Gene-centric Meta-analysis in 87,736 Individuals of European Ancestry Identifies Multiple Blood-Pressure-Related Loci

V. Tragante; M.R. Barnes; S.K. Ganesh; M.B. Lanktree; W. Guo; N. Franceschini; E.N. Smith; T. Johnson; M.V. Holmes; S. Padmanabhan; K.J. Karczewski; B. Almoguera; J. Barnard; J. Baumert; Y.P.C. Chang; C.C. Elbers; M. Farrall; M.E. Fischer; T.R. Gaunt; J.M.I.H. Gho; C. Gieger; A. Goel; Y. Gong; A. Isaacs; M.E. Kleber; I.M. Leach; C.W. McDonough; M.F.L. Meijs; O. Melander; C.P. Nelson; I.M. Nolte; N. Pankratz; T.S. Price; J. Shaffer; S. Shah; M. Tomaszewski; P.J. van der Most; E.P.A. van Iperen; J.M. Vonk; K. Witkowska; C.O.L. Wong; L. Zhang; A.L. Beitelshees; G.S. Berenson; D.L. Bhatt; M. Brown; A. Burt; R.M. Cooper-DeHoff; J.M. Connell; K.J. Cruickshanks; S.P. Curtis; G. Davey-Smith; C. Delles; R.T. Gansevoort; X.Q. Guo; S. Haiqing; C.E. Hastie; M.H. Hofker; G.K. Hovingh; D.S. Kim; S.A. Kirkland; B.E. Klein; R. Klein; Y.R. Li; S. Maiwald; C. Newton-Cheh; E.T. O'Brien; N.C. Onland-Moret; W. Palmas; A. Parsa; B.W. Penninx; M. Pettinger; R.S. Vasan; J.E. Ranchalis; P.M. Ridker; L.M. Rose; P. Sever; D. Shimbo; L. Steele; R.P Stolk; B. Thorand; M.D. Trip; C.M. van Duijn; W.M. Verschuren; C. Wijmenga; S. Wyatt; J.H. Young; A.H. Zwinderman; C.R. Bezzina; E. Boerwinkle; J.P. Casas; M.J. Caulfield; A. Chakravarti; D.I. Chasman; K.W. Davidson; P.A. Doevendans; A.F. Dominiczak; G.A. FitzGerald; J.G. Gums; P.B. Munroe; B.J. Keating; Myriam Fornage; Hakon Hakonarson; Indrani Halder; Hans L. Hillege; Thomas Illig; Gail P. Jarvik; Julie A. Johnson; John J. P. Kastelein; Wolfgang Koenig; Meena Kumari; Winfried März; Sarah S. Murray; Jeffery R. O'Connell; Albertine J. Oldehinkel; James S. Pankow; Daniel J. Rader; Susan Redline; Muredach P. Reilly; Eric E. Schadt; Kandice Kottke-Marchant; Harold Snieder; Michael Snyder; Alice V. Stanton; Martin D. Tobin; André G. Uitterlinden; Pim van der Harst; Yvonne T. van der Schouw; Nilesh J. Samani; Hugh Watkins; Andrew D. Johnson; Alex P. Reiner; Xiaofeng Zhu; Paul I. W. de Bakker; Daniel Levy; Folkert W. Asselbergs

doi:https://doi.org/10.1016/j.ajhg.2013.12.016

Gene-centric Meta-analysis in 87,736 Individuals of European Ancestry Identifies Multiple Blood-Pressure-Related Loci

