Trans-ethnic association study of blood pressure determinants in over 750,000 individuals

doi:10.1038/s41588-018-0303-9

. 2019 Jan;51(1):51-62.

doi: 10.1038/s41588-018-0303-9. Epub 2018 Dec 21.

Trans-ethnic association study of blood pressure determinants in over 750,000 individuals

Ayush Giri^#^{1

2}, Jacklyn N Hellwege^#^{2

3}, Jacob M Keaton^#^{2

3}, Jihwan Park^#⁴, Chengxiang Qiu⁴, Helen R Warren^{5

6}, Eric S Torstenson^{2

3}, Csaba P Kovesdy⁷, Yan V Sun^{8

9}, Otis D Wilson^{2

10}, Cassianne Robinson-Cohen¹⁰, Christianne L Roumie^{11

12}, Cecilia P Chung¹³, Kelly A Birdwell^{10

14}, Scott M Damrauer^{15

16}, Scott L DuVall^{17

18}, Derek Klarin^{19

20

21

22}, Kelly Cho^{23

24

25}, Yu Wang²⁶, Evangelos Evangelou^{27

28}, Claudia P Cabrera^{5

6}, Louise V Wain^{29

30}, Rojesh Shrestha⁴, Brian S Mautz³, Elvis A Akwo¹⁰, Muralidharan Sargurupremraj³¹, Stéphanie Debette^{31

32}, Michael Boehnke³³, Laura J Scott³³, Jian'an Luan³⁴, Jing-Hua Zhao³⁴, Sara M Willems³⁴, Sébastien Thériault^{35

36}, Nabi Shah^{37

38}, Christopher Oldmeadow³⁹, Peter Almgren⁴⁰, Ruifang Li-Gao⁴¹, Niek Verweij⁴², Thibaud S Boutin⁴³, Massimo Mangino^{44

45}, Ioanna Ntalla⁵, Elena Feofanova⁴⁶, Praveen Surendran⁴⁷, James P Cook⁴⁸, Savita Karthikeyan⁴⁷, Najim Lahrouchi^{21

49

50}, Chunyu Liu⁵¹, Nuno Sepúlveda⁵², Tom G Richardson⁵³, Aldi Kraja^{54

55

56}, Philippe Amouyel⁵⁷, Martin Farrall⁵⁸, Neil R Poulter⁵⁹; Understanding Society Scientific Group; International Consortium for Blood Pressure; Blood Pressure-International Consortium of Exome Chip Studies; Markku Laakso⁶⁰, Eleftheria Zeggini⁶¹, Peter Sever⁶², Robert A Scott³⁴, Claudia Langenberg³⁴, Nicholas J Wareham³⁴, David Conen⁶³, Colin Neil Alexander Palmer³⁷, John Attia^{39

64}, Daniel I Chasman⁶⁵, Paul M Ridker⁶⁵, Olle Melander⁴⁰, Dennis Owen Mook-Kanamori⁴¹, Pim van der Harst⁴², Francesco Cucca^{66

67}, David Schlessinger⁶⁸, Caroline Hayward⁴³, Tim D Spector⁴⁴, Marjo-Riitta Jarvelin^{69

