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 & 117 others 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

Research output: Contribution to journalArticle

82 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1663-1678
Number of pages16
JournalHuman Molecular Genetics
Volume22
Issue number8
DOIs
StatePublished - Apr 1 2013

Fingerprint

Blood Pressure
Genes
Introns
Single Nucleotide Polymorphism
Arterial Pressure
Chromosomes
Furin
Left Ventricular Hypertrophy
Coronary Artery Disease
Cohort Studies
Cardiovascular Diseases
Stroke
Hypertension
Phenotype

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Ganesh, S. K., Tragante, V., Guo, W., Guo, Y., Lanktree, M. B., Smith, E. N., ... 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

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

In: Human Molecular Genetics, Vol. 22, No. 8, 01.04.2013, p. 1663-1678.

Research output: Contribution to journalArticle

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
Ganesh SK, Tragante V, Guo W, Guo Y, Lanktree MB, Smith EN et al. Loci influencing blood pressure identified using a cardiovascular gene-centric array. Human Molecular Genetics. 2013 Apr 1;22(8):1663-1678. https://doi.org/10.1093/hmg/dds555
Ganesh, Santhi K. ; Tragante, Vinicius ; Guo, Wei ; Guo, Yiran ; Lanktree, Matthew B. ; Smith, Erin N. ; Johnson, Toby ; Castillo, Berta Almoguera ; Barnard, John ; Baumert, Jens ; Chang, Yen Pei Christy ; Elbers, Clara C. ; Farrall, Martin ; Fischer, Mary E. ; Franceschini, Nora ; Gaunt, Tom R. ; Gho, Johannes M.I.H. ; Gieger, Christian ; Gong, Yan ; Isaacs, Aaron ; Kleber, Marcus E. ; Leach, Irene Mateo ; McDonough, Caitrin W. ; Meijs, Matthijs F.L. ; Mellander, Olle ; Molony, Cliona M. ; Nolte, Ilja M. ; Padmanabhan, Sandosh ; Price, Tom S. ; Rajagopalan, Ramakrishnan ; Shaffer, Jonathan ; Shah, Sonia ; Shen, Haiqing ; Soranzo, Nicole ; van der Most, Peter J. ; Van Iperen, Erik P.A. ; Van Setten, Jessic A. ; Vonk, Judith M. ; Zhang, Li ; Beitelshees, Amber L. ; Berenson, Gerald S. ; Bhatt, Deepak L. ; Boer, Jolanda M.A. ; Boerwinkle, Eric ; Burkley, Ben ; Burt, Amber ; Chakravarti, Aravinda ; Chen, Wei ; Cooper-DeHoff, Rhonda M. ; Curtis, Sean P. ; Dreisbach, Albert ; Duggan, David ; Ehret, Georg B. ; Fabsitz, Richard R. ; Fornage, Myriam ; Fox, Ervin ; Furlong, Clement E. ; Gansevoort, Ron T. ; Hofker, Marten H. ; Hovingh, G. Kees ; Kirkland, Susan A. ; Kottke-Marchant, Kandice ; Kutlar, Abdullah ; LaCroix, Andrea Z. ; Langaee, Taimour Y. ; Li, Yun R. ; Lin, Honghuang ; Liu, Kiang ; Maiwald, Steffi ; Malik, Rainer ; Murugesan, Gurunathan ; Newton-Cheh, Christopher ; O'Connell, Jeffery R. ; Onland-Moret, N. Charlotte ; Ouwehand, Willem H. ; Palmas, Walter ; Penninx, Brenda W. ; Pepine, Carl J. ; Pettinger, Mary ; Polak, Joseph F. ; Ramachandran, Vasan S. ; Ranchalis, Jane ; Redline, Susan ; Ridker, Paul M. ; Rose, Lynda M. ; Scharnag, Hubert ; Schork, Nicholas J. ; Shimbo, Daichi ; Shuldiner, Alan R. ; Srinivasan, Sathanur R. ; Stolk, Ronald P. ; Taylor, Herman A. ; Thorand, Barbara ; Trip, Mieke D. ; van Duijn, Cornelia M. ; Verschuren, W. Monique ; Wijmenga, Cisca ; Winkelmann, Bernhard R. ; Wyatt, Sharon ; Young, J. Hunter ; Boehm, Bernhard O. ; Caulfield, Mark J. ; Chasman, Daniel I. ; Davidson, Karina W. ; Doevendans, Pieter A. ; FitzGerald, Garret A. ; Gums, John G. ; Hakonarson, Hakon ; Hillege, Hans L. ; Illig, Thomas ; Jarvik, Gail P. ; Johnson, Julie A. ; Kastelein, John J.P. ; Koenig, Wolfgang ; Study, Life Lines Cohort ; März, Winfried ; Mitchell, Braxton D. ; Murray, Sarah S. ; Oldehinkel, Albertine J. ; Rader, Daniel J. ; Reilly, Muredach P. ; Reiner, Alex P. ; Schadt, Eric E. ; Silverstein, Roy L. ; Snieder, Harold ; Stanton, Alice V. ; Uitterlinden, André G. ; van der Harst, Pim ; van der Schouw, Yvonne T. ; Samani, Nilesh J. ; Johnson, Andrew D. ; Munroe, Patricia B. ; de Bakker, Paul I.W. ; Zhu, Xiaofeng ; Levy, Daniel ; Keating, Brendan J. ; Asselbergs, Folkert W. / Loci influencing blood pressure identified using a cardiovascular gene-centric array. In: Human Molecular Genetics. 2013 ; Vol. 22, No. 8. pp. 1663-1678.
@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.}",
year = "2013",
month = "4",
day = "1",
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.

PY - 2013/4/1

Y1 - 2013/4/1

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.

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U2 - 10.1093/hmg/dds555

DO - 10.1093/hmg/dds555

M3 - Article

VL - 22

SP - 1663

EP - 1678

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 8

ER -