V. Tragante, M.R. Barnes, S.K. Ganesh, M.B. Lanktree, W. Guo, N. Franceschini, E.N. Smith, T. Johnson, M.V. Holmes, S. Padmanabhan, K.J. Karczewski, B. Almoguera, J. Barnard, J. Baumert, Y.P.C. Chang, C.C. Elbers, M. Farrall, M.E. Fischer, T.R. Gaunt, J.M.I.H. GhoC. Gieger, A. Goel, Y. Gong, A. Isaacs, M.E. Kleber, I.M. Leach, C.W. McDonough, M.F.L. Meijs, O. Melander, C.P. Nelson, I.M. Nolte, N. Pankratz, T.S. Price, J. Shaffer, S. Shah, M. Tomaszewski, P.J. van der Most, E.P.A. van Iperen, J.M. Vonk, K. Witkowska, C.O.L. Wong, L. Zhang, A.L. Beitelshees, G.S. Berenson, D.L. Bhatt, M. Brown, A. Burt, R.M. Cooper-DeHoff, J.M. Connell, K.J. Cruickshanks, S.P. Curtis, G. Davey-Smith, C. Delles, R.T. Gansevoort, X.Q. Guo, S. Haiqing, C.E. Hastie, M.H. Hofker, G.K. Hovingh, D.S. Kim, S.A. Kirkland, B.E. Klein, R. Klein, Y.R. Li, S. Maiwald, C. Newton-Cheh, E.T. O'Brien, N.C. Onland-Moret, W. Palmas, A. Parsa, B.W. Penninx, M. Pettinger, R.S. Vasan, J.E. Ranchalis, P.M. Ridker, L.M. Rose, P. Sever, D. Shimbo, L. Steele, R.P Stolk, B. Thorand, M.D. Trip, C.M. van Duijn, W.M. Verschuren, C. Wijmenga, S. Wyatt, J.H. Young, A.H. Zwinderman, C.R. Bezzina, E. Boerwinkle, J.P. Casas, M.J. Caulfield, A. Chakravarti, D.I. Chasman, K.W. Davidson, P.A. Doevendans, A.F. Dominiczak, G.A. FitzGerald, J.G. Gums, P.B. Munroe, B.J. Keating, Myriam Fornage, Hakon Hakonarson, Indrani Halder, Hans L. Hillege, Thomas Illig, Gail P. Jarvik, Julie A. Johnson, John J. P. Kastelein, Wolfgang Koenig, Meena Kumari, Winfried März, Sarah S. Murray, Jeffery R. O'Connell, Albertine J. Oldehinkel, James S. Pankow, Daniel J. Rader, Susan Redline, Muredach P. Reilly, Eric E. Schadt, Kandice Kottke-Marchant, Harold Snieder, Michael Snyder, Alice V. Stanton, Martin D. Tobin, André G. Uitterlinden, Pim van der Harst, Yvonne T. van der Schouw, Nilesh J. Samani, Hugh Watkins, Andrew D. Johnson, Alex P. Reiner, Xiaofeng Zhu, Paul I. W. de Bakker, Daniel Levy, Folkert W. Asselbergs

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

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Abstract

Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ~50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification

Original language	English
Pages (from-to)	349-360
Journal	American journal of human genetics
Volume	94
Issue number	3
DOIs	https://doi.org/10.1016/j.ajhg.2013.12.016
Publication status	Published - 2014

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Cite this

Tragante, V., Barnes, M. R., Ganesh, S. K., Lanktree, M. B., Guo, W., Franceschini, N., Smith, E. N., Johnson, T., Holmes, M. V., Padmanabhan, S., Karczewski, K. J., Almoguera, B., Barnard, J., Baumert, J., Chang, Y. P. C., Elbers, C. C., Farrall, M., Fischer, M. E., Gaunt, T. R., ... Asselbergs, F. W. (2014). Gene-centric Meta-analysis in 87,736 Individuals of European Ancestry Identifies Multiple Blood-Pressure-Related Loci. American journal of human genetics, 94(3), 349-360. https://doi.org/10.1016/j.ajhg.2013.12.016