70

71

72

73}, Branwen J Hennig^{74

75

76}, Nicholas J Timpson⁵³, Wei-Qi Wei⁷⁷, Joshua C Smith⁷⁷, Yaomin Xu^{26

77}, Michael E Matheny^{11

12

26

77}, Edward E Siew^{10

12}, Cecilia Lindgren^{21

78

79}, Karl-Heinz Herzig^{80

81}, George Dedoussis⁸², Joshua C Denny⁷⁷, Bruce M Psaty^{83

84

85

86}, Joanna M M Howson⁴⁷, Patricia B Munroe^{5

6}, Christopher Newton-Cheh⁴⁹, Mark J Caulfield^{5

6}, Paul Elliott^{69

87

88}, J Michael Gaziano^{23

65}, John Concato^{89

90}, Peter W F Wilson^{91

92}, Philip S Tsao^{93

94}, Digna R Velez Edwards^{1

2

77}, Katalin Susztak^{4

95}; Million Veteran Program; Christopher J O'Donnell^{65

96}, Adriana M Hung^{97

98}, Todd L Edwards^{99

100}

Affiliations

¹ Division of Quantitative Sciences, Department of Obstetrics & Gynecology, Vanderbilt Genetics Institute, Vanderbilt Epidemiology Center, Institute for Medicine and Public Health, Vanderbilt University Medical Center, Nashville, TN, USA.
² Biomedical Laboratory Research and Development, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, TN, USA.
³ Division of Epidemiology, Department of Medicine, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN, USA.
⁴ Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA.
⁵ William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁶ National Institute for Health Research Barts Cardiovascular Biomedical Research Centre, Queen Mary University of London, London, UK.
⁷ Nephrology Section, Memphis VA Medical Center, Memphis, TN, USA.
⁸ Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA.
⁹ Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, USA.
¹⁰ Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹¹ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹² Geriatrics Research Education and Clinical Center, Tennessee Valley Health System, Veteran's Health Administration, Nashville, TN, USA.
¹³ Division of Rheumatology and Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁴ Division of Nephrology, Department of Medicine, Nashville Veteran Affairs Hospital, Nashville, TN, USA.
¹⁵ Department of Surgery, Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.
¹⁶ Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁷ VA Salt Lake City Health Care System, Salt Lake City, UT, USA.
¹⁸ University of Utah School of Medicine, Salt Lake City, UT, USA.
¹⁹ VA Boston Health Care System, Boston, MA, USA.
²⁰ Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
²¹ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
²² Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
²³ Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.
²⁴ Division of Aging, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
²⁵ Department of Medicine, Harvard Medical School, Boston, MA, USA.
²⁶ Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁷ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
²⁸ Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
²⁹ Department of Health Sciences, University of Leicester, Leicester, UK.
³⁰ National Institute for Health Research, Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
³¹ University of Bordeaux, Bordeaux Population Health Research Center, INSERM UMR 1219, Bordeaux, France.
³² Department of Neurology, Bordeaux University Hospital, Bordeaux, France.
³³ Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
³⁴ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.
³⁵ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
³⁶ Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Quebec City, Quebec, Canada.
³⁷ Division of Molecular and Clinical Medicine, Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
³⁸ Department of Pharmacy, COMSATS University Islamabad, Abbottabad, Pakistan.
³⁹ Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
⁴⁰ Department of Clinical Sciences, Lund University, Malmö, Sweden.
⁴¹ Leiden University Medical Center, Leiden, the Netherlands.
⁴² Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
⁴³ Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
⁴⁴ Department of Twin Research and Genetic Epidemiology, Kings College London, London, UK.
⁴⁵ NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London, UK.
