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Meta-Analysis
. 2011 Sep 11;43(10):1005-11.
doi: 10.1038/ng.922.

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure

Louise V Wain  1 , Germaine C Verwoert, Paul F O'Reilly, Gang Shi, Toby Johnson, Andrew D Johnson, Murielle Bochud, Kenneth M Rice, Peter Henneman, Albert V Smith, Georg B Ehret, Najaf Amin, Martin G Larson, Vincent Mooser, David Hadley, Marcus Dörr, Joshua C Bis, Thor Aspelund, Tõnu Esko, A Cecile J W Janssens, Jing Hua Zhao, Simon Heath, Maris Laan, Jingyuan Fu, Giorgio Pistis, Jian'an Luan, Pankaj Arora, Gavin Lucas, Nicola Pirastu, Irene Pichler, Anne U Jackson, Rebecca J Webster, Feng Zhang, John F Peden, Helena Schmidt, Toshiko Tanaka, Harry Campbell, Wilmar Igl, Yuri Milaneschi, Jouke-Jan Hottenga, Veronique Vitart, Daniel I Chasman, Stella Trompet, Jennifer L Bragg-Gresham, Behrooz Z Alizadeh, John C Chambers, Xiuqing Guo, Terho Lehtimäki, Brigitte Kühnel, Lorna M Lopez, Ozren Polašek, Mladen Boban, Christopher P Nelson, Alanna C Morrison, Vasyl Pihur, Santhi K Ganesh, Albert Hofman, Suman Kundu, Francesco U S Mattace-Raso, Fernando Rivadeneira, Eric J G Sijbrands, Andre G Uitterlinden, Shih-Jen Hwang, Ramachandran S Vasan, Thomas J Wang, Sven Bergmann, Peter Vollenweider, Gérard Waeber, Jaana Laitinen, Anneli Pouta, Paavo Zitting, Wendy L McArdle, Heyo K Kroemer, Uwe Völker, Henry Völzke, Nicole L Glazer, Kent D Taylor, Tamara B Harris, Helene Alavere, Toomas Haller, Aime Keis, Mari-Liis Tammesoo, Yurii Aulchenko, Inês Barroso, Kay-Tee Khaw, Pilar Galan, Serge Hercberg, Mark Lathrop, Susana Eyheramendy, Elin Org, Siim Sõber, Xiaowen Lu, Ilja M Nolte, Brenda W Penninx, Tanguy Corre, Corrado Masciullo, Cinzia Sala, Leif Groop, Benjamin F Voight, Olle Melander, Christopher J O'Donnell, Veikko Salomaa, Adamo Pio d'Adamo, Antonella Fabretto, Flavio Faletra, Sheila Ulivi, Fabiola M Del Greco, Maurizio Facheris, Francis S Collins, Richard N Bergman, John P Beilby, Joseph Hung, A William Musk, Massimo Mangino, So-Youn Shin, Nicole Soranzo, Hugh Watkins, Anuj Goel, Anders Hamsten, Pierre Gider, Marisa Loitfelder, Marion Zeginigg, Dena Hernandez, Samer S Najjar, Pau Navarro, Sarah H Wild, Anna Maria Corsi, Andrew Singleton, Eco J C de Geus, Gonneke Willemsen, Alex N Parker, Lynda M Rose, Brendan Buckley, David Stott, Marco Orru, Manuela Uda; LifeLines Cohort Study; Melanie M van der Klauw, Weihua Zhang, Xinzhong Li, James Scott, Yii-Der Ida Chen, Gregory L Burke, Mika Kähönen, Jorma Viikari, Angela Döring, Thomas Meitinger, Gail Davies, John M Starr, Valur Emilsson, Andrew Plump, Jan H Lindeman, Peter A C 't Hoen, Inke R König; EchoGen consortium; Janine F Felix, Robert Clarke, Jemma C Hopewell, Halit Ongen, Monique Breteler, Stéphanie Debette, Anita L Destefano, Myriam Fornage; AortaGen Consortium; Gary F Mitchell; CHARGE Consortium Heart Failure Working Group; Nicholas L Smith; KidneyGen consortium; Hilma Holm, Kari Stefansson, Gudmar Thorleifsson, Unnur Thorsteinsdottir; CKDGen consortium; Cardiogenics consortium; CardioGram; Nilesh J Samani, Michael Preuss, Igor Rudan, Caroline Hayward, Ian J Deary, H-Erich Wichmann, Olli T Raitakari, Walter Palmas, Jaspal S Kooner, Ronald P Stolk, J Wouter Jukema, Alan F Wright, Dorret I Boomsma, Stefania Bandinelli, Ulf B Gyllensten, James F Wilson, Luigi Ferrucci, Reinhold Schmidt, Martin Farrall, Tim D Spector, Lyle J Palmer, Jaakko Tuomilehto, Arne Pfeufer, Paolo Gasparini, David Siscovick, David Altshuler, Ruth J F Loos, Daniela Toniolo, Harold Snieder, Christian Gieger, Pierre Meneton, Nicholas J Wareham, Ben A Oostra, Andres Metspalu, Lenore Launer, Rainer Rettig, David P Strachan, Jacques S Beckmann, Jacqueline C M Witteman, Jeanette Erdmann, Ko Willems van Dijk, Eric Boerwinkle, Michael Boehnke, Paul M Ridker, Marjo-Riitta Jarvelin, Aravinda Chakravarti, Goncalo R Abecasis, Vilmundur Gudnason, Christopher Newton-Cheh, Daniel Levy, Patricia B Munroe, Bruce M Psaty, Mark J Caulfield, Dabeeru C Rao, Martin D Tobin, Paul Elliott, Cornelia M van Duijn
Collaborators, Affiliations
Meta-Analysis

