Loci influencing blood pressure identified using a cardiovascular gene-centric array

Santhi K. Ganesh; Vinicius Tragante; Wei Guo; Yiran Guo; Matthew B. Lanktree; Erin N. Smith; Toby Johnson; Berta Almoguera Castillo; John Barnard; Jens Baumert; Yen Pei Christy Chang; Clara C. Elbers; Martin Farrall; Mary E. Fischer; Nora Franceschini; Tom R. Gaunt; Johannes M.I.H. Gho; Christian Gieger; Yan Gong; Aaron Isaacs; Marcus E. Kleber; Irene Mateo Leach; Caitrin W. McDonough; Matthijs F.L. Meijs; Olle Mellander; Cliona M. Molony; Ilja M. Nolte; Sandosh Padmanabhan; Tom S. Price; Ramakrishnan Rajagopalan; Jonathan Shaffer; Sonia Shah; Haiqing Shen; Nicole Soranzo; Peter J. van der Most; Erik P.A. Van Iperen; Jessic A. Van Setten; Judith M. Vonk; Li Zhang; Amber L. Beitelshees; Gerald S. Berenson; Deepak L. Bhatt; Jolanda M.A. Boer; Eric Boerwinkle; Ben Burkley; Amber Burt; Aravinda Chakravarti; Wei Chen; Rhonda M. Cooper-DeHoff; Sean P. Curtis; Albert Dreisbach; David Duggan; Georg B. Ehret; Richard R. Fabsitz; Myriam Fornage; Ervin Fox; Clement E. Furlong; Ron T. Gansevoort; Marten H. Hofker; G. Kees Hovingh; Susan A. Kirkland; Kandice Kottke-Marchant; Abdullah Kutlar; Andrea Z. LaCroix; Taimour Y. Langaee; Yun R. Li; Honghuang Lin; Kiang Liu; Steffi Maiwald; Rainer Malik; Gurunathan Murugesan; Christopher Newton-Cheh; Jeffery R. O'Connell; N. Charlotte Onland-Moret; Willem H. Ouwehand; Walter Palmas; Brenda W. Penninx; Carl J. Pepine; Mary Pettinger; Joseph F. Polak; Vasan S. Ramachandran; Jane Ranchalis; Susan Redline; Paul M. Ridker; Lynda M. Rose; Hubert Scharnag; Nicholas J. Schork; Daichi Shimbo; Alan R. Shuldiner; Sathanur R. Srinivasan; Ronald P. Stolk; Herman A. Taylor; Barbara Thorand; Mieke D. Trip; Cornelia M. van Duijn; W. Monique Verschuren; Cisca Wijmenga; Bernhard R. Winkelmann; Sharon Wyatt; J. Hunter Young; Bernhard O. Boehm; Mark J. Caulfield; Daniel I. Chasman; Karina W. Davidson; Pieter A. Doevendans; Garret A. FitzGerald; John G. Gums; Hakon Hakonarson; Hans L. Hillege; Thomas Illig; Gail P. Jarvik; Julie A. Johnson; John J.P. Kastelein; Wolfgang Koenig; Life Lines Cohort Study; Winfried März; Braxton D. Mitchell; Sarah S. Murray; Albertine J. Oldehinkel; Daniel J. Rader; Muredach P. Reilly; Alex P. Reiner; Eric E. Schadt; Roy L. Silverstein; Harold Snieder; Alice V. Stanton; André G. Uitterlinden; Pim van der Harst; Yvonne T. van der Schouw; Nilesh J. Samani; Andrew D. Johnson; Patricia B. Munroe; Paul I.W. de Bakker; Xiaofeng Zhu; Daniel Levy; Brendan J. Keating; Folkert W. Asselbergs

doi:10.1093/hmg/dds555

Loci influencing blood pressure identified using a cardiovascular gene-centric array

Santhi K. Ganesh, Vinicius Tragante, Wei Guo, Yiran Guo, Matthew B. Lanktree, Erin N. Smith, Toby Johnson, Berta Almoguera Castillo, John Barnard, Jens Baumert, Yen Pei Christy Chang, Clara C. Elbers, Martin Farrall, Mary E. Fischer, Nora Franceschini, Tom R. Gaunt, Johannes M.I.H. Gho, Christian Gieger, Yan Gong, Aaron IsaacsMarcus E. Kleber, Irene Mateo Leach, Caitrin W. McDonough, Matthijs F.L. Meijs, Olle Mellander, Cliona M. Molony, Ilja M. Nolte, Sandosh Padmanabhan, Tom S. Price, Ramakrishnan Rajagopalan, Jonathan Shaffer, Sonia Shah, Haiqing Shen, Nicole Soranzo, Peter J. van der Most, Erik P.A. Van Iperen, Jessic A. Van Setten, Judith M. Vonk, Li Zhang, Amber L. Beitelshees, Gerald S. Berenson, Deepak L. Bhatt, Jolanda M.A. Boer, Eric Boerwinkle, Ben Burkley, Amber Burt, Aravinda Chakravarti, Wei Chen, Rhonda M. Cooper-DeHoff, Sean P. Curtis, Albert Dreisbach, David Duggan, Georg B. Ehret, Richard R. Fabsitz, Myriam Fornage, Ervin Fox, Clement E. Furlong, Ron T. Gansevoort, Marten H. Hofker, G. Kees Hovingh, Susan A. Kirkland, Kandice Kottke-Marchant, Abdullah Kutlar, Andrea Z. LaCroix, Taimour Y. Langaee, Yun R. Li, Honghuang Lin, Kiang Liu, Steffi Maiwald, Rainer Malik, Gurunathan Murugesan, Christopher Newton-Cheh, Jeffery R. O'Connell, N. Charlotte Onland-Moret, Willem H. Ouwehand, Walter Palmas, Brenda W. Penninx, Carl J. Pepine, Mary Pettinger, Joseph F. Polak, Vasan S. Ramachandran, Jane Ranchalis, Susan Redline, Paul M. Ridker, Lynda M. Rose, Hubert Scharnag, Nicholas J. Schork, Daichi Shimbo, Alan R. Shuldiner, Sathanur R. Srinivasan, Ronald P. Stolk, Herman A. Taylor, Barbara Thorand, Mieke D. Trip, Cornelia M. van Duijn, W. Monique Verschuren, Cisca Wijmenga, Bernhard R. Winkelmann, Sharon Wyatt, J. Hunter Young, Bernhard O. Boehm, Mark J. Caulfield, Daniel I. Chasman, Karina W. Davidson, Pieter A. Doevendans, Garret A. FitzGerald, John G. Gums, Hakon Hakonarson, Hans L. Hillege, Thomas Illig, Gail P. Jarvik, Julie A. Johnson, John J.P. Kastelein, Wolfgang Koenig, Life Lines Cohort Study, Winfried März, Braxton D. Mitchell, Sarah S. Murray, Albertine J. Oldehinkel, Daniel J. Rader, Muredach P. Reilly, Alex P. Reiner, Eric E. Schadt, Roy L. Silverstein, Harold Snieder, Alice V. Stanton, André G. Uitterlinden, Pim van der Harst, Yvonne T. van der Schouw, Nilesh J. Samani, Andrew D. Johnson, Patricia B. Munroe, Paul I.W. de Bakker, Xiaofeng Zhu, Daniel Levy, Brendan J. Keating, Folkert W. Asselbergs

Pulmonary Disease

Research output: Contribution to journal › Article › peer-review

102 Scopus citations

Abstract

Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ~50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ~2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10^-6). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.