⁴⁶ Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁴⁷ BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁴⁸ Department of Biostatistics, University of Liverpool, Liverpool, UK.
⁴⁹ Cardiovascular Research Center, Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁵⁰ Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
⁵¹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
⁵² Immunology and Infection Department, London School of Hygiene & Tropical Medicine, London, UK.
⁵³ MRC Integrative Epidemiology Unit (IEU), Bristol Medical School (Population Health Sciences), University of Bristol, Oakfield House, Oakfield Grove, Bristol, UK.
⁵⁴ Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
⁵⁵ Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA.
⁵⁶ Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA.
⁵⁷ Risk Factors and Molecular Determinants of Aging-Related Diseases (RID-AGE), University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167, Lille, France.
⁵⁸ Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, Oxford, UK.
⁵⁹ International Centre for Circulatory Health, Imperial College London, London, UK.
⁶⁰ University of Eastern Finland, School of Medicine, Kuopio, Finland.
⁶¹ Wellcome Trust Sanger Institute, Hinxton, UK.
⁶² National Heart and Lung Institute, Imperial College London, Hammersmith Campus, London, UK.
⁶³ Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
⁶⁴ Faculty of Health, University of Newcastle, Newcastle, New South Wales, Australia.
⁶⁵ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁶⁶ Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, Cagliari, Italy.
⁶⁷ Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sassari, Italy.
⁶⁸ Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, MD, USA.
⁶⁹ MRC-PHE Centre for Environment & Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
⁷⁰ Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
⁷¹ Biocenter Oulu, University of Oulu, Oulu, Finland.
⁷² Unit of Primary Health Care, Oulu University Hospital, OYS, Oulu, Finland.
⁷³ Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, Middlesex, UK.
⁷⁴ Wellcome Trust, London, UK.
⁷⁵ MRC Unit The Gambia, Atlantic Boulevard, Fajara, Banjul, The Gambia.
⁷⁶ London School of Hygiene & Tropical Medicine, London, UK.
⁷⁷ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁷⁸ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
⁷⁹ Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
⁸⁰ Institute of Biomedicine, Biocenter of Oulu, Medical Research Center, Oulu University and Oulu University Hospital, Oulu, Finland.
⁸¹ Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, Poznan, Poland.
⁸² Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece.
⁸³ Departments of Medicine, University of Washington, Seattle, WA, USA.
⁸⁴ Departments of Epidemiology, University of Washington, Seattle, WA, USA.
⁸⁵ Departments of Health Services, University of Washington, Seattle, WA, USA.
⁸⁶ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
⁸⁷ National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare NHS Trust, Imperial College London, London, UK.
⁸⁸ UK Dementia Research Institute at Imperial College London, London, UK.
⁸⁹ Clinical Epidemiology Research Center (CERC), VA Cooperative Studies Program, VA Connecticut Healthcare System, West Haven, CT, USA.
⁹⁰ Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
⁹¹ Atlanta VA Medical Center, Atlanta, GA, USA.
⁹² Emory Clinical Cardiovascular Research Institute, Atlanta, GA, USA.
⁹³ VA Palo Alto Health Care System, Palo Alto, CA, USA.
⁹⁴ Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
⁹⁵ Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
⁹⁶ VA Boston Healthcare, Section of Cardiology and Department of Medicine, Boston, MA, USA.
⁹⁷ Biomedical Laboratory Research and Development, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, TN, USA. adriana.hung@vanderbilt.edu.
⁹⁸ Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. adriana.hung@vanderbilt.edu.
⁹⁹ Biomedical Laboratory Research and Development, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, TN, USA. todd.l.edwards@vanderbilt.edu.
¹⁰⁰ Division of Epidemiology, Department of Medicine, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN, USA. todd.l.edwards@vanderbilt.edu.

