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

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; Fotios Drenos; John D Eicher; Alun Evans; Steven C Hunt; Yun Kyoung Kim; Mika Kivimaki; Diana Kuh; Li Lin; Martin D Tobin; Louise V Wain; James F Wilson; Richard S Cooper; Andrew Wong; Meena Kumari; Colin N A Palmer; CHARGE-EchoGen Consortium

doi:10.1038/ng.3667

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

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 ShahMarcus 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, Fotios Drenos, John D Eicher, Alun Evans, Steven C Hunt, Yun Kyoung Kim, Mika Kivimaki, Diana Kuh, Li Lin, Martin D Tobin, Louise V Wain, James F Wilson, Richard S Cooper, Andrew Wong, Meena Kumari, Colin N A Palmer, CHARGE-EchoGen Consortium

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

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	14
Journal	Nature Genetics
Volume	48
Issue number	10
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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MRC UoB UNITE Unit - programme 3
Timpson, N. J. (Principal Investigator) & Timpson, N. J. (Principal Investigator)
1/06/13 → 31/03/18
Project: Research
MRC UoB UNITE Unit - Programme 5
Lawlor, D. A. (Principal Investigator) & Lawlor, D. A. (Principal Investigator)
1/06/13 → 31/03/18
Project: Research
CENTRE FOR CASUAL ANALYSES IN TRANSLATIONAL EPIDEMIOLOGY (CAiTE)
Davey Smith, G. (Principal Investigator)
1/09/07 → 1/09/13
Project: Research

Cite this

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., Kaakinen, M., Bouatia-Naji, N., Kristiansson, K., ... CHARGE-EchoGen Consortium (2016). The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals. Nature Genetics, 48(10), 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 = "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 Fotios Drenos and Eicher, {John D} and Alun Evans and Hunt, {Steven C} and Kim, {Yun Kyoung} and Mika Kivimaki and Diana Kuh and Li Lin and Tobin, {Martin D} and Wain, {Louise V} and Wilson, {James F} and Cooper, {Richard S} and Andrew Wong and Meena Kumari and Palmer, {Colin N A} and {CHARGE-EchoGen Consortium}",

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doi = "10.1038/ng.3667",

language = "English",

volume = "48",

pages = "1171--1184",

journal = "Nature Genetics",

issn = "1061-4036",

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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, Drenos, F, Eicher, JD, Evans, A, Hunt, SC, Kim, YK, Kivimaki, M, Kuh, D, Lin, L, Tobin, MD, Wain, LV, Wilson, JF, Cooper, RS, Wong, A, Kumari, M, Palmer, CNA & CHARGE-EchoGen Consortium 2016, 'The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals', Nature Genetics, vol. 48, no. 10, 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 - 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 - Drenos, Fotios

AU - Eicher, John D

AU - Evans, Alun

AU - Hunt, Steven C

AU - Kim, Yun Kyoung

AU - Kivimaki, Mika

AU - Kuh, Diana

AU - Lin, Li

AU - Tobin, Martin D

AU - Wain, Louise V

AU - Wilson, James F

AU - Cooper, Richard S

AU - Wong, Andrew

AU - Kumari, Meena

AU - Palmer, Colin N A

AU - CHARGE-EchoGen Consortium

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

U2 - 10.1038/ng.3667

DO - 10.1038/ng.3667

M3 - Article (Academic Journal)

C2 - 27618452

SN - 1061-4036

VL - 48

SP - 1171

EP - 1184

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

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

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MRC UoB UNITE Unit - programme 3

MRC UoB UNITE Unit - Programme 5

CENTRE FOR CASUAL ANALYSES IN TRANSLATIONAL EPIDEMIOLOGY (CAiTE)

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