Original language	English (US)
Pages (from-to)	1663-1678
Number of pages	16
Journal	Human Molecular Genetics
Volume	22
Issue number	8
DOIs	https://doi.org/10.1093/hmg/dds555
State	Published - Apr 2013

ASJC Scopus subject areas

Molecular Biology
Genetics
Genetics(clinical)

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10.1093/hmg/dds555

Cite this

Ganesh, S. K., Tragante, V., Guo, W., Guo, Y., Lanktree, M. B., Smith, E. N., Johnson, T., Castillo, B. A., Barnard, J., Baumert, J., Chang, Y. P. C., Elbers, C. C., Farrall, M., Fischer, M. E., Franceschini, N., Gaunt, T. R., Gho, J. M. I. H., Gieger, C., Gong, Y., ... Asselbergs, F. W. (2013). Loci influencing blood pressure identified using a cardiovascular gene-centric array. Human Molecular Genetics, 22(8), 1663-1678. https://doi.org/10.1093/hmg/dds555

Ganesh, SK, Tragante, V, Guo, W, Guo, Y, Lanktree, MB, Smith, EN, Johnson, T, Castillo, BA, Barnard, J, Baumert, J, Chang, YPC, Elbers, CC, Farrall, M, Fischer, ME, Franceschini, N, Gaunt, TR, Gho, JMIH, Gieger, C, Gong, Y, Isaacs, A, Kleber, ME, Leach, IM, McDonough, CW, Meijs, MFL, Mellander, O, Molony, CM, Nolte, IM, Padmanabhan, S, Price, TS, Rajagopalan, R, Shaffer, J, Shah, S, Shen, H, Soranzo, N, van der Most, PJ, Van Iperen, EPA, Van Setten, JA, Vonk, JM, Zhang, L, Beitelshees, AL, Berenson, GS, Bhatt, DL, Boer, JMA, Boerwinkle, E, Burkley, B, Burt, A, Chakravarti, A, Chen, W, Cooper-DeHoff, RM, Curtis, SP, Dreisbach, A, Duggan, D, Ehret, GB, Fabsitz, RR, Fornage, M, Fox, E, Furlong, CE, Gansevoort, RT, Hofker, MH, Hovingh, GK, Kirkland, SA, Kottke-Marchant, K, Kutlar, A, LaCroix, AZ, Langaee, TY, Li, YR, Lin, H, Liu, K, Maiwald, S, Malik, R, Murugesan, G, Newton-Cheh, C, O'Connell, JR, Onland-Moret, NC, Ouwehand, WH, Palmas, W, Penninx, BW, Pepine, CJ, Pettinger, M, Polak, JF, Ramachandran, VS, Ranchalis, J, Redline, S, Ridker, PM, Rose, LM, Scharnag, H, Schork, NJ, Shimbo, D, Shuldiner, AR, Srinivasan, SR, Stolk, RP, Taylor, HA, Thorand, B, Trip, MD, van Duijn, CM, Verschuren, WM, Wijmenga, C, Winkelmann, BR, Wyatt, S, Young, JH, Boehm, BO, Caulfield, MJ, Chasman, DI, Davidson, KW, Doevendans, PA, FitzGerald, GA, Gums, JG, Hakonarson, H, Hillege, HL, Illig, T, Jarvik, GP, Johnson, JA, Kastelein, JJP, Koenig, W, Study, LLC, März, W, Mitchell, BD, Murray, SS, Oldehinkel, AJ, Rader, DJ, Reilly, MP, Reiner, AP, Schadt, EE, Silverstein, RL, Snieder, H, Stanton, AV, Uitterlinden, AG, van der Harst, P, van der Schouw, YT, Samani, NJ, Johnson, AD, Munroe, PB, de Bakker, PIW, Zhu, X, Levy, D, Keating, BJ & Asselbergs, FW 2013, 'Loci influencing blood pressure identified using a cardiovascular gene-centric array', Human Molecular Genetics, vol. 22, no. 8, pp. 1663-1678. https://doi.org/10.1093/hmg/dds555

@article{72d3409363734df5941beb81ebdf82f2,

title = "Loci influencing blood pressure identified using a cardiovascular gene-centric array",

abstract = "Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ~50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ~2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10-6). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.",