^# Contributed equally.

PMID: 30578418
PMCID: PMC6365102
DOI: 10.1038/s41588-018-0303-9

Trans-ethnic association study of blood pressure determinants in over 750,000 individuals

Ayush Giri et al. Nat Genet. 2019 Jan.

. 2019 Jan;51(1):51-62.

doi: 10.1038/s41588-018-0303-9. Epub 2018 Dec 21.

Authors

Affiliations

¹ Division of Quantitative Sciences, Department of Obstetrics & Gynecology, Vanderbilt Genetics Institute, Vanderbilt Epidemiology Center, Institute for Medicine and Public Health, Vanderbilt University Medical Center, Nashville, TN, USA.
² Biomedical Laboratory Research and Development, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, TN, USA.
³ Division of Epidemiology, Department of Medicine, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN, USA.
⁴ Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA, USA.
⁵ William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
⁶ National Institute for Health Research Barts Cardiovascular Biomedical Research Centre, Queen Mary University of London, London, UK.
⁷ Nephrology Section, Memphis VA Medical Center, Memphis, TN, USA.
⁸ Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA.
⁹ Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, USA.
¹⁰ Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹¹ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹² Geriatrics Research Education and Clinical Center, Tennessee Valley Health System, Veteran's Health Administration, Nashville, TN, USA.
¹³ Division of Rheumatology and Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁴ Division of Nephrology, Department of Medicine, Nashville Veteran Affairs Hospital, Nashville, TN, USA.
¹⁵ Department of Surgery, Corporal Michael Crescenz VA Medical Center, Philadelphia, PA, USA.
¹⁶ Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁷ VA Salt Lake City Health Care System, Salt Lake City, UT, USA.
¹⁸ University of Utah School of Medicine, Salt Lake City, UT, USA.
¹⁹ VA Boston Health Care System, Boston, MA, USA.
²⁰ Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
²¹ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
²² Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
²³ Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), VA Boston Healthcare System, Boston, MA, USA.
²⁴ Division of Aging, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
²⁵ Department of Medicine, Harvard Medical School, Boston, MA, USA.
²⁶ Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁷ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
²⁸ Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
²⁹ Department of Health Sciences, University of Leicester, Leicester, UK.
³⁰ National Institute for Health Research, Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
³¹ University of Bordeaux, Bordeaux Population Health Research Center, INSERM UMR 1219, Bordeaux, France.
³² Department of Neurology, Bordeaux University Hospital, Bordeaux, France.
³³ Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
³⁴ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.
³⁵ Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
³⁶ Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Quebec City, Quebec, Canada.
³⁷ Division of Molecular and Clinical Medicine, Pat Macpherson Centre for Pharmacogenetics and Pharmacogenomics, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
³⁸ Department of Pharmacy, COMSATS University Islamabad, Abbottabad, Pakistan.
³⁹ Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
⁴⁰ Department of Clinical Sciences, Lund University, Malmö, Sweden.
⁴¹ Leiden University Medical Center, Leiden, the Netherlands.
⁴² Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
⁴³ Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
⁴⁴ Department of Twin Research and Genetic Epidemiology, Kings College London, London, UK.
⁴⁵ NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London, UK.
⁴⁶ Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, TX, USA.
⁴⁷ BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
⁴⁸ Department of Biostatistics, University of Liverpool, Liverpool, UK.
⁴⁹ Cardiovascular Research Center, Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁵⁰ Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
⁵¹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
⁵² Immunology and Infection Department, London School of Hygiene & Tropical Medicine, London, UK.
⁵³ MRC Integrative Epidemiology Unit (IEU), Bristol Medical School (Population Health Sciences), University of Bristol, Oakfield House, Oakfield Grove, Bristol, UK.
⁵⁴ Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA.
⁵⁵ Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA.
⁵⁶ Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA.
⁵⁷ Risk Factors and Molecular Determinants of Aging-Related Diseases (RID-AGE), University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167, Lille, France.
⁵⁸ Department of Cardiovascular Medicine, The Wellcome Trust Centre for Human Genetics, Oxford, UK.
⁵⁹ International Centre for Circulatory Health, Imperial College London, London, UK.
⁶⁰ University of Eastern Finland, School of Medicine, Kuopio, Finland.
⁶¹ Wellcome Trust Sanger Institute, Hinxton, UK.
⁶² National Heart and Lung Institute, Imperial College London, Hammersmith Campus, London, UK.
⁶³ Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada.
⁶⁴ Faculty of Health, University of Newcastle, Newcastle, New South Wales, Australia.
⁶⁵ Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁶⁶ Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, Cagliari, Italy.
⁶⁷ Dipartimento di Scienze Biomediche, Università degli Studi di Sassari, Sassari, Italy.
⁶⁸ Laboratory of Genetics and Genomics, National Institute on Aging, NIH, Baltimore, MD, USA.
⁶⁹ MRC-PHE Centre for Environment & Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
⁷⁰ Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.
⁷¹ Biocenter Oulu, University of Oulu, Oulu, Finland.
⁷² Unit of Primary Health Care, Oulu University Hospital, OYS, Oulu, Finland.
⁷³ Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, Middlesex, UK.
⁷⁴ Wellcome Trust, London, UK.
⁷⁵ MRC Unit The Gambia, Atlantic Boulevard, Fajara, Banjul, The Gambia.
⁷⁶ London School of Hygiene & Tropical Medicine, London, UK.
⁷⁷ Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA.
⁷⁸ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
⁷⁹ Big Data Institute at the Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK.
⁸⁰ Institute of Biomedicine, Biocenter of Oulu, Medical Research Center, Oulu University and Oulu University Hospital, Oulu, Finland.
⁸¹ Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, Poznan, Poland.
⁸² Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece.
⁸³ Departments of Medicine, University of Washington, Seattle, WA, USA.
⁸⁴ Departments of Epidemiology, University of Washington, Seattle, WA, USA.
⁸⁵ Departments of Health Services, University of Washington, Seattle, WA, USA.
⁸⁶ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
⁸⁷ National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare NHS Trust, Imperial College London, London, UK.
⁸⁸ UK Dementia Research Institute at Imperial College London, London, UK.
⁸⁹ Clinical Epidemiology Research Center (CERC), VA Cooperative Studies Program, VA Connecticut Healthcare System, West Haven, CT, USA.
⁹⁰ Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
⁹¹ Atlanta VA Medical Center, Atlanta, GA, USA.
⁹² Emory Clinical Cardiovascular Research Institute, Atlanta, GA, USA.
⁹³ VA Palo Alto Health Care System, Palo Alto, CA, USA.
⁹⁴ Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
⁹⁵ Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
⁹⁶ VA Boston Healthcare, Section of Cardiology and Department of Medicine, Boston, MA, USA.
⁹⁷ Biomedical Laboratory Research and Development, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, TN, USA. adriana.hung@vanderbilt.edu.
⁹⁸ Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. adriana.hung@vanderbilt.edu.
⁹⁹ Biomedical Laboratory Research and Development, Tennessee Valley Healthcare System (626)/Vanderbilt University, Nashville, TN, USA. todd.l.edwards@vanderbilt.edu.
¹⁰⁰ Division of Epidemiology, Department of Medicine, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN, USA. todd.l.edwards@vanderbilt.edu.

^# Contributed equally.

