Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk

Helen R Warren, Evangelos Evangelou, Claudia P Cabrera, He Gao, Meixia Ren, Borbala Mifsud, Ioanna Ntalla, Praveen Surendran, Chunyu Liu, James P Cook, Aldi T Kraja, Fotios Drenos, Marie Loh, Niek Verweij, Jonathan Marten, Ibrahim Karaman, Marcelo P Segura Lepe, Paul F O'Reilly, Joanne Knight, Harold Snieder & 35 others Norihiro Kato, Jiang He, E Shyong Tai, M Abdullah Said, David Porteous, Maris Alver, Neil Poulter, Martin Farrall, Ron T Gansevoort, Sandosh Padmanabhan, Reedik Mägi, Alice Stanton, John Connell, Stephan J L Bakker, Andres Metspalu, Denis C Shields, Simon Thom, Morris Brown, Peter Sever, Tõnu Esko, Caroline Hayward, Pim van der Harst, Danish Saleheen, Rajiv Chowdhury, John C Chambers, Daniel I Chasman, Aravinda Chakravarti, The International Consortium of Blood Pressure (ICBP) 1000G Analyses, The CHD Exome+ Consortium, The ExomeBP Consortium, The T2D-GENES Consortium, The GoT2DGenes Consortium, The Cohorts for Heart and Ageing Research in Genome Epidemiology (CHARGE) BP Exome Consortium, The International Genomics of Blood Pressure (iGEN-BP) Consortium, The UK Biobank CardioMetabolic Consortium BP working group

Research output: Contribution to journalArticle

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Abstract

Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk.

Original languageEnglish
Pages (from-to)403-415
Number of pages16
JournalNature Genetics
Volume49
Issue number3
Early online date30 Jan 2017
DOIs
Publication statusPublished - Jan 2017

Fingerprint

Genome-Wide Association Study
Blood Pressure
Cardiovascular Diseases
Precision Medicine
Computer Simulation
Blood Vessels
Life Style
Hypertension
Genes