author = "Ganesh, {Santhi K.} and Vinicius Tragante and Wei Guo and Yiran Guo and Lanktree, {Matthew B.} and Smith, {Erin N.} and Toby Johnson and Castillo, {Berta Almoguera} and John Barnard and Jens Baumert and Chang, {Yen Pei Christy} and Elbers, {Clara C.} and Martin Farrall and Fischer, {Mary E.} and Nora Franceschini and Gaunt, {Tom R.} and Gho, {Johannes M.I.H.} and Christian Gieger and Yan Gong and Aaron Isaacs and Kleber, {Marcus E.} and Leach, {Irene Mateo} and McDonough, {Caitrin W.} and Meijs, {Matthijs F.L.} and Olle Mellander and Molony, {Cliona M.} and Nolte, {Ilja M.} and Sandosh Padmanabhan and Price, {Tom S.} and Ramakrishnan Rajagopalan and Jonathan Shaffer and Sonia Shah and Haiqing Shen and Nicole Soranzo and {van der Most}, {Peter J.} and {Van Iperen}, {Erik P.A.} and {Van Setten}, {Jessic A.} and Vonk, {Judith M.} and Li Zhang and Beitelshees, {Amber L.} and Berenson, {Gerald S.} and Bhatt, {Deepak L.} and Boer, {Jolanda M.A.} and Eric Boerwinkle and Ben Burkley and Amber Burt and Aravinda Chakravarti and Wei Chen and Cooper-DeHoff, {Rhonda M.} and Curtis, {Sean P.} and Albert Dreisbach and David Duggan and Ehret, {Georg B.} and Fabsitz, {Richard R.} and Myriam Fornage and Ervin Fox and Furlong, {Clement E.} and Gansevoort, {Ron T.} and Hofker, {Marten H.} and Hovingh, {G. Kees} and Kirkland, {Susan A.} and Kandice Kottke-Marchant and Abdullah Kutlar and LaCroix, {Andrea Z.} and Langaee, {Taimour Y.} and Li, {Yun R.} and Honghuang Lin and Kiang Liu and Steffi Maiwald and Rainer Malik and Gurunathan Murugesan and Christopher Newton-Cheh and O'Connell, {Jeffery R.} and Onland-Moret, {N. Charlotte} and Ouwehand, {Willem H.} and Walter Palmas and Penninx, {Brenda W.} and Pepine, {Carl J.} and Mary Pettinger and Polak, {Joseph F.} and Ramachandran, {Vasan S.} and Jane Ranchalis and Susan Redline and Ridker, {Paul M.} and Rose, {Lynda M.} and Hubert Scharnag and Schork, {Nicholas J.} and Daichi Shimbo and Shuldiner, {Alan R.} and Srinivasan, {Sathanur R.} and Stolk, {Ronald P.} and Taylor, {Herman A.} and Barbara Thorand and Trip, {Mieke D.} and {van Duijn}, {Cornelia M.} and Verschuren, {W. Monique} and Cisca Wijmenga and Winkelmann, {Bernhard R.} and Sharon Wyatt and Young, {J. Hunter} and Boehm, {Bernhard O.} and Caulfield, {Mark J.} and Chasman, {Daniel I.} and Davidson, {Karina W.} and Doevendans, {Pieter A.} and FitzGerald, {Garret A.} and Gums, {John G.} and Hakon Hakonarson and Hillege, {Hans L.} and Thomas Illig and Jarvik, {Gail P.} and Johnson, {Julie A.} and Kastelein, {John J.P.} and Wolfgang Koenig and Study, {Life Lines Cohort} and Winfried M{\"a}rz and Mitchell, {Braxton D.} and Murray, {Sarah S.} and Oldehinkel, {Albertine J.} and Rader, {Daniel J.} and Reilly, {Muredach P.} and Reiner, {Alex P.} and Schadt, {Eric E.} and Silverstein, {Roy L.} and Harold Snieder and Stanton, {Alice V.} and Uitterlinden, {Andr{\'e} G.} and {van der Harst}, Pim and {van der Schouw}, {Yvonne T.} and Samani, {Nilesh J.} and Johnson, {Andrew D.} and Munroe, {Patricia B.} and {de Bakker}, {Paul I.W.} and Xiaofeng Zhu and Daniel Levy and Keating, {Brendan J.} and Asselbergs, {Folkert W.}",