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title = "Gene-centric Meta-analysis in 87,736 Individuals of European Ancestry Identifies Multiple Blood-Pressure-Related Loci",

abstract = "Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ~50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification",

author = "V. Tragante and M.R. Barnes and S.K. Ganesh and M.B. Lanktree and W. Guo and N. Franceschini and E.N. Smith and T. Johnson and M.V. Holmes and S. Padmanabhan and K.J. Karczewski and B. Almoguera and J. Barnard and J. Baumert and Y.P.C. Chang and C.C. Elbers and M. Farrall and M.E. Fischer and T.R. Gaunt and J.M.I.H. Gho and C. Gieger and A. Goel and Y. Gong and A. Isaacs and M.E. Kleber and I.M. Leach and C.W. McDonough and M.F.L. Meijs and O. Melander and C.P. Nelson and I.M. Nolte and N. Pankratz and T.S. Price and J. Shaffer and S. Shah and M. Tomaszewski and {van der Most}, P.J. and {van Iperen}, E.P.A. and J.M. Vonk and K. Witkowska and C.O.L. Wong and L. Zhang and A.L. Beitelshees and G.S. Berenson and D.L. Bhatt and M. Brown and A. Burt and R.M. Cooper-DeHoff and J.M. Connell and K.J. Cruickshanks and S.P. Curtis and G. Davey-Smith and C. Delles and R.T. Gansevoort and X.Q. Guo and S. Haiqing and C.E. Hastie and M.H. Hofker and G.K. Hovingh and D.S. Kim and S.A. Kirkland and B.E. Klein and R. Klein and Y.R. Li and S. Maiwald and C. Newton-Cheh and E.T. O'Brien and N.C. Onland-Moret and W. Palmas and A. Parsa and B.W. Penninx and M. Pettinger and R.S. Vasan and J.E. Ranchalis and P.M. Ridker and L.M. Rose and P. Sever and D. Shimbo and L. Steele and R.P Stolk and B. Thorand and M.D. Trip and {van Duijn}, C.M. and W.M. Verschuren and C. Wijmenga and S. Wyatt and J.H. Young and A.H. Zwinderman and C.R. Bezzina and E. Boerwinkle and J.P. Casas and M.J. Caulfield and A. Chakravarti and D.I. Chasman and K.W. Davidson and P.A. Doevendans and A.F. Dominiczak and G.A. FitzGerald and J.G. Gums and P.B. Munroe and B.J. Keating and Myriam Fornage and Hakon Hakonarson and Indrani Halder and Hillege, {Hans L.} and Thomas Illig and Jarvik, {Gail P.} and Johnson, {Julie A.} and Kastelein, {John J. P.} and Wolfgang Koenig and Meena Kumari and Winfried M{\"a}rz and Murray, {Sarah S.} and O'Connell, {Jeffery R.} and Oldehinkel, {Albertine J.} and Pankow, {James S.} and Rader, {Daniel J.} and Susan Redline and Reilly, {Muredach P.} and Schadt, {Eric E.} and Kandice Kottke-Marchant and Harold Snieder and Michael Snyder and Stanton, {Alice V.} and Tobin, {Martin D.} and Uitterlinden, {Andr{\'e} G.} and {van der Harst}, Pim and {van der Schouw}, {Yvonne T.} and Samani, {Nilesh J.} and Hugh Watkins and Johnson, {Andrew D.} and Reiner, {Alex P.} and Xiaofeng Zhu and {de Bakker}, {Paul I. W.} and Daniel Levy and Asselbergs, {Folkert W.}",

year = "2014",

doi = "https://doi.org/10.1016/j.ajhg.2013.12.016",

language = "English",

volume = "94",

pages = "349--360",

journal = "American journal of human genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "3",

