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Blood Pressure Loci Identified with a Gene-Centric Array.

Journal article
Authors Toby Johnson
Tom R Gaunt
Stephen J Newhouse
Sandosh Padmanabhan
Maciej Tomaszewski
Meena Kumari
Richard W Morris
Ioanna Tzoulaki
Eoin T O'Brien
Neil R Poulter
Peter Sever
Denis C Shields
Simon Thom
Sasiwarang G Wannamethee
Peter H Whincup
Morris J Brown
John M Connell
Richard J Dobson
Philip J Howard
Charles A Mein
Abiodun Onipinla
Sue Shaw-Hawkins
Yun Zhang
George Davey Smith
Ian N M Day
Debbie A Lawlor
Alison H Goodall
F Gerald Fowkes
Gonçalo R Abecasis
Paul Elliott
Vesela Gateva
Peter S Braund
Paul R Burton
Christopher P Nelson
Martin D Tobin
Pim van der Harst
Nicola Glorioso
Hani Neuvrith
Erika Salvi
Jan A Staessen
Andrea Stucchi
Nabila Devos
Xavier Jeunemaitre
Pierre-François Plouin
Jean Tichet
Peeter Juhanson
Elin Org
Margus Putku
Siim Sõber
Gudrun Veldre
Margus Viigimaa
Anna Levinsson
Annika Rosengren
Dag Thelle
Claire E Hastie
Thomas Hedner
Wai K Lee
Olle Melander
Björn Wahlstrand
Rebecca Hardy
Andrew Wong
Jackie A Cooper
Jutta Palmen
Li Chen
Alexandre F R Stewart
George A Wells
Harm-Jan Westra
Marcel G M Wolfs
Robert Clarke
Maria Grazia Franzosi
Anuj Goel
Anders Hamsten
Mark Lathrop
John F Peden
Udo Seedorf
Hugh Watkins
Willem H Ouwehand
Jennifer Sambrook
Jonathan Stephens
Juan-Pablo Casas
Fotios Drenos
Michael V Holmes
Mika Kivimaki
Sonia Shah
Tina Shah
Philippa J Talmud
John Whittaker
Chris Wallace
Christian Delles
Maris Laan
Diana Kuh
Steve E Humphries
Fredrik Nyberg
Daniele Cusi
Robert Roberts
Christopher Newton-Cheh
Lude Franke
Alice V Stanton
Anna F Dominiczak
Martin Farrall
Aroon D Hingorani
Nilesh J Samani
Mark J Caulfield
Patricia B Munroe
Published in American Journal of Human Genetics
Volume 89
Issue 6
Pages 688–700
ISSN 1537-6605
Publication year 2011
Published at Institute of Medicine, School of Public Health and Community Medicine
Institute of Medicine
Institute of Medicine, Department of Emergeny and Cardiovascular Medicine
Institute of Medicine, Department of Internal Medicine
Pages 688–700
Language en
Links dx.doi.org/10.1016/j.ajhg.2011.10.0...
Subject categories Public health medicine research areas, Cardiac and Cardiovascular Systems, Molecular medicine (genetics and pathology)

Abstract

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.

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