note = "Funding Information: ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268-201100008C, HSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL-087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402 and National Institutes of Health contract HHSN268200625226C. Atherosclerotic Risk in Communities: University of North Carolina at Chapel Hill (N01-HC-55015, N01-HC-55018), Baylor Medical College (N01-HC-55016), University of Mississippi Medical Center(N01-HC-55021), University of Minnesota (N01-HC-55019), Johns Hopkins University (N01-HC-55020), University of Texas, Houston (N01-HC-55022). The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Funding Information: Lifelines: The LifeLines Cohort Study, and generation and management of GWAS genotype data for the LifeLines Cohort Study, is supported by the Netherlands Organization of Scientific Research NWO (grant 175.010.2007.006), the Economic Structure Enhancing Fund (FES) of the Dutch government, the Ministry of Economic Affairs, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the Northern Netherlands Collaboration of Provinces (SNN), the Province of Groningen, University Medical Center Groningen, the University of Groningen, Dutch Kidney Foundation and Dutch Diabetes Research Foundation. Funding Information: CFS: Cleveland Family Study was supported by funding from the National Heart, Lung and Blood Institute, National Institutes of Health, US Department of Health and Human Services and Case Western Reserve University (R01-HL-46380, M01-RR-00080). Funding Information: MONICA/KORA: The MONICA/KORA Augsburg studies were financed by the Helmholtz Zentrum M{\"u}nchen, German Research Center for Environmental Health, Neuherberg, Germany and supported by grants from the German Federal Ministry of Education and Research (BMBF). Part of this work was financed by the German National Genome Research Network (NGFNplus, project number 01GS0834), by the German Research Foundation (TH-784/2-1 and TH-784/2-2), by the European Foundation for the Study of Diabetes and through additional funds from the Helmholtz Zentrum M{\"u}nchen, the German Diabetes Center and the University of Ulm. Furthermore, the research was supported within the Munich Center of Health Sciences (MC Health) as part of the Ludwig Maximilians University innovative. Funding Information: NORDIL: This work was supported by the British Heart Foundation (grant number CH/98001 to A.F.D., RG/07/005/ 23633 to A.F.D., S.P. and C.D.) and a Special Project, for genotyping of the Swedish extremes from the NORDIL and MDC cohorts; and by Pharmacia. We thank Professor Thomas Hedner (Department of Clinical Pharmacology, Sahl-grenska Academy, Gotheburg, Sweden) and Professor Sverre Kjeldsen (Ullevaal University Hospital, University of Oslo, Oslo, Norway), who are investigators of the NORDIL study. Professor Kjeldsen is also an investigator of the ASCOT trial. Funding Information: NBS: This work was supported by the Wellcome Trust (grant number 076113/C/04/Z); by the National Institute for Health Research (grant number RP-PG-0310-1002) program grant to NHSBT, and a National Institute for Health Research grant to the Cambridge Comprehensive Biomedical Research Center; and by the British Heart Foundation (grant number PG/07/132/24256) for HumanCVD BeadChip genotyping for the UKBS-CC cohort. We acknowledge use of DNA from the UK Blood Services collection of Common Controls (UKBS-CC collection), funded by the Wellcome Trust and by the National Institute for Health Research. The collection was established as part of the Wellcome Trust Case Control Consortium (WTCCC 2007). Funding Information: PennCAC: The University of Pennsylvania Coronary Artery Calcification Study (PennCAC) gratefully acknowledges internal funding from the University of Pennsylvania and the participation of the study subject and is indebted to the investigators on these teams. Funding Information: BHS: ENS, SSM and NJS are supported in part by NIH/ NCRR Grant Number UL1 RR025774. The BHS was supported by grants HD-061437 and HD-062783 from the National Institute of Child Health and Human Development, and AG-16592 from the National Institute on Aging. Funding Information: MESA: Multi-Ethnic Study of Atherosclerosis: support for MESA is provided by contracts N01-HC-95159 through N01-HC-95169 and CTSA UL1-RR-024156. Funding for genotyp-ing was provided by NHLBI Contract N02-HL-6-4278 and N01-HC-65226. Funding Information: AMC-PAS: Funding for PAS was provided by Ipse Movet; Bloodomics (LSHM-CT-2004-503485). Funding Information: LURIC: LURIC thanks their participants and researchers and acknowledges that it has received funding through the sixth Framework Program (integrated project Bloodomics, grant LSHM-CT-2004-503485) and seventh Framework Program (integrated project Atheroremo, Grant Agreement number 201668) of the European Union. Funding Information: NESDA: The infrastructure for the NESDA study is funded through the Geestkracht program of the Dutch Scientific Organization (ZON-MW, grant number 10-000-1002) and matching funds from participating universities and mental health care organizations. Genotyping in NESDA was funded by the Genetic Association Information Network of the Foundation for the US National Institutes of Health. Statistical analyses were carried out on the Genetic Cluster Computer (http:// www.geneticcluster.org), which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003) along with a supplement from the Dutch Brain Foundation. Funding Information: NSHS95: Nova Scotia Health Survey 1995 (NSHS95) was supported by grants HL-091099, HL-080665, HL-076857, HL-084034, HL-088117, HL-07854 and HL-072866 from the NHLBI; by the National Health and Welfare of Canada, Ottawa, Ontario; by the Nova Scotia Department of Health, Halifax and by the Heart and Stroke Foundation of New Brunswick, Saint John. Funding Information: MDC: This work was supported by the Swedish Medical Research Council; by the Swedish Heart and Lung Foundation; by the Medical Faculty of Lund University, Malmo University Hospital; by the Albert P_ahlsson Research Foundation; by the Crafoord foundation; by the Ernhold Lundstroms Research Foundation, the Region Skane; by the Hulda and Conrad Mossfelt Foundation; by the King Gustaf V and Queen Victoria Foundation; by the Lennart Hanssons Memorial Fund and by the Marianne and Marcus Wallenberg Foundation. Funding Information: SMART: Folkert W. Asselbergs is supported by a clinical fellowship from the Netherlands Organization for Health Research and Development (ZonMw grant 90700342). M.F.L.M. was financially supported by EUGeneHeart, grant number LSHM-CT-2005-018833. The authors acknowledge all MR technicians, research nurses and medical students involved in SMART Heart for valuable support. Funding Information: Amish: The Amish studies were funded by the National Institutes of Health (R01 HL088119, R01 AG18728, U01 HL72515, U01 GM074518 with additional funding for cardiochip analysis provided by an American Heart Association Scientist Development grant (0830146N to H.S.). Genotyping of cardiochip was carried out in the Genomics Core at the University of Maryland, Baltimore with support from the Mid-Atlantic Nutrition and Obesity Research Center (NIH P30 DK072488). Funding Information: WHI: The Women{\textquoteright}s Health Initiative (WHI) program is funded by the National Heart, Lung and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268-201100003C, HHSN268201100004C and HHSN27120110-0004C. Funding Information: MEDAL: MEDAL was supported by Merck & Co (White-house Station, NJ, USA). The authors thank Amarjot Kaur and the current or former employees of Merck Research Laboratories who contributed to the conduct and analysis of the MEDAL data. Funding Information: AIBIII: The Allied Irish Bank workers III study was supported by the Higher Education Authority (Ireland), Program for research in Third-Level Institutions Cycle 3, Program for Human Genomics. We thank the Allied Irish Bank and their employees for facilitating the study. Funding Information: GRAPHIC: This work was supported by the British Heart Foundation (grant numbers RG/2001004, PG/07/132/24256) for recruitment and genotyping of the GRAPHIC cohort. N.J.S. was supported by a British Heart Foundation Chair of Cardiology (grant number CH/03/001. This study is part of the research portfolio supported by the Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease. Funding Information: CLEAR: CLEAR support (GPJ) came from R01 HL67406, the Northwest Institute of Genetic Medicine and the State of Washington Life Sciences Discovery Fund. The CLEAR investigators sincerely thank the participants for their efforts. Funding Information: TRAILS: TRAILS (Tracking Adolescents{\textquoteright} Individual Lives Survey) is a collaborative project involving various departments of the University Medical Center and University of Gro-ningen, the Erasmus University Medical Center Rotterdam, the University of Utrecht, the Radboud Medical Center Nijmegen, and the Parnassia Bavo group, all in the Netherlands. TRAILS has been financially supported by grants from the Netherlands Organization for Scientific Research NWO (Medical Research Council program grant GB-MW 940-38-011; ZonMW Brainpower grant 100-001-004; ZonMw Risk Behavior and Dependence grants 60-60600-98-018 and 60-60600-97-118; ZonMw Culture and Health grant 261-98-710; Social Sciences Council medium-sized investment grants GB-MaGW 480-01-006 and GB-MaGW 480-07-001; Social Sciences Council project grants GB-MaGW 457-03-018, GB-MaGW 452-04-314, and GB-MaGW 452-06-004; NWO large-sized investment grant 175.010.2003.005; NWO Longitudinal Survey and Panel Funding 481-08-013); the Sophia Foundation for Medical Research (projects 301 and 393), the Dutch Ministry of Justice (WODC), the European Science Foundation (EuroSTRESS project FP-006), the Dutch Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP32) and the participating universities. We are grateful to all adolescents, their parents and teachers who participated in this research and to everyone who worked on this project and made it possible. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org), which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003) along with a supplement from the Dutch Brain Foundation. Funding Information: This work was supported by the British Heart Foundation (grant number PG/07/131/24254 to P.B.M.) for HumanCVD BeadChip genotyping for the AIBIII, ASCOT, BRIGHT, MDC and NORDIL cohorts; by the Wellcome Trust (grant number 093078/Z/10/Z to T.J.) and in part by a VIP award from the Wellcome Trust to Queen Mary University of London in the 2009/2010 academic year. Funding Information: PREVEND: PREVEND genetics is supported by the Dutch Kidney Foundation (Grant E033), the National Institutes of Health (grant LM010098), The Netherlands organization for health research and development (NWO VENI grant 916.761.70) and the Dutch Inter University Cardiology Institute Netherlands. Funding Information: BRIGHT: {"}This work was supported by the Medical Research Council of Great Britain (grant number G9521010D) and by the British Heart Foundation (grant number PG/02/ 128). A.F.D. was supported by the British Heart Foundation (grant numbers RG/07/005/23633, SP/08/005/25115) and by the European Union Ingenious HyperCare Consortium: Integrated Genomics, Clinical Research, and Care in Hypertension (grant number LSHM-C7-2006-037093). The BRIGHT study is extremely grateful to all the patients who participated in the study and the BRIGHT nursing team. We would also like to thank the Barts Genome Center staff for their assistance with this project. This work forms part of the research themes contributing to the translational research portfolio for Barts and the London Cardiovascular Biomedical Research Unit, which is supported and funded by the National Institute for Health Research. Funding Information: BWHHS: The British Women{\textquoteright}s Heart and Health Study is supported by funding from the British Heart Foundation and the Department of Health Policy Research Program (England). We thank the BWHHS data collection team, general practitioners who helped with recruitment of participants and the participants. We thank all of the participants and the general practitioners, research nurses and data management staff who supported data collection and preparation. The BWHHS is coordinated by Shah Ebrahim (PI), Debbie Lawlor and Juan-Pablo Casas, with genotyping funded by the BHF (PG/07/131/24254, PI Tom Gaunt).The BRIGHT study was supported by the Medical Research Council of Great Britain (G9521010D) and the British Heart Foundation. (PG/02/128). Funding Information: INVEST: The INternational VErapamil SR Trandolapril (INVEST) genetic substudy was funded by NIH grants HL074730, HL69758, HL077113, GM074492 and RR017568, a grant from Abbott Pharmaceuticals and the Florida Opportunity Fund and NIH/NCRR clinical and Translational Science Award (CTSA) to University of Florida UL1 TR000064. INVEST and Pharmacogenomics Evaluation of Antihypertensive Responses (PEAR) studies thank the participants and the investigators who made this collection possible. Funding Information: WGHS: Women{\textquoteright}s genome health study: The WGHS is funded by the Donald W. Reynolds Foundation (Las Vegas, NV), the Fondation LeDucq (Paris, France), the National Heart, Lung and Blood Institute (NHLBI; HL043851) and the National Cancer Institute (NCI; CA047988). Funding for genotyping and collaborative scientific support was provided by Amgen. Funding Information: CCCS: CCCS was supported by grant P50HL81011 from the National Heart, Lung and Blood Institute, National Institutes of Health, US Department of Health and Human Services. The authors thank the CHARISMA investigators for phenotype and sample collection. Funding Information: WHII: This work was supported by the British Heart Foundation (grant numbers PG/07/133/24260, RG/08/008, SP/07/ 007/23671), Senior Fellowship to A.D.H. (grant number FS/ 2005/125), Chair for S.E.H.; by the National Heart Lung and Blood Institute (grant number HL36310) for M.Kivimaki{\textquoteright}s and M.Kumari{\textquoteright}s contributions to this work; by the Medical Research Council (grant number G0802432) Population Health Scientist Fellowship to M.V.H.; by the Health and Safety Executive; by the Department of Health; by the National Institute on Aging in the USA (grant number AG13196); by the Agency for Health Care Policy Research (grant number HS06516); by the John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socioeconomic Status and Health. Funding Information: Procardis: This work was supported by the British Heart Foundation; by the European Community Sixth Framework Program (grant number LSHM-CT-2007-037273) and by AstraZeneca AB. R.C., M.F. is supported by the British Heart Foundation Center for Research Excellence. Funding Information: PEAR: PEAR was supported by the NIH Pharmacogenetics Research Network grant U01-GM074492; and CTSA grants UL1-TR000064 (University of Florida), UL1-TR000454 (Emory University) and UL1-TR000135 (Mayo Clinic); and funds from the Mayo Foundation. Funding Information: EPIC-NL: The EPIC-NL study was funded by {\textquoteleft}Europe against Cancer{\textquoteright} Program of the European Commission (SANCO), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch Cancer Society; ZonMW the Netherlands Organization for Health Research and Development, World Cancer Research Fund (The Netherlands). Genotyping of the IBC-chip was funded by IOP Genomics grant IGE05012 from NL Agency. Funding Information: ASCOT: This work was supported by Pfizer, New York, NY, USA, for the ASCOT study and the collection of the ASCOT DNA repository; by Servier Research Group, Paris, France; and by Leo Laboratories, Copenhagen, Denmark. We thank all ASCOT trial participants, physicians, nurses and practices in the participating countries for their important contribution to the study. In particular, we thank Clare Muckian and David Toomey for their help in DNA extraction, storage and handling. Funding Information: Rotterdam Study: The contributions of inhabitants, general practitioners and pharmacists of the Ommoord district to the Rotterdam Study are gratefully acknowledged. The Rotterdam Study is supported by the Erasmus Medical Center Rotterdam, the Erasmus University Rotterdam, the Netherlands Organization for Scientific Research (NWO), the Netherlands Organization for Health Research and Development (ZonMW), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. Funding Information: PROCARDIS: This work was supported by the British Heart Foundation; by the European Community Sixth Frame-work Program (grant number LSHM-CT-2007-037273) and by AstraZeneca AB. R.C., M.F. is supported by the British Heart Foundation Center for Research Excellence. Funding Information: FHS: The Framingham Heart Study research included in this study is funded by NIH grant/contract N01-HC-25195, R01-HL-092577, R01-HL-076784, R01-AG-028321 and by the NIH Intramural Research Program.",