}

Tragante, V, Barnes, MR, Ganesh, SK, Lanktree, MB, Guo, W, Franceschini, N, Smith, EN, Johnson, T, Holmes, MV, Padmanabhan, S, Karczewski, KJ, Almoguera, B, Barnard, J, Baumert, J, Chang, YPC, Elbers, CC, Farrall, M, Fischer, ME, Gaunt, TR, Gho, JMIH, Gieger, C, Goel, A, Gong, Y, Isaacs, A, Kleber, ME, Leach, IM, McDonough, CW, Meijs, MFL, Melander, O, Nelson, CP, Nolte, IM, Pankratz, N, Price, TS, Shaffer, J, Shah, S, Tomaszewski, M, van der Most, PJ, van Iperen, EPA, Vonk, JM, Witkowska, K, Wong, COL, Zhang, L, Beitelshees, AL, Berenson, GS, Bhatt, DL, Brown, M, Burt, A, Cooper-DeHoff, RM, Connell, JM, Cruickshanks, KJ, Curtis, SP, Davey-Smith, G, Delles, C, Gansevoort, RT, Guo, XQ, Haiqing, S, Hastie, CE, Hofker, MH, Hovingh, GK, Kim, DS, Kirkland, SA, Klein, BE, Klein, R, Li, YR, Maiwald, S, Newton-Cheh, C, O'Brien, ET, Onland-Moret, NC, Palmas, W, Parsa, A, Penninx, BW, Pettinger, M, Vasan, RS, Ranchalis, JE, Ridker, PM, Rose, LM, Sever, P, Shimbo, D, Steele, L, Stolk, RP, Thorand, B, Trip, MD, van Duijn, CM, Verschuren, WM, Wijmenga, C, Wyatt, S, Young, JH, Zwinderman, AH , Bezzina, CR, Boerwinkle, E, Casas, JP, Caulfield, MJ, Chakravarti, A, Chasman, DI, Davidson, KW, Doevendans, PA, Dominiczak, AF, FitzGerald, GA, Gums, JG, Munroe, PB, Keating, BJ, Fornage, M, Hakonarson, H, Halder, I, Hillege, HL, Illig, T, Jarvik, GP, Johnson, JA, Kastelein, JJP, Koenig, W, Kumari, M, März, W, Murray, SS, O'Connell, JR, Oldehinkel, AJ, Pankow, JS, Rader, DJ, Redline, S, Reilly, MP, Schadt, EE, Kottke-Marchant, K, Snieder, H, Snyder, M, Stanton, AV, Tobin, MD, Uitterlinden, AG, van der Harst, P, van der Schouw, YT, Samani, NJ, Watkins, H, Johnson, AD, Reiner, AP, Zhu, X, de Bakker, PIW, Levy, D & Asselbergs, FW 2014, 'Gene-centric Meta-analysis in 87,736 Individuals of European Ancestry Identifies Multiple Blood-Pressure-Related Loci', American journal of human genetics, vol. 94, no. 3, pp. 349-360. https://doi.org/10.1016/j.ajhg.2013.12.016

TY - JOUR

T1 - Gene-centric Meta-analysis in 87,736 Individuals of European Ancestry Identifies Multiple Blood-Pressure-Related Loci

AU - Tragante, V.

AU - Barnes, M.R.

AU - Ganesh, S.K.

AU - Lanktree, M.B.

AU - Guo, W.

AU - Franceschini, N.

AU - Smith, E.N.

AU - Johnson, T.

AU - Holmes, M.V.

AU - Padmanabhan, S.

AU - Karczewski, K.J.

AU - Almoguera, B.

AU - Barnard, J.

AU - Baumert, J.

AU - Chang, Y.P.C.

AU - Elbers, C.C.

AU - Farrall, M.

AU - Fischer, M.E.

AU - Gaunt, T.R.

AU - Gho, J.M.I.H.

AU - Gieger, C.

AU - Goel, A.

AU - Gong, Y.

AU - Isaacs, A.

AU - Kleber, M.E.

AU - Leach, I.M.

AU - McDonough, C.W.

AU - Meijs, M.F.L.

AU - Melander, O.

AU - Nelson, C.P.

AU - Nolte, I.M.

AU - Pankratz, N.

AU - Price, T.S.

