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

V Tragante; MR Barnes; SK Ganesh; MB Lanktree; W Guo; N Franceschini; EN Smith; T Johnson; MV Holmes; S Padmanabhan; KJ Karczewski; B Almoguera; J Barnard; J Baumert; YPC Chang; CC Elbers; M Farrall; ME Fischer; TR Gaunt; JMIH Gho; C Gieger; A Goel; Y Gong; Aaron Isaacs; ME Kleber; IM Leach; CW McDonough; MFL Meijs; O Melander; CP Nelson; IM (Ilja) Nolte; N Pankratz; TS Price; J Shaffer; S Shah; M Tomaszewski; PJ van der Most; EPA Van Iperen; JM Vonk; K Witkowska; COL Wong; Lei Zhang; AL Beitelshees; GS Berenson; DL Bhatt; M Brown; A Burt; RM Cooper-DeHoff; JM Connell; KJ Cruickshanks; SP Curtis; G Davey-Smith; C Delles; RT Gansevoort; XQ Guo; S Haiqing; CE Hastie; MH Hofker; GK Hovingh; DS Kim; SA Kirkland; BE Klein; R Klein; YR Li; S Maiwald; C Newton-Cheh; ET O'Brien; NC Onland-Moret; W Palmas; A Parsa; BW Penninx; M Pettinger; RS Vasan; JE Ranchalis; PM Ridker; LM Rose; P Sever; D Shimbo; L Steele; RP (Ronald) Stolk; B Thorand; MD Trip; Cornelia Duijn; WM Verschuren; C Wijmenga; S Wyatt; JH Young; AH Zwinderman; CR Bezzina; E Boerwinkle; JP Casas; MJ Caulfield; A Chakravarti; DI Chasman; KW Davidson; PA Doevendans; AF Dominiczak; GA FitzGerald; JG Gums; M Fornage; H Hakonarson; I Halder; HL Hillege; T Illig; GP Jarvik; JA Johnson; JJP Kastelein; W Koenig; M Kumari; W Marz; SS Murray; JR O'Connell; AJ (A.) Oldehinkel; JS Pankow; DJ Rader; S Redline; MP Reilly; EE Schadt; K Kottke-Marchant; H Snieder; M Snyder; AV Stanton; MD Tobin; André Uitterlinden; P van der Harst; YT van der Schouw; NJ Samani; H Watkins; AD Johnson; AP Reiner; XF Zhu; PIW de Bakker; D Levy; FW Asselbergs; PB Munroe; BJ Keating

doi: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, MR Barnes, SK Ganesh, MB Lanktree, W Guo, N Franceschini, EN Smith, T Johnson, MV Holmes, S Padmanabhan, KJ Karczewski, B Almoguera, J Barnard, J Baumert, YPC Chang, CC Elbers, M Farrall, ME Fischer, TR Gaunt, JMIH GhoC Gieger, A Goel, Y Gong, Aaron Isaacs, ME Kleber, IM Leach, CW McDonough, MFL Meijs, O Melander, CP Nelson, IM (Ilja) Nolte, N Pankratz, TS Price, J Shaffer, S Shah, M Tomaszewski, PJ van der Most, EPA Van Iperen, JM Vonk, K Witkowska, COL Wong, Lei Zhang, AL Beitelshees, GS Berenson, DL Bhatt, M Brown, A Burt, RM Cooper-DeHoff, JM Connell, KJ Cruickshanks, SP Curtis, G Davey-Smith, C Delles, RT Gansevoort, XQ Guo, S Haiqing, CE Hastie, MH Hofker, GK Hovingh, DS Kim, SA Kirkland, BE Klein, R Klein, YR Li, S Maiwald, C Newton-Cheh, ET O'Brien, NC Onland-Moret, W Palmas, A Parsa, BW Penninx, M Pettinger, RS Vasan, JE Ranchalis, PM Ridker, LM Rose, P Sever, D Shimbo, L Steele, RP (Ronald) Stolk, B Thorand, MD Trip, Cornelia Duijn, WM Verschuren, C Wijmenga, S Wyatt, JH Young, AH Zwinderman, CR Bezzina, E Boerwinkle, JP Casas, MJ Caulfield, A Chakravarti, DI Chasman, KW Davidson, PA Doevendans, AF Dominiczak, GA FitzGerald, JG Gums, M Fornage, H Hakonarson, I Halder, HL Hillege, T Illig, GP Jarvik, JA Johnson, JJP Kastelein, W Koenig, M Kumari, W Marz, SS Murray, JR O'Connell, AJ (A.) Oldehinkel, JS Pankow, DJ Rader, S Redline, MP Reilly, EE Schadt, K Kottke-Marchant, H Snieder, M Snyder, AV Stanton, MD Tobin, André Uitterlinden, P van der Harst, YT van der Schouw, NJ Samani, H Watkins, AD Johnson, AP Reiner, XF Zhu, PIW de Bakker, D Levy, FW Asselbergs, PB Munroe, BJ Keating