year = "2013",

month = apr,

doi = "10.1093/hmg/dds555",

language = "English (US)",

volume = "22",

pages = "1663--1678",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "8",

}

TY - JOUR

T1 - Loci influencing blood pressure identified using a cardiovascular gene-centric array

AU - Ganesh, Santhi K.

AU - Tragante, Vinicius

AU - Guo, Wei

AU - Guo, Yiran

AU - Lanktree, Matthew B.

AU - Smith, Erin N.

AU - Johnson, Toby

AU - Castillo, Berta Almoguera

AU - Barnard, John

AU - Baumert, Jens

AU - Chang, Yen Pei Christy

AU - Elbers, Clara C.

AU - Farrall, Martin

AU - Fischer, Mary E.

AU - Franceschini, Nora

AU - Gaunt, Tom R.

AU - Gho, Johannes M.I.H.

AU - Gieger, Christian

AU - Gong, Yan

AU - Isaacs, Aaron

AU - Kleber, Marcus E.

AU - Leach, Irene Mateo

AU - McDonough, Caitrin W.

AU - Meijs, Matthijs F.L.

AU - Mellander, Olle

AU - Molony, Cliona M.

AU - Nolte, Ilja M.

AU - Padmanabhan, Sandosh

AU - Price, Tom S.

AU - Rajagopalan, Ramakrishnan

AU - Shaffer, Jonathan

AU - Shah, Sonia

AU - Shen, Haiqing

AU - Soranzo, Nicole

AU - van der Most, Peter J.

AU - Van Iperen, Erik P.A.

