Gene-centric Meta-analysis in 87,736 Individuals of European Ancestry Identifies Multiple Blood-Pressure-Related Loci

V Tragante, MR Barnes, SK Ganesh, MB Lanktree, W Guo, N Franceschini, EN Smith, T Johnson, MV Holmes, S Padmanabhan, KJ Karczewski, B Almoguera, J Barnard, J Baumert, YPC Chang, CC Elbers, M Farrall, ME Fischer, TR Gaunt, JMIH GhoC Gieger, A Goel, Y Gong, Aaron Isaacs, ME Kleber, IM Leach, CW McDonough, MFL Meijs, O Melander, CP Nelson, IM (Ilja) Nolte, N Pankratz, TS Price, J Shaffer, S Shah, M Tomaszewski, PJ van der Most, EPA Van Iperen, JM Vonk, K Witkowska, COL Wong, Lei Zhang, AL Beitelshees, GS Berenson, DL Bhatt, M Brown, A Burt, RM Cooper-DeHoff, JM Connell, KJ Cruickshanks, SP Curtis, G Davey-Smith, C Delles, RT Gansevoort, XQ Guo, S Haiqing, CE Hastie, MH Hofker, GK Hovingh, DS Kim, SA Kirkland, BE Klein, R Klein, YR Li, S Maiwald, C Newton-Cheh, ET O'Brien, NC Onland-Moret, W Palmas, A Parsa, BW Penninx, M Pettinger, RS Vasan, JE Ranchalis, PM Ridker, LM Rose, P Sever, D Shimbo, L Steele, RP (Ronald) Stolk, B Thorand, MD Trip, Cornelia Duijn, WM Verschuren, C Wijmenga, S Wyatt, JH Young, AH Zwinderman, CR Bezzina, E Boerwinkle, JP Casas, MJ Caulfield, A Chakravarti, DI Chasman, KW Davidson, PA Doevendans, AF Dominiczak, GA FitzGerald, JG Gums, M Fornage, H Hakonarson, I Halder, HL Hillege, T Illig, GP Jarvik, JA Johnson, JJP Kastelein, W Koenig, M Kumari, W Marz, SS Murray, JR O'Connell, AJ (A.) Oldehinkel, JS Pankow, DJ Rader, S Redline, MP Reilly, EE Schadt, K Kottke-Marchant, H Snieder, M Snyder, AV Stanton, MD Tobin, André Uitterlinden, P van der Harst, YT van der Schouw, NJ Samani, H Watkins, AD Johnson, AP Reiner, XF Zhu, PIW de Bakker, D Levy, FW Asselbergs, PB Munroe, BJ Keating

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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 similar to 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 x 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.
Original languageUndefined/Unknown
Pages (from-to)349-360
Number of pages12
JournalAmerican Journal of Human Genetics
Volume94
Issue number3
DOIs
Publication statusPublished - 2014

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