AU - Shaffer, J.

AU - Shah, S.

AU - Tomaszewski, M.

AU - van der Most, P.J.

AU - van Iperen, E.P.A.

AU - Vonk, J.M.

AU - Witkowska, K.

AU - Wong, C.O.L.

AU - Zhang, L.

AU - Beitelshees, A.L.

AU - Berenson, G.S.

AU - Bhatt, D.L.

AU - Brown, M.

AU - Burt, A.

AU - Cooper-DeHoff, R.M.

AU - Connell, J.M.

AU - Cruickshanks, K.J.

AU - Curtis, S.P.

AU - Davey-Smith, G.

AU - Delles, C.

AU - Gansevoort, R.T.

AU - Guo, X.Q.

AU - Haiqing, S.

AU - Hastie, C.E.

AU - Hofker, M.H.

AU - Hovingh, G.K.

AU - Kim, D.S.

AU - Kirkland, S.A.

AU - Klein, B.E.

AU - Klein, R.

AU - Li, Y.R.

AU - Maiwald, S.

AU - Newton-Cheh, C.

AU - O'Brien, E.T.

AU - Onland-Moret, N.C.

AU - Palmas, W.

AU - Parsa, A.

AU - Penninx, B.W.

AU - Pettinger, M.

AU - Vasan, R.S.

AU - Ranchalis, J.E.

AU - Ridker, P.M.

AU - Rose, L.M.

AU - Sever, P.

AU - Shimbo, D.

AU - Steele, L.

AU - Stolk, R.P

AU - Thorand, B.

AU - Trip, M.D.

AU - van Duijn, C.M.

AU - Verschuren, W.M.

AU - Wijmenga, C.

AU - Wyatt, S.

AU - Young, J.H.

AU - Zwinderman, A.H.

AU - Bezzina, C.R.

AU - Boerwinkle, E.

AU - Casas, J.P.

AU - Caulfield, M.J.

AU - Chakravarti, A.

AU - Chasman, D.I.

AU - Davidson, K.W.

AU - Doevendans, P.A.

AU - Dominiczak, A.F.

AU - FitzGerald, G.A.

AU - Gums, J.G.

AU - Munroe, P.B.

AU - Keating, B.J.

AU - Fornage, Myriam

AU - Hakonarson, Hakon

AU - Halder, Indrani

AU - Hillege, Hans L.

AU - Illig, Thomas

AU - Jarvik, Gail P.

AU - Johnson, Julie A.

AU - Kastelein, John J. P.

AU - Koenig, Wolfgang

AU - Kumari, Meena

AU - März, Winfried

AU - Murray, Sarah S.

AU - O'Connell, Jeffery R.

AU - Oldehinkel, Albertine J.

AU - Pankow, James S.

AU - Rader, Daniel J.

AU - Redline, Susan

AU - Reilly, Muredach P.

AU - Schadt, Eric E.

AU - Kottke-Marchant, Kandice

AU - Snieder, Harold

AU - Snyder, Michael

AU - Stanton, Alice V.

AU - Tobin, Martin D.

AU - Uitterlinden, André G.

AU - van der Harst, Pim

AU - van der Schouw, Yvonne T.

AU - Samani, Nilesh J.

AU - Watkins, Hugh

AU - Johnson, Andrew D.

AU - Reiner, Alex P.

AU - Zhu, Xiaofeng

AU - de Bakker, Paul I. W.

AU - Levy, Daniel

AU - Asselbergs, Folkert W.

PY - 2014

Y1 - 2014

N2 - Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ~50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification

AB - Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ~50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification

U2 - https://doi.org/10.1016/j.ajhg.2013.12.016

DO - https://doi.org/10.1016/j.ajhg.2013.12.016

M3 - Article

C2 - 24560520

SN - 0002-9297

VL - 94

SP - 349

EP - 360

JO - American journal of human genetics

JF - American journal of human genetics

IS - 3

ER -