AU - Van Setten, Jessic A.

AU - Vonk, Judith M.

AU - Zhang, Li

AU - Beitelshees, Amber L.

AU - Berenson, Gerald S.

AU - Bhatt, Deepak L.

AU - Boer, Jolanda M.A.

AU - Boerwinkle, Eric

AU - Burkley, Ben

AU - Burt, Amber

AU - Chakravarti, Aravinda

AU - Chen, Wei

AU - Cooper-DeHoff, Rhonda M.

AU - Curtis, Sean P.

AU - Dreisbach, Albert

AU - Duggan, David

AU - Ehret, Georg B.

AU - Fabsitz, Richard R.

AU - Fornage, Myriam

AU - Fox, Ervin

AU - Furlong, Clement E.

AU - Gansevoort, Ron T.

AU - Hofker, Marten H.

AU - Hovingh, G. Kees

AU - Kirkland, Susan A.

AU - Kottke-Marchant, Kandice

AU - Kutlar, Abdullah

AU - LaCroix, Andrea Z.

AU - Langaee, Taimour Y.

AU - Li, Yun R.

AU - Lin, Honghuang

AU - Liu, Kiang

AU - Maiwald, Steffi

AU - Malik, Rainer

AU - Murugesan, Gurunathan

AU - Newton-Cheh, Christopher

AU - O'Connell, Jeffery R.

AU - Onland-Moret, N. Charlotte

AU - Ouwehand, Willem H.

AU - Palmas, Walter

AU - Penninx, Brenda W.

AU - Pepine, Carl J.

AU - Pettinger, Mary

AU - Polak, Joseph F.

AU - Ramachandran, Vasan S.

AU - Ranchalis, Jane

AU - Redline, Susan

AU - Ridker, Paul M.

AU - Rose, Lynda M.

AU - Scharnag, Hubert

AU - Schork, Nicholas J.

AU - Shimbo, Daichi

AU - Shuldiner, Alan R.

AU - Srinivasan, Sathanur R.

AU - Stolk, Ronald P.

AU - Taylor, Herman A.

AU - Thorand, Barbara

AU - Trip, Mieke D.

AU - van Duijn, Cornelia M.

AU - Verschuren, W. Monique

AU - Wijmenga, Cisca

AU - Winkelmann, Bernhard R.

AU - Wyatt, Sharon

AU - Young, J. Hunter

AU - Boehm, Bernhard O.

AU - Caulfield, Mark J.

AU - Chasman, Daniel I.

AU - Davidson, Karina W.

AU - Doevendans, Pieter A.

AU - FitzGerald, Garret A.

AU - Gums, John G.

AU - Hakonarson, Hakon

AU - Hillege, Hans L.

AU - Illig, Thomas

AU - Jarvik, Gail P.

AU - Johnson, Julie A.

AU - Kastelein, John J.P.

AU - Koenig, Wolfgang

AU - Study, Life Lines Cohort

AU - März, Winfried

AU - Mitchell, Braxton D.

AU - Murray, Sarah S.

AU - Oldehinkel, Albertine J.

AU - Rader, Daniel J.

AU - Reilly, Muredach P.

AU - Reiner, Alex P.

AU - Schadt, Eric E.

AU - Silverstein, Roy L.

AU - Snieder, Harold

AU - Stanton, Alice V.

AU - Uitterlinden, André G.

AU - van der Harst, Pim

AU - van der Schouw, Yvonne T.

AU - Samani, Nilesh J.

AU - Johnson, Andrew D.

AU - Munroe, Patricia B.

AU - de Bakker, Paul I.W.

AU - Zhu, Xiaofeng

AU - Levy, Daniel

AU - Keating, Brendan J.

AU - Asselbergs, Folkert W.