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure

Louise V Wain et al. Nat Genet. .

Abstract

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.

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Conflict of interest statement

Competing Financial Interests

A.C. is managed by Johns Hopkins Medicine. I.B. and spouse own stock in Incyte Ltd and GlaxoSmithKline. A.N.P is an employee of Amgen. G.F.M. is owner of Cardiovascular Engineering, Inc, a company that designs and manufactures devices that measure vascular stiffness. The company uses these devices in clinical studies that evaluate the effects of diseases and interventions on vascular stiffness. V.M. is an employee of GlaxoSmithKline plc. A.Plump is an employee of Merck and Co, Inc.

Figures

Figure 1
Figure 1
Regional association plots of the 8 SNPs at 7 loci showing genome-wide significant association (P<5×10-8) with pulse pressure and/or mean arterial pressure. Statistical significance of each SNP shown on the –log10 scale as a function of chromosome position (NCBI build 36) in the meta-analysis of stage 1 only. The sentinel SNP at each locus is shown in blue; the correlations (r2) of each of the surrounding SNPs to the sentinel SNP are shown in the colours indicated in the key. Fine –scale recombination rate is shown in blue. Gene positions are indicated at the bottom.
Figure 1
Figure 1
Regional association plots of the 8 SNPs at 7 loci showing genome-wide significant association (P<5×10-8) with pulse pressure and/or mean arterial pressure. Statistical significance of each SNP shown on the –log10 scale as a function of chromosome position (NCBI build 36) in the meta-analysis of stage 1 only. The sentinel SNP at each locus is shown in blue; the correlations (r2) of each of the surrounding SNPs to the sentinel SNP are shown in the colours indicated in the key. Fine –scale recombination rate is shown in blue. Gene positions are indicated at the bottom.
Figure 1
Figure 1
Regional association plots of the 8 SNPs at 7 loci showing genome-wide significant association (P<5×10-8) with pulse pressure and/or mean arterial pressure. Statistical significance of each SNP shown on the –log10 scale as a function of chromosome position (NCBI build 36) in the meta-analysis of stage 1 only. The sentinel SNP at each locus is shown in blue; the correlations (r2) of each of the surrounding SNPs to the sentinel SNP are shown in the colours indicated in the key. Fine –scale recombination rate is shown in blue. Gene positions are indicated at the bottom.
Figure 1
Figure 1
Regional association plots of the 8 SNPs at 7 loci showing genome-wide significant association (P<5×10-8) with pulse pressure and/or mean arterial pressure. Statistical significance of each SNP shown on the –log10 scale as a function of chromosome position (NCBI build 36) in the meta-analysis of stage 1 only. The sentinel SNP at each locus is shown in blue; the correlations (r2) of each of the surrounding SNPs to the sentinel SNP are shown in the colours indicated in the key. Fine –scale recombination rate is shown in blue. Gene positions are indicated at the bottom.
Figure 1
Figure 1
Regional association plots of the 8 SNPs at 7 loci showing genome-wide significant association (P<5×10-8) with pulse pressure and/or mean arterial pressure. Statistical significance of each SNP shown on the –log10 scale as a function of chromosome position (NCBI build 36) in the meta-analysis of stage 1 only. The sentinel SNP at each locus is shown in blue; the correlations (r2) of each of the surrounding SNPs to the sentinel SNP are shown in the colours indicated in the key. Fine –scale recombination rate is shown in blue. Gene positions are indicated at the bottom.