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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 similar to 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 x 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	Undefined/Unknown
Pages (from-to)	349-360
Number of pages	12
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

Research programs

EMC MM-01-39-09-A
EMC NIHES-01-64-02

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This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ajhg.2013.12.016

Cite this

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., ... Keating, BJ. (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

@article{4769f666c6014c89acfdf63128b54604,

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 similar to 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 x 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 MR Barnes and SK Ganesh and MB Lanktree and W Guo and N Franceschini and EN Smith and T Johnson and MV Holmes and S Padmanabhan and KJ Karczewski and B Almoguera and J Barnard and J Baumert and YPC Chang and CC Elbers and M Farrall and ME Fischer and TR Gaunt and JMIH Gho and C Gieger and A Goel and Y Gong and Aaron Isaacs and ME Kleber and IM Leach and CW McDonough and MFL Meijs and O Melander and CP Nelson and Nolte, {IM (Ilja)} and N Pankratz and TS Price and J Shaffer and S Shah and M Tomaszewski and {van der Most}, PJ and {Van Iperen}, EPA and JM Vonk and K Witkowska and COL Wong and Lei Zhang and AL Beitelshees and GS Berenson and DL Bhatt and M Brown and A Burt and RM Cooper-DeHoff and JM Connell and KJ Cruickshanks and SP Curtis and G Davey-Smith and C Delles and RT Gansevoort and XQ Guo and S Haiqing and CE Hastie and MH Hofker and GK Hovingh and DS Kim and SA Kirkland and BE Klein and R Klein and YR Li and S Maiwald and C Newton-Cheh and ET O'Brien and NC Onland-Moret and W Palmas and A Parsa and BW Penninx and M Pettinger and RS Vasan and JE Ranchalis and PM Ridker and LM Rose and P Sever and D Shimbo and L Steele and Stolk, {RP (Ronald)} and B Thorand and MD Trip and Cornelia Duijn and WM Verschuren and C Wijmenga and S Wyatt and JH Young and AH Zwinderman and CR Bezzina and E Boerwinkle and JP Casas and MJ Caulfield and A Chakravarti and DI Chasman and KW Davidson and PA Doevendans and AF Dominiczak and GA FitzGerald and JG Gums and M Fornage and H Hakonarson and I Halder and HL Hillege and T Illig and GP Jarvik and JA Johnson and JJP Kastelein and W Koenig and M Kumari and W Marz and SS Murray and JR O'Connell and Oldehinkel, {AJ (A.)} and JS Pankow and DJ Rader and S Redline and MP Reilly and EE Schadt and K Kottke-Marchant and H Snieder and M Snyder and AV Stanton and MD Tobin and Andr{\'e} Uitterlinden and {van der Harst}, P and {van der Schouw}, YT and NJ Samani and H Watkins and AD Johnson and AP Reiner and XF Zhu and {de Bakker}, PIW and D Levy and FW Asselbergs and PB Munroe and BJ Keating",

year = "2014",

doi = "10.1016/j.ajhg.2013.12.016",

language = "Undefined/Unknown",

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, Duijn, C, 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, Fornage, M, Hakonarson, H, Halder, I, Hillege, HL, Illig, T, Jarvik, GP, Johnson, JA, Kastelein, JJP, Koenig, W, Kumari, M, Marz, 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, A, van der Harst, P, van der Schouw, YT, Samani, NJ, Watkins, H, Johnson, AD, Reiner, AP, Zhu, XF, de Bakker, PIW, Levy, D, Asselbergs, FW, Munroe, PB & Keating, BJ 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, MR

