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

Authors:
Vinicius Tragante Michael R Barnes Santhi K Ganesh Matthew B Lanktree Wei Guo Nora Franceschini Erin N Smith Toby Johnson Michael V Holmes Sandosh Padmanabhan Konrad J Karczewski Berta Almoguera John Barnard Jens Baumert Yen-Pei Christy Chang Clara C Elbers Martin Farrall Mary E Fischer Tom R Gaunt Johannes M I H Gho Christian Gieger Anuj Goel Yan Gong Aaron Isaacs Marcus E Kleber Irene Mateo Leach Caitrin W McDonough Matthijs F L Meijs Olle Melander Christopher P Nelson Ilja M Nolte Nathan Pankratz Tom S Price Jonathan Shaffer Sonia Shah Maciej Tomaszewski Peter J van der Most Erik P A Van Iperen Judith M Vonk Kate Witkowska Caroline O L Wong Li Zhang Amber L Beitelshees Gerald S Berenson Deepak L Bhatt Morris Brown Amber Burt Rhonda M Cooper-DeHoff John M Connell Karen J Cruickshanks Sean P Curtis George Davey-Smith Christian Delles Ron T Gansevoort Xiuqing Guo Shen Haiqing Claire E Hastie Marten H Hofker G Kees Hovingh Daniel S Kim Susan A Kirkland Barbara E Klein Ronald Klein Yun R Li Steffi Maiwald Christopher Newton-Cheh Eoin T O'Brien N Charlotte Onland-Moret Walter Palmas Afshin Parsa Brenda W Penninx Mary Pettinger Ramachandran S Vasan Jane E Ranchalis Paul M Ridker Lynda M Rose Peter Sever Daichi Shimbo Laura Steele Ronald P Stolk Barbara Thorand Mieke D Trip Cornelia M van Duijn W Monique Verschuren Cisca Wijmenga Sharon Wyatt J Hunter Young Aeilko H Zwinderman Connie R Bezzina Eric Boerwinkle Juan P Casas Mark J Caulfield Aravinda Chakravarti Daniel I Chasman Karina W Davidson Pieter A Doevendans Anna F Dominiczak Garret A FitzGerald John G Gums Myriam Fornage Hakon Hakonarson Indrani Halder Hans L Hillege Thomas Illig Gail P Jarvik Julie A Johnson John J P Kastelein Wolfgang Koenig Meena Kumari Winfried März Sarah S Murray Jeffery R O'Connell Albertine J Oldehinkel James S Pankow Daniel J Rader Susan Redline Muredach P Reilly Eric E Schadt Kandice Kottke-Marchant Harold Snieder Michael Snyder Alice V Stanton Martin D Tobin André G Uitterlinden Pim van der Harst Yvonne T van der Schouw Nilesh J Samani Hugh Watkins Andrew D Johnson Alex P Reiner Xiaofeng Zhu Paul I W de Bakker Daniel Levy Folkert W Asselbergs Patricia B Munroe Brendan J Keating

Am J Hum Genet 2014 Mar 20;94(3):349-60. Epub 2014 Feb 20.

Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

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.

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http://dx.doi.org/10.1016/j.ajhg.2013.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951943PMC
March 2014
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