PMID: 30578418
PMCID: PMC6365102
DOI: 10.1038/s41588-018-0303-9

Abstract

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells.

PubMed Disclaimer

Conflict of interest statement

COMPETING INTERESTS

Figures

**Figure 1.. Study design schematic.**
Flowchart depicting strategy for the three association analysis strategies (common, rare, and exonic variants), as well as replication selection criteria and numbers of samples and SNPs by stage. Subsequent TWAS and PheWAS analyses using common variant summary statistics are also presented. SBP, systolic blood pressure; DBP, diastolic blood pressure; PP, pulse pressure; SNP, single nucleotide polymorphism; ICBP, International Consortium for Blood Pressure; BP-ICE, Blood Pressure-International Consortium for Exomechip; BioVU, Vanderbilt University biorepository; ADE, adverse drug events

**Figure 2.. Manhattan plots summarizing discovery and replication meta-analysis for (a) SBP, (b) DBP, and (c) pulse pressure.**
Manhattan plot of the discovery + replication meta-analysis. The y axis shows the –log10 P-values and the x axis shows the chromosomal positions. The horizontal red line represents the thresholds of P-value = 5 × 10⁻⁸ for genome-wide significance. SNPs in red are in previously identified loci (includes discovery only; N_eff-max = 459,670 for SBP, 459,093 for DBP, and 459,305 for pulse pressure) whereas SNPs in orange are in novel loci (includes discovery + replication; N_eff-max = 760,226 for SBP, 767,920 for DBP, and 759,768 for pulse pressure). All P-values are computed for associations between genotyped/imputed SNPs and blood pressure traits as dependent variables in multivariable adjusted logistic regression models. SBP, systolic blood pressure; DBP, diastolic blood pressure

**Figure 3.. Mapping blood pressure-associated genes to murine kidney cell type clusters for (a) SBP, (b) DBP, and (c) pulse pressure.**
Average expression level of GWAS/eQTL defined genes in murine kidney cell types. Expression levels were determined in 43,745 kidney cells derived from seven mice. Mean expression values of the genes were calculated in each cluster. Color scheme is based on Z-score distribution obtained from two-sided Wald test. Z-scores are not corrected for multiple comparisons. Each row represents one gene and each column is single cell type cluster (as defined by Park et al.) on the heat map. Endo: endothelial, vascular, descending loop of Henle, Podo: podocyte, PT: proximal tubule, LOH: ascending loop of Henle, DCT: distal convoluted tubule, CD-PC: collecting duct principal cell, CD-IC: CD intercalated cell, Fib: fibroblast, Macro: macrophage, Neutro: neutrophil, NK: natural killer cell.

See this image and copyright information in PMC

Comment in

The genetic architecture of blood pressure.
Carney EF. Carney EF. Nat Rev Nephrol. 2019 Apr;15(4):192. doi: 10.1038/s41581-019-0117-8. Nat Rev Nephrol. 2019. PMID: 30670871 No abstract available.
Genetics of Blood Pressure Regulation: Possible Paths in the Labyrinth.
Foco L, Pattaro C. Foco L, et al. Am J Kidney Dis. 2019 Sep;74(3):421-424. doi: 10.1053/j.ajkd.2019.05.001. Epub 2019 Jun 17. Am J Kidney Dis. 2019. PMID: 31221530 No abstract available.