N1 - Funding Information: ARIC: The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268-201100008C, HSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268201100012C), R01HL-087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402 and National Institutes of Health contract HHSN268200625226C. Atherosclerotic Risk in Communities: University of North Carolina at Chapel Hill (N01-HC-55015, N01-HC-55018), Baylor Medical College (N01-HC-55016), University of Mississippi Medical Center(N01-HC-55021), University of Minnesota (N01-HC-55019), Johns Hopkins University (N01-HC-55020), University of Texas, Houston (N01-HC-55022). The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Funding Information: Lifelines: The LifeLines Cohort Study, and generation and management of GWAS genotype data for the LifeLines Cohort Study, is supported by the Netherlands Organization of Scientific Research NWO (grant 175.010.2007.006), the Economic Structure Enhancing Fund (FES) of the Dutch government, the Ministry of Economic Affairs, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the Northern Netherlands Collaboration of Provinces (SNN), the Province of Groningen, University Medical Center Groningen, the University of Groningen, Dutch Kidney Foundation and Dutch Diabetes Research Foundation. Funding Information: CFS: Cleveland Family Study was supported by funding from the National Heart, Lung and Blood Institute, National Institutes of Health, US Department of Health and Human Services and Case Western Reserve University (R01-HL-46380, M01-RR-00080). Funding Information: MONICA/KORA: The MONICA/KORA Augsburg studies were financed by the Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany and supported by grants from the German Federal Ministry of Education and Research (BMBF). Part of this work was financed by the German National Genome Research Network (NGFNplus, project number 01GS0834), by the German Research Foundation (TH-784/2-1 and TH-784/2-2), by the European Foundation for the Study of Diabetes and through additional funds from the Helmholtz Zentrum München, the German Diabetes Center and the University of Ulm. Furthermore, the research was supported within the Munich Center of Health Sciences (MC Health) as part of the Ludwig Maximilians University innovative. Funding Information: NORDIL: This work was supported by the British Heart Foundation (grant number CH/98001 to A.F.D., RG/07/005/ 23633 to A.F.D., S.P. and C.D.) and a Special Project, for genotyping of the Swedish extremes from the NORDIL and MDC cohorts; and by Pharmacia. We thank Professor Thomas Hedner (Department of Clinical Pharmacology, Sahl-grenska Academy, Gotheburg, Sweden) and Professor Sverre Kjeldsen (Ullevaal University Hospital, University of Oslo, Oslo, Norway), who are investigators of the NORDIL study. Professor Kjeldsen is also an investigator of the ASCOT trial. Funding Information: NBS: This work was supported by the Wellcome Trust (grant number 076113/C/04/Z); by the National Institute for Health Research (grant number RP-PG-0310-1002) program grant to NHSBT, and a National Institute for Health Research grant to the Cambridge Comprehensive Biomedical Research Center; and by the British Heart Foundation (grant number PG/07/132/24256) for HumanCVD BeadChip genotyping for the UKBS-CC cohort. We acknowledge use of DNA from the UK Blood Services collection of Common Controls (UKBS-CC collection), funded by the Wellcome Trust and by the National Institute for Health Research. The collection was established as part of the Wellcome Trust Case Control Consortium (WTCCC 2007). Funding Information: PennCAC: The University of Pennsylvania Coronary Artery Calcification Study (PennCAC) gratefully acknowledges internal funding from the University of Pennsylvania and the participation of the study subject and is indebted to the investigators on these teams. Funding Information: BHS: ENS, SSM and NJS are supported in part by NIH/ NCRR Grant Number UL1 RR025774. The BHS was supported by grants HD-061437 and HD-062783 from the National Institute of Child Health and Human Development, and AG-16592 from the National Institute on Aging. Funding Information: MESA: Multi-Ethnic Study of Atherosclerosis: support for MESA is provided by contracts N01-HC-95159 through N01-HC-95169 and CTSA UL1-RR-024156. Funding for genotyp-ing was provided by NHLBI Contract N02-HL-6-4278 and N01-HC-65226. Funding Information: AMC-PAS: Funding for PAS was provided by Ipse Movet; Bloodomics (LSHM-CT-2004-503485). Funding Information: LURIC: LURIC thanks their participants and researchers and acknowledges that it has received funding through the sixth Framework Program (integrated project Bloodomics, grant LSHM-CT-2004-503485) and seventh Framework Program (integrated project Atheroremo, Grant Agreement number 201668) of the European Union. Funding Information: NESDA: The infrastructure for the NESDA study is funded through the Geestkracht program of the Dutch Scientific Organization (ZON-MW, grant number 10-000-1002) and matching funds from participating universities and mental health care organizations. Genotyping in NESDA was funded by the Genetic Association Information Network of the Foundation for the US National Institutes of Health. Statistical analyses were carried out on the Genetic Cluster Computer (http:// www.geneticcluster.org), which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003) along with a supplement from the Dutch Brain Foundation. Funding Information: NSHS95: Nova Scotia Health Survey 1995 (NSHS95) was supported by grants HL-091099, HL-080665, HL-076857, HL-084034, HL-088117, HL-07854 and HL-072866 from the NHLBI; by the National Health and Welfare of Canada, Ottawa, Ontario; by the Nova Scotia Department of Health, Halifax and by the Heart and Stroke Foundation of New Brunswick, Saint John. Funding Information: MDC: This work was supported by the Swedish Medical Research Council; by the Swedish Heart and Lung Foundation; by the Medical Faculty of Lund University, Malmo University Hospital; by the Albert P_ahlsson Research Foundation; by the Crafoord foundation; by the Ernhold Lundstroms Research Foundation, the Region Skane; by the Hulda and Conrad Mossfelt Foundation; by the King Gustaf V and Queen Victoria Foundation; by the Lennart Hanssons Memorial Fund and by the Marianne and Marcus Wallenberg Foundation. Funding Information: SMART: Folkert W. Asselbergs is supported by a clinical fellowship from the Netherlands Organization for Health Research and Development (ZonMw grant 90700342). M.F.L.M. was financially supported by EUGeneHeart, grant number LSHM-CT-2005-018833. The authors acknowledge all MR technicians, research nurses and medical students involved in SMART Heart for valuable support. Funding Information: Amish: The Amish studies were funded by the National Institutes of Health (R01 HL088119, R01 AG18728, U01 HL72515, U01 GM074518 with additional funding for cardiochip analysis provided by an American Heart Association Scientist Development grant (0830146N to H.S.). Genotyping of cardiochip was carried out in the Genomics Core at the University of Maryland, Baltimore with support from the Mid-Atlantic Nutrition and Obesity Research Center (NIH P30 DK072488). Funding Information: WHI: The Women’s Health Initiative (WHI) program is funded by the National Heart, Lung and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268-201100003C, HHSN268201100004C and HHSN27120110-0004C. Funding Information: MEDAL: MEDAL was supported by Merck & Co (White-house Station, NJ, USA). The authors thank Amarjot Kaur and the current or former employees of Merck Research Laboratories who contributed to the conduct and analysis of the MEDAL data. Funding Information: AIBIII: The Allied Irish Bank workers III study was supported by the Higher Education Authority (Ireland), Program for research in Third-Level Institutions Cycle 3, Program for Human Genomics. We thank the Allied Irish Bank and their employees for facilitating the study. Funding Information: GRAPHIC: This work was supported by the British Heart Foundation (grant numbers RG/2001004, PG/07/132/24256) for recruitment and genotyping of the GRAPHIC cohort. N.J.S. was supported by a British Heart Foundation Chair of Cardiology (grant number CH/03/001. This study is part of the research portfolio supported by the Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease. Funding Information: CLEAR: CLEAR support (GPJ) came from R01 HL67406, the Northwest Institute of Genetic Medicine and the State of Washington Life Sciences Discovery Fund. The CLEAR investigators sincerely thank the participants for their efforts. Funding Information: TRAILS: TRAILS (Tracking Adolescents’ Individual Lives Survey) is a collaborative project involving various departments of the University Medical Center and University of Gro-ningen, the Erasmus University Medical Center Rotterdam, the University of Utrecht, the Radboud Medical Center Nijmegen, and the Parnassia Bavo