Meta-analysis identifies common and rare variants influencing blood pressure and overlapping with metabolic trait loci.
Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.
Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, USA.|Department of Biostatistics, School of Public Health, Boston University, Boston, Massachusetts, USA.|Population Sciences Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
Chunyu
C
Liu
Division of Statistical Genomics, Department of Genetics and Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri, USA.
Aldi T
AT
Kraja
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.
Jennifer A
0000-0002-3575-5468
JA
Smith
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.
Jennifer A
JA
Brody
Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Nora
N
Franceschini
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.
Joshua C
JC
Bis
Department of Biostatistics, University of Washington, Seattle, Washington, USA.
Kenneth
K
Rice
Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston Texas, USA.
Alanna C
AC
Morrison
Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Yingchang
Y
Lu
DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.|Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Germany.
Stefan
S
Weiss
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA.
Xiuqing
X
Guo
Division of General Medicine, Columbia University Medical Center, New York, New York, USA.
Walter
W
Palmas
George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Lisa W
LW
Martin
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA.
Yii-Der Ida
YD
Chen
Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Praveen
P
Surendran
Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK.|MRC Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, UK.
Fotios
F
Drenos
Department of Biostatistics, University of Liverpool, Liverpool, UK.|Department of Health Sciences, University of Leicester, Leicester, UK.
James P
JP
Cook
Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, USA.
Paul L
PL
Auer
Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, USA.|Population Sciences Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.|Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Audrey Y
AY
Chu
Vanderbilt Epidemiology Center, Vanderbilt Genetics Institute, Institute for Medicine and Public Health, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Ayush
A
Giri
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.
Wei
W
Zhao
Icelandic Heart Association, Kopavogur, Iceland.
Johanna
J
Jakobsdottir
Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
Li-An
0000-0003-2731-1346
LA
Lin
Division of Public Health Sciences, Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
Jeanette M
JM
Stafford
Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands.
Najaf
N
Amin
Department of Data Science, School of Population Health, University of Mississippi Medical Center, Jackson, Mississippi, USA.
Hao
H
Mei
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA.
Jie
J
Yao
Bill and Melinda Gates Foundation, Seattle, Washington, USA.
Arend
A
Voorman
Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, USA.|Department of Biostatistics, School of Public Health, Boston University, Boston, Massachusetts, USA.|Department of Mathematics and Statistics, Boston University, Boston, Massachusetts, USA.
Martin G
MG
Larson
Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston Texas, USA.
Megan L
ML
Grove
Icelandic Heart Association, Kopavogur, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Albert V
0000-0003-1942-5845
AV
Smith
Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, USA.|Population Sciences Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
Shih-Jen
SJ
Hwang
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
Han
0000-0002-9510-4923
H
Chen
Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, USA.|Population Sciences Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
Tianxiao
T
Huan
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Boston, Massachusetts, USA.
Gulum
G
Kosova
Division of Cardiology, Department of Medicine and Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.
Nathan O
NO
Stitziel
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Boston, Massachusetts, USA.
Sekar
S
Kathiresan
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.|NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
Nilesh
N
Samani
Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.|DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany.
Heribert
H
Schunkert
Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.|William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Panos
0000-0001-9251-070X
P
Deloukas
Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland, USA.
Man
0000-0002-3839-0281
M
Li
Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), Bolzano, Italy (affiliated with the University of Lübeck, Lübeck, Germany).
Christian
C
Fuchsberger
Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), Bolzano, Italy (affiliated with the University of Lübeck, Lübeck, Germany).
Cristian
C
Pattaro
Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany.
Mathias
M
Gorski
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Charles
C
Kooperberg
Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
George J
GJ
Papanicolaou
Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
Jacques E
JE
Rossouw
Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, Michigan, USA.
Jessica D
JD
Faul
Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA.
Sharon L R
SL
Kardia
Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA.
Claude
C
Bouchard
Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Leslie J
LJ
Raffel
Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands.|Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands.
André G
AG
Uitterlinden
Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands.