Figure 1
Figure 1
Regional association plots of the 8 SNPs at 7 loci showing genome-wide significant association (P<5×10-8) with pulse pressure and/or mean arterial pressure. Statistical significance of each SNP shown on the –log10 scale as a function of chromosome position (NCBI build 36) in the meta-analysis of stage 1 only. The sentinel SNP at each locus is shown in blue; the correlations (r2) of each of the surrounding SNPs to the sentinel SNP are shown in the colours indicated in the key. Fine –scale recombination rate is shown in blue. Gene positions are indicated at the bottom.
Figure 1
Figure 1
Regional association plots of the 8 SNPs at 7 loci showing genome-wide significant association (P<5×10-8) with pulse pressure and/or mean arterial pressure. Statistical significance of each SNP shown on the –log10 scale as a function of chromosome position (NCBI build 36) in the meta-analysis of stage 1 only. The sentinel SNP at each locus is shown in blue; the correlations (r2) of each of the surrounding SNPs to the sentinel SNP are shown in the colours indicated in the key. Fine –scale recombination rate is shown in blue. Gene positions are indicated at the bottom.
Figure 1
Figure 1
Regional association plots of the 8 SNPs at 7 loci showing genome-wide significant association (P<5×10-8) with pulse pressure and/or mean arterial pressure. Statistical significance of each SNP shown on the –log10 scale as a function of chromosome position (NCBI build 36) in the meta-analysis of stage 1 only. The sentinel SNP at each locus is shown in blue; the correlations (r2) of each of the surrounding SNPs to the sentinel SNP are shown in the colours indicated in the key. Fine –scale recombination rate is shown in blue. Gene positions are indicated at the bottom.
Figure 2
Figure 2
Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) effect sizes (beta coefficients) for all BP SNPs identified in the present study and Ehret et al., obtained from follow-up samples only. Beta coefficients are shown as standard deviation (s.d.) differences so that SBP and DBP are measured on comparable scales. Points are colour-coded according to whether they are genome-wide significant (P<5×10-8) for Pulse Pressure (PP) (red), Mean Arterial Pressure (MAP) (blue) or both PP and MAP (purple) in stages 1 and 2 of the present study, while those that are significant only for SBP and/or DBP from Ehret et al. are shown in black. The novel SNPs found in the present study are labelled with their rs-numbers. For illustration purposes the effect allele for each SNP is defined such that the direction of the SBP effect is always positive.
See this image and copyright information in PMC

References

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    1. Levy D, et al. Genome-wide association study of blood pressure and hypertension. Nat Genet. 2009;41:677–87. - PMC - PubMed
    1. Newton-Cheh C, et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet. 2009;41:666–76. - PMC - PubMed
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    1. Rose G. Strategies of prevention: the individual and the population. In: Marmot M, E P, editors. Coronary heart disease epidemiology: From aetiology to Public health. Oxford University Press; Oxford: 2005. pp. 631–41.

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