Cited by

Genome-wide association study on blood pressure traits in the Iranian population suggests ZBED9 as a new locus for hypertension.
Kolifarhood G, Sabour S, Akbarzadeh M, Sedaghati-Khayat B, Guity K, Rasekhi Dehkordi S, Amiri Roudbar M, Hadaegh F, Azizi F, Daneshpour MS. Kolifarhood G, et al. Sci Rep. 2021 Jun 3;11(1):11699. doi: 10.1038/s41598-021-90925-w. Sci Rep. 2021. PMID: 34083597 Free PMC article.
Investigation of gene-gene interactions in cardiac traits and serum fatty acid levels in the LURIC Health Study.
Zhou J, Passero K, Palmiero NE, Müller-Myhsok B, Kleber ME, Maerz W, Hall MA. Zhou J, et al. PLoS One. 2020 Sep 11;15(9):e0238304. doi: 10.1371/journal.pone.0238304. eCollection 2020. PLoS One. 2020. PMID: 32915819 Free PMC article.
Identification of Genetic Factors Underlying the Association between Sodium Intake Habits and Hypertension Risk.
Kwon YJ, Kim JO, Park JM, Choi JE, Park DH, Song Y, Kim SJ, Lee JW, Hong KW. Kwon YJ, et al. Nutrients. 2020 Aug 25;12(9):2580. doi: 10.3390/nu12092580. Nutrients. 2020. PMID: 32854392 Free PMC article.
HisCoM-G×E: Hierarchical Structural Component Analysis of Gene-Based Gene-Environment Interactions.
Choi S, Lee S, Huh I, Hwang H, Park T. Choi S, et al. Int J Mol Sci. 2020 Sep 14;21(18):6724. doi: 10.3390/ijms21186724. Int J Mol Sci. 2020. PMID: 32937825 Free PMC article.
Adiposity impacts cognitive function in Asian populations: an epidemiological and Mendelian Randomization study.
Mina T, Yew YW, Ng HK, Sadhu N, Wansaicheong G, Dalan R, Low DYW, Lam BCC, Riboli E, Lee ES, Ngeow J, Elliott P, Griva K, Loh M, Lee J, Chambers J. Mina T, et al. Lancet Reg Health West Pac. 2023 Feb 14;33:100710. doi: 10.1016/j.lanwpc.2023.100710. eCollection 2023 Apr. Lancet Reg Health West Pac. 2023. PMID: 36851942 Free PMC article.

See all "Cited by" articles

References

1. Lawes CMM, Vander Hoorn S, Rodgers A & International Society of Hypertension. Global burden of blood-pressure-related disease, 2001. Lancet Lond. Engl 371, 1513–1518 (2008). - PubMed
1. Forouzanfar MH et al. Global Burden of Hypertension and Systolic Blood Pressure of at Least 110 to 115 mm Hg, 1990–2015. JAMA 317, 165–182 (2017). - PubMed
1. Lewington S et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet Lond. Engl 360, 1903–1913 (2002). - PubMed
1. Whelton PK et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J. Am. Coll. Cardiol (2017). 10.1016/j.jacc.2017.11.006 - DOI - PubMed
1. Muntner P et al. Potential U.S. Population Impact of the 2017 ACC/AHA High Blood Pressure Guideline. J. Am. Coll. Cardiol 71, 109–118 (2018).

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- The Lens - Patent Citations Database
Miscellaneous
- NCI CPTAC Assay Portal

[1] Lawes CMM, Vander Hoorn S, Rodgers A & International Society of Hypertension. Global burden of blood-pressure-related disease, 2001. Lancet Lond. Engl 371, 1513–1518 (2008). - PubMed

[2] Lawes CMM, Vander Hoorn S, Rodgers A & International Society of Hypertension. Global burden of blood-pressure-related disease, 2001. Lancet Lond. Engl 371, 1513–1518 (2008). - PubMed

[3] Forouzanfar MH et al. Global Burden of Hypertension and Systolic Blood Pressure of at Least 110 to 115 mm Hg, 1990–2015. JAMA 317, 165–182 (2017). - PubMed

[4] Forouzanfar MH et al. Global Burden of Hypertension and Systolic Blood Pressure of at Least 110 to 115 mm Hg, 1990–2015. JAMA 317, 165–182 (2017). - PubMed

[5] Lewington S et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet Lond. Engl 360, 1903–1913 (2002). - PubMed

[6] Lewington S et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet Lond. Engl 360, 1903–1913 (2002). - PubMed

[7] Whelton PK et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J. Am. Coll. Cardiol (2017). 10.1016/j.jacc.2017.11.006 - DOI - PubMed

[8] Whelton PK et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J. Am. Coll. Cardiol (2017). 10.1016/j.jacc.2017.11.006 - DOI - PubMed

[9] Muntner P et al. Potential U.S. Population Impact of the 2017 ACC/AHA High Blood Pressure Guideline. J. Am. Coll. Cardiol 71, 109–118 (2018).

[10] Muntner P et al. Potential U.S. Population Impact of the 2017 ACC/AHA High Blood Pressure Guideline. J. Am. Coll. Cardiol 71, 109–118 (2018).

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Trans-ethnic association study of blood pressure determinants in over 750,000 individuals

Affiliations

Trans-ethnic association study of blood pressure determinants in over 750,000 individuals

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

Similar articles

Cited by

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Miscellaneous

Abstract

Conflict of interest statement

Figures

Comment in

Similar articles

Cited by

References

Publication types

MeSH terms

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Miscellaneous