The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

CHARGE-EchoGen Consortium; CHARGE-HF Consortium; Wellcome Trust Case Control Consortium; Georg B. Ehret; Teresa Ferreira; Daniel I. Chasman; Anne U. Jackson; Ellen M. Schmidt; Toby Johnson; Gudmar Thorleifsson; Jian'an Luan; Louise A. Donnelly; Stavroula Kanoni; Ann-Kristin Petersen; Vasyl Pihur; Rona J. Strawbridge; Dmitry Shungin; Maria F. Hughes; Osorio Meirelles; Marika Kaakinen; Nabila Bouatia-Naji; Kati Kristiansson; Sonia Shah; Marcus E. Kleber; Xiuqing Guo; Leo-Pekka Lyytikäinen; Cristiano Fava; Niclas Eriksson; Ilja M. Nolte; Patrik K. Magnusson; Elias L. Salfati; Loukianos S. Rallidis; Elizabeth Theusch; Andrew J. P. Smith; Lasse Folkersen; Kate Witkowska; Tune H. Pers; Roby Joehanes; Stuart K. Kim; Lazaros Lataniotis; Rick Jansen; Andrew D. Johnson; Helen Warren; Young Jin Kim; Wei Zhao; Ying Wu; Bamidele O. Tayo; Murielle Bochud; Devin Absher; John M. Connell; Alex S. F. Doney; Andrew D. Morris; Colin N. A. Palmer; Christopher Newton-Cheh; Patricia B. Munroe

doi:10.1038/ng.3667

The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

CHARGE-EchoGen Consortium, CHARGE-HF Consortium, Wellcome Trust Case Control Consortium, Georg B. Ehret, Teresa Ferreira, Daniel I. Chasman, Anne U. Jackson, Ellen M. Schmidt, Toby Johnson, Gudmar Thorleifsson, Jian'an Luan, Louise A. Donnelly, Stavroula Kanoni, Ann-Kristin Petersen, Vasyl Pihur, Rona J. Strawbridge, Dmitry Shungin, Maria F. Hughes, Osorio Meirelles, Marika KaakinenNabila Bouatia-Naji, Kati Kristiansson, Sonia Shah, Marcus E. Kleber, Xiuqing Guo, Leo-Pekka Lyytikäinen, Cristiano Fava, Niclas Eriksson, Ilja M. Nolte, Patrik K. Magnusson, Elias L. Salfati, Loukianos S. Rallidis, Elizabeth Theusch, Andrew J. P. Smith, Lasse Folkersen, Kate Witkowska, Tune H. Pers, Roby Joehanes, Stuart K. Kim, Lazaros Lataniotis, Rick Jansen, Andrew D. Johnson, Helen Warren, Young Jin Kim, Wei Zhao, Ying Wu, Bamidele O. Tayo, Murielle Bochud, Devin Absher, John M. Connell, Alex S. F. Doney, Andrew D. Morris, Colin N. A. Palmer, Christopher Newton-Cheh (Lead / Corresponding author), Patricia B. Munroe (Lead / Corresponding author)

Population Health and Genomics

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317 Citations (Scopus)

Abstract

To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.

Original language	English
Pages (from-to)	1171-1184
Number of pages	16
Journal	Nature Genetics
Volume	48
Early online date	12 Sept 2016
DOIs	https://doi.org/10.1038/ng.3667
Publication status	Published - Oct 2016

Keywords

Genome-wide association studies
Hypertension

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10.1038/ng.3667

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CHARGE-EchoGen Consortium, CHARGE-HF Consortium, Wellcome Trust Case Control Consortium, Ehret, G. B., Ferreira, T., Chasman, D. I., Jackson, A. U., Schmidt, E. M., Johnson, T., Thorleifsson, G., Luan, J., Donnelly, L. A., Kanoni, S., Petersen, A.-K., Pihur, V., Strawbridge, R. J., Shungin, D., Hughes, M. F., Meirelles, O., ... Munroe, P. B. (2016). The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals. Nature Genetics, 48, 1171-1184. https://doi.org/10.1038/ng.3667

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title = "The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals",