Oscar H
OH
Franco
Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, USA.|Department of Preventive Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
Ramachandran S
RS
Vasan
Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, USA.|Cardiology Section, Department of Medicine, Boston Veterans Administration Healthcare, Boston, Massachusetts, USA.|Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
Christopher J
CJ
O'Donnell
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA.
Kent D
KD
Taylor
Northwestern University School of Medicine, Chicago, Illinois, USA.
Kiang
K
Liu
Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Erwin P
EP
Bottinger
Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Omri
O
Gottesman
Division of Statistical Genomics, Department of Genetics and Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri, USA.
E Warwick
EW
Daw
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Franco
F
Giulianini
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.|Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Santhi
S
Ganesh
Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Elias
E
Salfati
Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.
Tamara B
TB
Harris
Neuroepidemiology Section, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.
Lenore J
LJ
Launer
DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.|Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
Marcus
M
Dörr
DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.|Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany.
Stephan B
SB
Felix
DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.|Institute of Physiology, University of Greifswald, Greifswald, Germany.
Rainer
R
Rettig
DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.|DZD (German Center for Diabetes Research), site Greifswald, Greifswald, Germany.|Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
Henry
H
Völzke
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA.
Eric
E
Kim
Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan.
Wen-Jane
WJ
Lee
Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.|School of Medicine, National Yang-Ming University, Taipei, Taiwan.|School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
I-Te
IT
Lee
Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.|School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Institute of Medical Technology, National Chung-Hsing University, Taichung, Taiwan.|School of Medicine, National Defense Medical Center, Taipei, Taiwan.
Wayne H-H
WH
Sheu
Vanderbilt Epidemiology Center, Vanderbilt Genetics Institute, Institute for Medicine and Public Health, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Krystal S
KS
Tsosie
Vanderbilt Epidemiology Center, Vanderbilt Genetics Institute, Institute for Medicine and Public Health, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Digna R Velez
DR
Edwards
Epidemiology and Prevention Center for Genomics and Personalized Medicine Research, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, USA.
Yongmei
Y
Liu
Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA.
Adolfo
0000-0002-9501-600X
A
Correa
Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, Michigan, USA.
David R
DR
Weir
DZHK (German Center for Cardiovascular Research), partner site Greifswald, Greifswald, Germany.|Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Germany.
Uwe
U
Völker
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
Paul M
PM
Ridker
Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston Texas, USA.
Eric
E
Boerwinkle
Icelandic Heart Association, Kopavogur, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
Vilmundur
V
Gudnason
Department of Epidemiology, University of Washington, Seattle, Washington, USA.
Alexander P
AP
Reiner
Genetic Epidemiology Unit, Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands.
Cornelia M
CM
van Duijn
Division of Statistical Genomics, Department of Genetics and Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri, USA.
Ingrid B
IB
Borecki
Vanderbilt Epidemiology Center, Vanderbilt Genetics Institute, Institute for Medicine and Public Health, Vanderbilt University Medical Center, Nashville, Tennessee, USA.|Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Todd L
0000-0003-4318-6119
TL
Edwards
Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Aravinda
A
Chakravarti
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California, USA.|Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Medicine, Harbor-UCLA Medical Center, Torrance, California, USA.
Jerome I
JI
Rotter
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.|Department of Epidemiology, University of Washington, Seattle, Washington, USA.|Department of Health Services, University of Washington, Seattle, Washington, USA.|Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Bruce M
BM
Psaty
Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Ruth J F
RJ
Loos
Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
Myriam
M
Fornage
Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.|Cardiology, Geneva University Hospitals, Geneva, Switzerland.
Georg B
0000-0002-5730-0675
GB
Ehret
Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Boston, Massachusetts, USA.|Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
Christopher
C
Newton-Cheh
Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, Massachusetts, USA.|Population Sciences Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
Daniel
D
Levy
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
Daniel I
DI
Chasman
D001794:Blood Pressure / Q000235:genetics*; D059472:Exome; D014644:Genetic Variation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide