padmanabhan, Professor Sandosh and Dominiczak, Professor Anna and Delles, Professor Christian
Authors: Tragante, V., Barnes, M.R., Ganesh, S.K., Lanktree, M.B., Guo, W., Franceschini, N., Smith, E.N., Johnson, T., Holmes, M.V., Padmanabhan, S., Karczewski, K.J., Almoguera, B., Barnard, J., Baumert, J., Chang, Y.C., Elbers, C.C., Farrall, M., Fischer, M.E., Gaunt, T.R., Gho, J.M.I.H., Gieger, C., Goel, A., Gong, Y., Isaacs, A., Kleber, M.E., Leach, I.M., McDonough, C.W., Meijs, M.F.L., Melander, O., Nelson, C.P., Nolte, I.M., Pankratz, N., Price, T.S., Shaffer, J., Shah, S., Tomaszewski, M., van der Most, P.J., Van Iperen, E.P.A., Vonk, J.M., Witkowska, K., Wong, C.O.L., Zhang, L., Beitelshees, A.L., Berenson, G.S., Bhatt, D.L., Brown, M., Burt, A., Cooper-DeHoff, R.M., Connell, J.M., Cruickshanks, K.J., Curtis, S.P., Davey-Smith, G., Delles, C., Gansevoort, R.T., Guo, X., Haiqing, S., Hastie, C.E., Hofker, M.H., Hovingh, G.K., Kim, D.S., Kirkland, S.A., Klein, B.E., Klein, R., Li, Y.R., Maiwald, S., Newton-Cheh, C., O’Brien, E.T., Onland-Moret, N.C., Palmas, W., Parsa, A., Penninx, B.W., Pettinger, M., Vasan, R.S., Ranchalis, J.E., M Ridker, P., Rose, L.M., Sever, P., Shimbo, D., Steele, L., Stolk, R.P., Thorand, B., Trip, M.D., van Duijn, C.M., Verschuren, W.M., Wijmenga, C., Wyatt, S., Young, J.H., Zwinderman, A.H., Bezzina, C.R., Boerwinkle, E., Casas, J.P., Caulfield, M.J., Chakravarti, A., Chasman, D.I., Davidson, K.W., Doevendans, P.A., Dominiczak, A.F., FitzGerald, G.A., Gums, J.G., Fornage, M., Hakonarson, H., Halder, I., Hillege, H.L., Illig, T., Jarvik, G.P., Johnson, J.A., Kastelein, J.J.P., Koenig, W., Kumari, M., März, W., Murray, S.S., O’Connell, J.R., Oldehinkel, A.J., Pankow, J.S., Rader, D.J., Redline, S., Reilly, M.P., Schadt, E.E., Kottke-Marchant, K., Snieder, H., Snyder, M., Stanton, A.V., Tobin, M.D., Uitterlinden, A.G., van der Harst, P., van der Schouw, Y.T., Samani, N.J., Watkins, H., Johnson, A.D., Reiner, A.P., Zhu, X., de Bakker, P.I.W., Levy, D., Asselbergs, F.W., Munroe, P.B., and Keating, B.J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:American Journal of Human Genetics
Publisher:Cell Press
ISSN:0002-9297
ISSN (Online):1537-6605
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
348311The British genetics of hypertension study - application to enhance TDT and control recruitment for fine mapping genes for hypertensionAnna DominiczakBritish Heart Foundation (BHF)PG/02/128 MCPG1RI CARDIOVASCULAR & MEDICAL SCIENCES
464051Genomics and proteomics of hypertension and its vascular complications: the pathwayomic strategies.Anna DominiczakBritish Heart Foundation (BHF)RG/07/005/23633RI CARDIOVASCULAR & MEDICAL SCIENCES
483571Collaborative strategy for a definitive genome scan in essential hypertension: high fidelity phenotyping and "hypercontrols"Anna DominiczakBritish Heart Foundation (BHF)SP/08/005/25115RI CARDIOVASCULAR & MEDICAL SCIENCES