abstract = "To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.",

keywords = "Genome-wide association studies, Hypertension",

author = "{CHARGE-EchoGen Consortium} and {CHARGE-HF Consortium} and {Wellcome Trust Case Control Consortium} and Ehret, {Georg B.} and Teresa Ferreira and Chasman, {Daniel I.} and Jackson, {Anne U.} and Schmidt, {Ellen M.} and Toby Johnson and Gudmar Thorleifsson and Jian'an Luan and Donnelly, {Louise A.} and Stavroula Kanoni and Ann-Kristin Petersen and Vasyl Pihur and Strawbridge, {Rona J.} and Dmitry Shungin and Hughes, {Maria F.} and Osorio Meirelles and Marika Kaakinen and Nabila Bouatia-Naji and Kati Kristiansson and Sonia Shah and Kleber, {Marcus E.} and Xiuqing Guo and Leo-Pekka Lyytik{\"a}inen and Cristiano Fava and Niclas Eriksson and Nolte, {Ilja M.} and Magnusson, {Patrik K.} and Salfati, {Elias L.} and Rallidis, {Loukianos S.} and Elizabeth Theusch and Smith, {Andrew J. P.} and Lasse Folkersen and Kate Witkowska and Pers, {Tune H.} and Roby Joehanes and Kim, {Stuart K.} and Lazaros Lataniotis and Rick Jansen and Johnson, {Andrew D.} and Helen Warren and Kim, {Young Jin} and Wei Zhao and Ying Wu and Tayo, {Bamidele O.} and Murielle Bochud and Devin Absher and Connell, {John M.} and Doney, {Alex S. F.} and Morris, {Andrew D.} and Palmer, {Colin N. A.} and Christopher Newton-Cheh and Munroe, {Patricia B.}",

year = "2016",

month = oct,

doi = "10.1038/ng.3667",

language = "English",

volume = "48",

pages = "1171--1184",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

}

CHARGE-EchoGen Consortium, CHARGE-HF Consortium, Wellcome Trust Case Control Consortium, Ehret, GB, Ferreira, T, Chasman, DI, Jackson, AU, Schmidt, EM, Johnson, T, Thorleifsson, G, Luan, J, Donnelly, LA, Kanoni, S, Petersen, A-K, Pihur, V, Strawbridge, RJ, Shungin, D, Hughes, MF, Meirelles, O, Kaakinen, M, Bouatia-Naji, N, Kristiansson, K, Shah, S, Kleber, ME, Guo, X, Lyytikäinen, L-P, Fava, C, Eriksson, N, Nolte, IM, Magnusson, PK, Salfati, EL, Rallidis, LS, Theusch, E, Smith, AJP, Folkersen, L, Witkowska, K, Pers, TH, Joehanes, R, Kim, SK, Lataniotis, L, Jansen, R, Johnson, AD, Warren, H, Kim, YJ, Zhao, W, Wu, Y, Tayo, BO, Bochud, M, Absher, D, Connell, JM, Doney, ASF, Morris, AD, Palmer, CNA, Newton-Cheh, C & Munroe, PB 2016, 'The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals', Nature Genetics, vol. 48, pp. 1171-1184. https://doi.org/10.1038/ng.3667

TY - JOUR

T1 - The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

AU - CHARGE-EchoGen Consortium

AU - CHARGE-HF Consortium

AU - Wellcome Trust Case Control Consortium

AU - Ehret, Georg B.

AU - Ferreira, Teresa

AU - Chasman, Daniel I.

AU - Jackson, Anne U.

AU - Schmidt, Ellen M.

AU - Johnson, Toby

AU - Thorleifsson, Gudmar

AU - Luan, Jian'an

AU - Donnelly, Louise A.

AU - Kanoni, Stavroula

AU - Petersen, Ann-Kristin

AU - Pihur, Vasyl

AU - Strawbridge, Rona J.

AU - Shungin, Dmitry

AU - Hughes, Maria F.

AU - Meirelles, Osorio

AU - Kaakinen, Marika

AU - Bouatia-Naji, Nabila

AU - Kristiansson, Kati

AU - Shah, Sonia

AU - Kleber, Marcus E.

AU - Guo, Xiuqing

AU - Lyytikäinen, Leo-Pekka

AU - Fava, Cristiano

AU - Eriksson, Niclas

AU - Nolte, Ilja M.

AU - Magnusson, Patrik K.

AU - Salfati, Elias L.

AU - Rallidis, Loukianos S.

AU - Theusch, Elizabeth

AU - Smith, Andrew J. P.

AU - Folkersen, Lasse

AU - Witkowska, Kate

AU - Pers, Tune H.

AU - Joehanes, Roby

AU - Kim, Stuart K.

AU - Lataniotis, Lazaros

AU - Jansen, Rick

AU - Johnson, Andrew D.

AU - Warren, Helen

AU - Kim, Young Jin

AU - Zhao, Wei

AU - Wu, Ying

AU - Tayo, Bamidele O.

AU - Bochud, Murielle

AU - Absher, Devin

AU - Connell, John M.

AU - Doney, Alex S. F.

AU - Morris, Andrew D.

AU - Palmer, Colin N. A.

AU - Newton-Cheh, Christopher

AU - Munroe, Patricia B.

PY - 2016/10

Y1 - 2016/10

N2 - To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.

AB - To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.

KW - Genome-wide association studies

KW - Hypertension

UR - https://ora.ox.ac.uk/objects/uuid:af680707-f9c2-44b5-9be6-9db160a9ba5d

U2 - 10.1038/ng.3667

DO - 10.1038/ng.3667

M3 - Article

C2 - 27618452

SN - 1061-4036

VL - 48

SP - 1171

EP - 1184

JO - Nature Genetics

JF - Nature Genetics

ER -

The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

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Keywords

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Palmer, Colin

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The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

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