Keywords

  • Genome-wide association studies
  • Hypertension

Cite this

Warren, H. R., Evangelou, E., Cabrera, C. P., Gao, H., Ren, M., Mifsud, B., ... The UK Biobank CardioMetabolic Consortium BP working group (2017). Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk. Nature Genetics, 49(3), 403-415. https://doi.org/10.1038/ng.3768
Warren, Helen R ; Evangelou, Evangelos ; Cabrera, Claudia P ; Gao, He ; Ren, Meixia ; Mifsud, Borbala ; Ntalla, Ioanna ; Surendran, Praveen ; Liu, Chunyu ; Cook, James P ; Kraja, Aldi T ; Drenos, Fotios ; Loh, Marie ; Verweij, Niek ; Marten, Jonathan ; Karaman, Ibrahim ; Lepe, Marcelo P Segura ; O'Reilly, Paul F ; Knight, Joanne ; Snieder, Harold ; Kato, Norihiro ; He, Jiang ; Tai, E Shyong ; Said, M Abdullah ; Porteous, David ; Alver, Maris ; Poulter, Neil ; Farrall, Martin ; Gansevoort, Ron T ; Padmanabhan, Sandosh ; Mägi, Reedik ; Stanton, Alice ; Connell, John ; Bakker, Stephan J L ; Metspalu, Andres ; Shields, Denis C ; Thom, Simon ; Brown, Morris ; Sever, Peter ; Esko, Tõnu ; Hayward, Caroline ; van der Harst, Pim ; Saleheen, Danish ; Chowdhury, Rajiv ; Chambers, John C ; Chasman, Daniel I ; Chakravarti, Aravinda ; The International Consortium of Blood Pressure (ICBP) 1000G Analyses ; The CHD Exome+ Consortium ; The ExomeBP Consortium ; The T2D-GENES Consortium ; The GoT2DGenes Consortium ; The Cohorts for Heart and Ageing Research in Genome Epidemiology (CHARGE) BP Exome Consortium ; The International Genomics of Blood Pressure (iGEN-BP) Consortium ; The UK Biobank CardioMetabolic Consortium BP working group. / Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk. In: Nature Genetics. 2017 ; Vol. 49, No. 3. pp. 403-415.
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abstract = "Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk.",
keywords = "Genome-wide association studies , Hypertension",
author = "Warren, {Helen R} and Evangelos Evangelou and Cabrera, {Claudia P} and He Gao and Meixia Ren and Borbala Mifsud and Ioanna Ntalla and Praveen Surendran and Chunyu Liu and Cook, {James P} and Kraja, {Aldi T} and Fotios Drenos and Marie Loh and Niek Verweij and Jonathan Marten and Ibrahim Karaman and Lepe, {Marcelo P Segura} and O'Reilly, {Paul F} and Joanne Knight and Harold Snieder and Norihiro Kato and Jiang He and Tai, {E Shyong} and Said, {M Abdullah} and David Porteous and Maris Alver and Neil Poulter and Martin Farrall and Gansevoort, {Ron T} and Sandosh Padmanabhan and Reedik M{\"a}gi and Alice Stanton and John Connell and Bakker, {Stephan J L} and Andres Metspalu and Shields, {Denis C} and Simon Thom and Morris Brown and Peter Sever and T{\~o}nu Esko and Caroline Hayward and {van der Harst}, Pim and Danish Saleheen and Rajiv Chowdhury and Chambers, {John C} and Chasman, {Daniel I} and Aravinda Chakravarti and {The International Consortium of Blood Pressure (ICBP) 1000G Analyses} and {The CHD Exome+ Consortium} and {The ExomeBP Consortium} and {The T2D-GENES Consortium} and {The GoT2DGenes Consortium} and {The Cohorts for Heart and Ageing Research in Genome Epidemiology (CHARGE) BP Exome Consortium} and {The International Genomics of Blood Pressure (iGEN-BP) Consortium} and {The UK Biobank CardioMetabolic Consortium BP working group} and Nabi Shah and Doney, {Alex S F} and Palmer, {Colin N A}",
note = "H.R.W., C.P.C., M.R., M.R.B., P.B.M., M.B. and M.J.C. were funded by the National Institute for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Biomedical Research Unit at Barts and The London School of Medicine and Dentistry. H.G. was funded by the NIHR Imperial College Health Care NHS Trust and Imperial College London Biomedical Research Centre. M.R. was a recipient of a grant from the China Scholarship Council (2011632047). B.M. holds an MRC eMedLab Medical Bioinformatics Career Development Fellowship, funded from award MR/L016311/1. J.M.M.H. was funded by the UK Medical Research Council (G0800270), British Heart Foundation (SP/09/002), UK National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council (268834) and European Commission Framework Programme 7 (HEALTH-F2-2012-279233). B.K. holds a British Heart Foundation Personal Chair (CH/13/2/30154). N.J.S. holds a chair funded by the British Heart Foundation and is an NIHR Senior Investigator. F.D. was funded by the MRC Unit at the University of Bristol (MC_UU_12013/1-9). P. Surendran was funded by the UK Medical Research Council (G0800270). C.L. and A.K. were funded by NHLBI intramural funding. C.N.-C. was funded by the National Institutes of Health (HL113933, HL124262). P.v.d.H. was funded by ZonMw grant 90.700.441, Marie Sklodowska-Curie GF (call, H2020-MSCA-IF-2014; project ID, 661395). N.V. was supported by a Marie Sklodowska-Curie GF grant (661395) and ICIN-NHI. N.P. received funding from the UK National Institute for Health Research Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London and also from his Senior Investigator Award. P. Sever was supported by the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London. S.T. was supported by the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London. P.F.O'R. received funding from the UK Medical Research Council (MR/N015746/1) and the Wellcome Trust (109863/Z/15/Z). I.K. was supported by the EU PhenoMeNal project (Horizon 2020, 654241). A.C. was funded by the National Institutes of Health (HL128782, HL086694). M.F. was supported by a Wellcome Trust core award (090532/Z/09/Z) and the BHF Centre of Research Excellence, Oxford (RE/13/1/30181). C.H. was funded by an MRC core grant for QTL in Health and Disease programme. Some of this work used the ALICE and SPECTRE High-Performance Computing Facilities at the University of Leicester. M.J.C. is a National Institute for Health Research (NIHR) senior investigator. P.E. is a National Institute for Health Research (NIHR) senior investigator and acknowledges support from the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London, and the NIHR Health Protection Research Unit in Health Impact of Environmental Hazards (HPRU-2012-10141). As director of the MRC-PHE Centre for Environment and Health, P.E. acknowledges support from the Medical Research Council and Public Health England (MR/L01341X/1). This work used the computing resources of the UK Medical Bioinformatics partnership–aggregation, integration, visualisation and analysis of large, complex data (UK MED-BIO), which is supported by the Medical Research Council (MR/L01632X/1). This research was supported by the British Heart Foundation (grant SP/13/2/30111). Project title: Large-Scale Comprehensive Genotyping of UK Biobank for Cardiometabolic Traits and Diseases: UK CardioMetabolic Consortium (UKCMC). This research has been conducted using the UK Biobank Resource under application number 236.",
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Warren, HR, Evangelou, E, Cabrera, CP, Gao, H, Ren, M, Mifsud, B, Ntalla, I, Surendran, P, Liu, C, Cook, JP, Kraja, AT, Drenos, F, Loh, M, Verweij, N, Marten, J, Karaman, I, Lepe, MPS, O'Reilly, PF, Knight, J, Snieder, H, Kato, N, He, J, Tai, ES, Said, MA, Porteous, D, Alver, M, Poulter, N, Farrall, M, Gansevoort, RT, Padmanabhan, S, Mägi, R, Stanton, A, Connell, J, Bakker, SJL, Metspalu, A, Shields, DC, Thom, S, Brown, M, Sever, P, Esko, T, Hayward, C, van der Harst, P, Saleheen, D, Chowdhury, R, Chambers, JC, Chasman, DI, Chakravarti, A, The International Consortium of Blood Pressure (ICBP) 1000G Analyses, The CHD Exome+ Consortium, The ExomeBP Consortium, The T2D-GENES Consortium, The GoT2DGenes Consortium, The Cohorts for Heart and Ageing Research in Genome Epidemiology (CHARGE) BP Exome Consortium, The International Genomics of Blood Pressure (iGEN-BP) Consortium & The UK Biobank CardioMetabolic Consortium BP working group 2017, 'Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk', Nature Genetics, vol. 49, no. 3, pp. 403-415. https://doi.org/10.1038/ng.3768

Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk. / Warren, Helen R; Evangelou, Evangelos; Cabrera, Claudia P; Gao, He; Ren, Meixia; Mifsud, Borbala; Ntalla, Ioanna; Surendran, Praveen; Liu, Chunyu; Cook, James P; Kraja, Aldi T; Drenos, Fotios; Loh, Marie; Verweij, Niek; Marten, Jonathan; Karaman, Ibrahim; Lepe, Marcelo P Segura; O'Reilly, Paul F; Knight, Joanne; Snieder, Harold; Kato, Norihiro; He, Jiang; Tai, E Shyong; Said, M Abdullah; Porteous, David; Alver, Maris; Poulter, Neil; Farrall, Martin; Gansevoort, Ron T; Padmanabhan, Sandosh; Mägi, Reedik; Stanton, Alice; Connell, John; Bakker, Stephan J L; Metspalu, Andres; Shields, Denis C; Thom, Simon; Brown, Morris; Sever, Peter; Esko, Tõnu; Hayward, Caroline; van der Harst, Pim; Saleheen, Danish; Chowdhury, Rajiv; Chambers, John C; Chasman, Daniel I; Chakravarti, Aravinda; The International Consortium of Blood Pressure (ICBP) 1000G Analyses; The CHD Exome+ Consortium; The ExomeBP Consortium; The T2D-GENES Consortium; The GoT2DGenes Consortium; The Cohorts for Heart and Ageing Research in Genome Epidemiology (CHARGE) BP Exome Consortium; The International Genomics of Blood Pressure (iGEN-BP) Consortium; The UK Biobank CardioMetabolic Consortium BP working group.

In: Nature Genetics, Vol. 49, No. 3, 01.2017, p. 403-415.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk

AU - Warren, Helen R

AU - Evangelou, Evangelos

AU - Cabrera, Claudia P

AU - Gao, He

AU - Ren, Meixia

AU - Mifsud, Borbala

AU - Ntalla, Ioanna

AU - Surendran, Praveen

AU - Liu, Chunyu

AU - Cook, James P

AU - Kraja, Aldi T

AU - Drenos, Fotios

AU - Loh, Marie

AU - Verweij, Niek

AU - Marten, Jonathan

AU - Karaman, Ibrahim

AU - Lepe, Marcelo P Segura

AU - O'Reilly, Paul F

AU - Knight, Joanne

AU - Snieder, Harold

AU - Kato, Norihiro

AU - He, Jiang

AU - Tai, E Shyong

AU - Said, M Abdullah

AU - Porteous, David

AU - Alver, Maris

AU - Poulter, Neil

AU - Farrall, Martin

AU - Gansevoort, Ron T

AU - Padmanabhan, Sandosh

AU - Mägi, Reedik

AU - Stanton, Alice

AU - Connell, John

AU - Bakker, Stephan J L

AU - Metspalu, Andres

AU - Shields, Denis C

AU - Thom, Simon

AU - Brown, Morris

AU - Sever, Peter

AU - Esko, Tõnu

AU - Hayward, Caroline

AU - van der Harst, Pim

AU - Saleheen, Danish

AU - Chowdhury, Rajiv

AU - Chambers, John C

AU - Chasman, Daniel I

AU - Chakravarti, Aravinda

AU - The International Consortium of Blood Pressure (ICBP) 1000G Analyses

AU - The CHD Exome+ Consortium

AU - The ExomeBP Consortium

AU - The T2D-GENES Consortium

AU - The GoT2DGenes Consortium

AU - The Cohorts for Heart and Ageing Research in Genome Epidemiology (CHARGE) BP Exome Consortium