AU - Ganesh, SK

AU - Lanktree, MB

AU - Guo, W

AU - Franceschini, N

AU - Smith, EN

AU - Johnson, T

AU - Holmes, MV

AU - Padmanabhan, S

AU - Karczewski, KJ

AU - Almoguera, B

AU - Barnard, J

AU - Baumert, J

AU - Chang, YPC

AU - Elbers, CC

AU - Farrall, M

AU - Fischer, ME

AU - Gaunt, TR

AU - Gho, JMIH

AU - Gieger, C

AU - Goel, A

AU - Gong, Y

AU - Isaacs, Aaron

AU - Kleber, ME

AU - Leach, IM

AU - McDonough, CW

AU - Meijs, MFL

AU - Melander, O

AU - Nelson, CP

AU - Nolte, IM (Ilja)

AU - Pankratz, N

AU - Price, TS

AU - Shaffer, J

AU - Shah, S

AU - Tomaszewski, M

AU - van der Most, PJ

AU - Van Iperen, EPA

AU - Vonk, JM

AU - Witkowska, K

AU - Wong, COL

AU - Zhang, Lei

AU - Beitelshees, AL

AU - Berenson, GS

AU - Bhatt, DL

AU - Brown, M

AU - Burt, A

AU - Cooper-DeHoff, RM

AU - Connell, JM

AU - Cruickshanks, KJ

AU - Curtis, SP

AU - Davey-Smith, G

AU - Delles, C

AU - Gansevoort, RT

AU - Guo, XQ

AU - Haiqing, S

AU - Hastie, CE

AU - Hofker, MH

AU - Hovingh, GK

AU - Kim, DS

AU - Kirkland, SA

AU - Klein, BE

AU - Klein, R

AU - Li, YR

AU - Maiwald, S

AU - Newton-Cheh, C

AU - O'Brien, ET

AU - Onland-Moret, NC

AU - Palmas, W

AU - Parsa, A

AU - Penninx, BW

AU - Pettinger, M

AU - Vasan, RS

AU - Ranchalis, JE

AU - Ridker, PM

AU - Rose, LM

AU - Sever, P

AU - Shimbo, D

AU - Steele, L

AU - Stolk, RP (Ronald)

AU - Thorand, B

AU - Trip, MD

AU - Duijn, Cornelia

AU - Verschuren, WM

AU - Wijmenga, C

AU - Wyatt, S

AU - Young, JH

AU - Zwinderman, AH

AU - Bezzina, CR

AU - Boerwinkle, E

AU - Casas, JP

AU - Caulfield, MJ

AU - Chakravarti, A

AU - Chasman, DI

AU - Davidson, KW

AU - Doevendans, PA

AU - Dominiczak, AF

AU - FitzGerald, GA

AU - Gums, JG

AU - Fornage, M

AU - Hakonarson, H

AU - Halder, I

AU - Hillege, HL

AU - Illig, T

AU - Jarvik, GP

AU - Johnson, JA

AU - Kastelein, JJP

AU - Koenig, W

AU - Kumari, M

AU - Marz, W

AU - Murray, SS

AU - O'Connell, JR

AU - Oldehinkel, AJ (A.)

AU - Pankow, JS

AU - Rader, DJ

AU - Redline, S

AU - Reilly, MP

AU - Schadt, EE

AU - Kottke-Marchant, K

AU - Snieder, H

AU - Snyder, M

AU - Stanton, AV

AU - Tobin, MD

AU - Uitterlinden, André

AU - van der Harst, P

AU - van der Schouw, YT

AU - Samani, NJ

AU - Watkins, H

AU - Johnson, AD

AU - Reiner, AP

AU - Zhu, XF

AU - de Bakker, PIW

AU - Levy, D

AU - Asselbergs, FW

AU - Munroe, PB

AU - Keating, BJ

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 similar to 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 x 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 similar to 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 x 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 - 10.1016/j.ajhg.2013.12.016

DO - 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 -