group, all in the Netherlands. TRAILS has been financially supported by grants from the Netherlands Organization for Scientific Research NWO (Medical Research Council program grant GB-MW 940-38-011; ZonMW Brainpower grant 100-001-004; ZonMw Risk Behavior and Dependence grants 60-60600-98-018 and 60-60600-97-118; ZonMw Culture and Health grant 261-98-710; Social Sciences Council medium-sized investment grants GB-MaGW 480-01-006 and GB-MaGW 480-07-001; Social Sciences Council project grants GB-MaGW 457-03-018, GB-MaGW 452-04-314, and GB-MaGW 452-06-004; NWO large-sized investment grant 175.010.2003.005; NWO Longitudinal Survey and Panel Funding 481-08-013); the Sophia Foundation for Medical Research (projects 301 and 393), the Dutch Ministry of Justice (WODC), the European Science Foundation (EuroSTRESS project FP-006), the Dutch Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL CP32) and the participating universities. We are grateful to all adolescents, their parents and teachers who participated in this research and to everyone who worked on this project and made it possible. Statistical analyses were carried out on the Genetic Cluster Computer (http://www.geneticcluster.org), which is financially supported by the Netherlands Scientific Organization (NWO 480-05-003) along with a supplement from the Dutch Brain Foundation. Funding Information: This work was supported by the British Heart Foundation (grant number PG/07/131/24254 to P.B.M.) for HumanCVD BeadChip genotyping for the AIBIII, ASCOT, BRIGHT, MDC and NORDIL cohorts; by the Wellcome Trust (grant number 093078/Z/10/Z to T.J.) and in part by a VIP award from the Wellcome Trust to Queen Mary University of London in the 2009/2010 academic year. Funding Information: PREVEND: PREVEND genetics is supported by the Dutch Kidney Foundation (Grant E033), the National Institutes of Health (grant LM010098), The Netherlands organization for health research and development (NWO VENI grant 916.761.70) and the Dutch Inter University Cardiology Institute Netherlands. Funding Information: BRIGHT: "This work was supported by the Medical Research Council of Great Britain (grant number G9521010D) and by the British Heart Foundation (grant number PG/02/ 128). A.F.D. was supported by the British Heart Foundation (grant numbers RG/07/005/23633, SP/08/005/25115) and by the European Union Ingenious HyperCare Consortium: Integrated Genomics, Clinical Research, and Care in Hypertension (grant number LSHM-C7-2006-037093). The BRIGHT study is extremely grateful to all the patients who participated in the study and the BRIGHT nursing team. We would also like to thank the Barts Genome Center staff for their assistance with this project. This work forms part of the research themes contributing to the translational research portfolio for Barts and the London Cardiovascular Biomedical Research Unit, which is supported and funded by the National Institute for Health Research. Funding Information: BWHHS: The British Women’s Heart and Health Study is supported by funding from the British Heart Foundation and the Department of Health Policy Research Program (England). We thank the BWHHS data collection team, general practitioners who helped with recruitment of participants and the participants. We thank all of the participants and the general practitioners, research nurses and data management staff who supported data collection and preparation. The BWHHS is coordinated by Shah Ebrahim (PI), Debbie Lawlor and Juan-Pablo Casas, with genotyping funded by the BHF (PG/07/131/24254, PI Tom Gaunt).The BRIGHT study was supported by the Medical Research Council of Great Britain (G9521010D) and the British Heart Foundation. (PG/02/128). Funding Information: INVEST: The INternational VErapamil SR Trandolapril (INVEST) genetic substudy was funded by NIH grants HL074730, HL69758, HL077113, GM074492 and RR017568, a grant from Abbott Pharmaceuticals and the Florida Opportunity Fund and NIH/NCRR clinical and Translational Science Award (CTSA) to University of Florida UL1 TR000064. INVEST and Pharmacogenomics Evaluation of Antihypertensive Responses (PEAR) studies thank the participants and the investigators who made this collection possible. Funding Information: WGHS: Women’s genome health study: The WGHS is funded by the Donald W. Reynolds Foundation (Las Vegas, NV), the Fondation LeDucq (Paris, France), the National Heart, Lung and Blood Institute (NHLBI; HL043851) and the National Cancer Institute (NCI; CA047988). Funding for genotyping and collaborative scientific support was provided by Amgen. Funding Information: CCCS: CCCS was supported by grant P50HL81011 from the National Heart, Lung and Blood Institute, National Institutes of Health, US Department of Health and Human Services. The authors thank the CHARISMA investigators for phenotype and sample collection. Funding Information: WHII: This work was supported by the British Heart Foundation (grant numbers PG/07/133/24260, RG/08/008, SP/07/ 007/23671), Senior Fellowship to A.D.H. (grant number FS/ 2005/125), Chair for S.E.H.; by the National Heart Lung and Blood Institute (grant number HL36310) for M.Kivimaki’s and M.Kumari’s contributions to this work; by the Medical Research Council (grant number G0802432) Population Health Scientist Fellowship to M.V.H.; by the Health and Safety Executive; by the Department of Health; by the National Institute on Aging in the USA (grant number AG13196); by the Agency for Health Care Policy Research (grant number HS06516); by the John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socioeconomic Status and Health. Funding Information: Procardis: This work was supported by the British Heart Foundation; by the European Community Sixth Framework Program (grant number LSHM-CT-2007-037273) and by AstraZeneca AB. R.C., M.F. is supported by the British Heart Foundation Center for Research Excellence. Funding Information: PEAR: PEAR was supported by the NIH Pharmacogenetics Research Network grant U01-GM074492; and CTSA grants UL1-TR000064 (University of Florida), UL1-TR000454 (Emory University) and UL1-TR000135 (Mayo Clinic); and funds from the Mayo Foundation. Funding Information: EPIC-NL: The EPIC-NL study was funded by ‘Europe against Cancer’ Program of the European Commission (SANCO), Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch Cancer Society; ZonMW the Netherlands Organization for Health Research and Development, World Cancer Research Fund (The Netherlands). Genotyping of the IBC-chip was funded by IOP Genomics grant IGE05012 from NL Agency. Funding Information: ASCOT: This work was supported by Pfizer, New York, NY, USA, for the ASCOT study and the collection of the ASCOT DNA repository; by Servier Research Group, Paris, France; and by Leo Laboratories, Copenhagen, Denmark. We thank all ASCOT trial participants, physicians, nurses and practices in the participating countries for their important contribution to the study. In particular, we thank Clare Muckian and David Toomey for their help in DNA extraction, storage and handling. Funding Information: Rotterdam Study: The contributions of inhabitants, general practitioners and pharmacists of the Ommoord district to the Rotterdam Study are gratefully acknowledged. The Rotterdam Study is supported by the Erasmus Medical Center Rotterdam, the Erasmus University Rotterdam, the Netherlands Organization for Scientific Research (NWO), the Netherlands Organization for Health Research and Development (ZonMW), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. Funding Information: PROCARDIS: This work was supported by the British Heart Foundation; by the European Community Sixth Frame-work Program (grant number LSHM-CT-2007-037273) and by AstraZeneca AB. R.C., M.F. is supported by the British Heart Foundation Center for Research Excellence. Funding Information: FHS: The Framingham Heart Study research included in this study is funded by NIH grant/contract N01-HC-25195, R01-HL-092577, R01-HL-076784, R01-AG-028321 and by the NIH Intramural Research Program.

PY - 2013/4

Y1 - 2013/4

N2 - Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ~50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ~2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10-6). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.

AB - Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped ~50 000 single-nucleotide polymorphisms (SNPs) that capture variation in ~2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10-6). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.

UR - http://www.scopus.com/inward/record.url?scp=84875781416&partnerID=8YFLogxK

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U2 - 10.1093/hmg/dds555

DO - 10.1093/hmg/dds555

M3 - Article

C2 - 23303523

AN - SCOPUS:84875781416

VL - 22

SP - 1663

EP - 1678

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 8

ER -

Loci influencing blood pressure identified using a cardiovascular gene-centric array

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