AU - The International Genomics of Blood Pressure (iGEN-BP) Consortium

AU - The UK Biobank CardioMetabolic Consortium BP working group

AU - Shah, Nabi

AU - Doney, Alex S F

AU - Palmer, Colin N A

N1 - H.R.W., C.P.C., M.R., M.R.B., P.B.M., M.B. and M.J.C. were funded by the National Institute for Health Research (NIHR) as part of the portfolio of translational research of the NIHR Biomedical Research Unit at Barts and The London School of Medicine and Dentistry. H.G. was funded by the NIHR Imperial College Health Care NHS Trust and Imperial College London Biomedical Research Centre. M.R. was a recipient of a grant from the China Scholarship Council (2011632047). B.M. holds an MRC eMedLab Medical Bioinformatics Career Development Fellowship, funded from award MR/L016311/1. J.M.M.H. was funded by the UK Medical Research Council (G0800270), British Heart Foundation (SP/09/002), UK National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council (268834) and European Commission Framework Programme 7 (HEALTH-F2-2012-279233). B.K. holds a British Heart Foundation Personal Chair (CH/13/2/30154). N.J.S. holds a chair funded by the British Heart Foundation and is an NIHR Senior Investigator. F.D. was funded by the MRC Unit at the University of Bristol (MC_UU_12013/1-9). P. Surendran was funded by the UK Medical Research Council (G0800270). C.L. and A.K. were funded by NHLBI intramural funding. C.N.-C. was funded by the National Institutes of Health (HL113933, HL124262). P.v.d.H. was funded by ZonMw grant 90.700.441, Marie Sklodowska-Curie GF (call, H2020-MSCA-IF-2014; project ID, 661395). N.V. was supported by a Marie Sklodowska-Curie GF grant (661395) and ICIN-NHI. N.P. received funding from the UK National Institute for Health Research Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London and also from his Senior Investigator Award. P. Sever was supported by the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London. S.T. was supported by the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London. P.F.O'R. received funding from the UK Medical Research Council (MR/N015746/1) and the Wellcome Trust (109863/Z/15/Z). I.K. was supported by the EU PhenoMeNal project (Horizon 2020, 654241). A.C. was funded by the National Institutes of Health (HL128782, HL086694). M.F. was supported by a Wellcome Trust core award (090532/Z/09/Z) and the BHF Centre of Research Excellence, Oxford (RE/13/1/30181). C.H. was funded by an MRC core grant for QTL in Health and Disease programme. Some of this work used the ALICE and SPECTRE High-Performance Computing Facilities at the University of Leicester. M.J.C. is a National Institute for Health Research (NIHR) senior investigator. P.E. is a National Institute for Health Research (NIHR) senior investigator and acknowledges support from the NIHR Biomedical Research Centre at Imperial College Healthcare NHS Trust and Imperial College London, and the NIHR Health Protection Research Unit in Health Impact of Environmental Hazards (HPRU-2012-10141). As director of the MRC-PHE Centre for Environment and Health, P.E. acknowledges support from the Medical Research Council and Public Health England (MR/L01341X/1). This work used the computing resources of the UK Medical Bioinformatics partnership–aggregation, integration, visualisation and analysis of large, complex data (UK MED-BIO), which is supported by the Medical Research Council (MR/L01632X/1). This research was supported by the British Heart Foundation (grant SP/13/2/30111). Project title: Large-Scale Comprehensive Genotyping of UK Biobank for Cardiometabolic Traits and Diseases: UK CardioMetabolic Consortium (UKCMC). This research has been conducted using the UK Biobank Resource under application number 236.

PY - 2017/1

Y1 - 2017/1

N2 - Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk.

AB - Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk.

KW - Genome-wide association studies

KW - Hypertension

U2 - 10.1038/ng.3768

DO - 10.1038/ng.3768

M3 - Article

VL - 49

SP - 403

EP - 415

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 3

ER -