Gene-Age Interactions in Blood Pressure Regulation: A Large-Scale Investigation with the CHARGE, Global BPgen, and ICBP Consortia
Jeannette Simino
(1)
,
Gang Shi
(1)
,
Joshua C. Bis
(2)
,
Daniel I. Chasman
(3)
,
Georg B. Ehret
(4, 5)
,
Xiangjun Gu
(6)
,
Xiuqing Guo
(7)
,
Shih-Jen Hwang
(8, 9)
,
Eric Sijbrands
(10)
,
Albert V. Smith
(11, 12)
,
Germaine C. Verwoert
(10)
,
Jennifer L. Bragg-Gresham
(13)
,
Gemma Cadby
(14, 15, 16)
,
Peng Chen
(17)
,
Ching-Yu Cheng
(18, 19, 20)
,
Tanguy Corre
(21, 22)
,
Rudolf A. de Boer
(23)
,
Anuj Goel
(24)
,
Toby Johnson
(25)
,
Chiea-Chuen Khor
(26, 19)
,
Carla Lluis-Ganella
(27)
,
Jian'An Luan
(28)
,
Leo-Pekka Lyytikäinen
(29, 30)
,
Ilja M. Nolte
(23)
,
Xueling Sim
(31, 13)
,
Siim Sober
(32)
,
Peter J. van Der Most
(23)
,
Niek Verweij
(23)
,
Jing Hua Zhao
(28)
,
Najaf Amin
(10)
,
Eric Boerwinkle
(6)
,
Claude Bouchard
(33)
,
Abbas Dehghan
(10)
,
Gudny Eiriksdottir
(11)
,
Roberto Elosua
(27, 34)
,
Oscar H. Franco
(10)
,
Christian Gieger
(35)
,
Tamara B. Harris
(36)
,
Serge Hercberg
(37)
,
Albert Hofman
(10)
,
Alan L. James
(38, 39)
,
Andrew D. Johnson
(8)
,
Mika Kähönen
(30)
,
Kay-Tee Khaw
(40)
,
Zoltán Kutalik
(21, 22)
,
Martin G. Larson
(8, 41)
,
Lenore J. Launer
(36)
,
Guo Li
(2)
,
Jianjun Liu
(17, 26)
,
Kiang Liu
(42)
,
Alanna C. Morrison
(6)
,
Gerjan Navis
(23)
,
Rick Twee-Hee Ong
(17)
,
George J. Papanicolau
(9)
,
Brenda W. Penninx
(23, 43, 44)
,
Bruce M. Psaty
(2, 45)
,
Leslie J. Raffel
(46)
,
Olli T. Raitakari
(47, 48)
,
Kenneth Rice
(49)
,
Fernando Rivadeneira
(10)
,
Lynda M. Rose
(3)
,
Serena Sanna
(50)
,
Robert A. Scott
(28)
,
David S. Siscovick
(2)
,
Ronald P. Stolk
(23)
,
André G. Uitterlinden
(10, 51)
,
Dhananjay Vaidya
(5)
,
Melanie M. van Der Klauw
(23)
,
Ramachandran S. Vasan
(8, 52)
,
Eranga Nishanthie Vithana
(19, 18, 20)
,
Uwe Voelker
(53)
,
Henry Voelzke
(54)
,
Hugh Watkins
(24)
,
Terri L. Young
(55, 18)
,
Tin Aung
(19, 20)
,
Murielle Bochud
,
Martin Farrall
(24)
,
Catharina A. Hartman
,
Maris Laan
(32)
,
Edward G. Lakatta
,
Terho Lehtimäki
(30, 29)
,
Ruth J. F. Loos
(28)
,
Gavin Lucas
(27)
,
Pierre Meneton
,
Lyle J. Palmer
(14, 16)
,
Rainer Rettig
,
Harold Snieder
(23)
,
E. Shyong Tai
,
Yik-Ying Teo
,
Pim van Der Harst
,
Myriam Fornage
,
Vilmundur Gudnason
(11, 12)
,
Daniel Levy
(9, 8)
,
Walter Palmas
,
Paul M. Ridker
(3)
,
Jerome I. Rotter
(7)
,
Cornelia M. van Duijn
(10, 51)
,
Jacqueline C. M. Witteman
(10)
,
Aravinda Chakravarti
(5)
,
Dabeeru C. Rao
1
WUSTL -
Washington University in Saint Louis
2 University of Washington [Seattle]
3 Brigham and Women's Hospital [Boston]
4 HUG - Hôpitaux Universitaires de Genève
5 JHU - Johns Hopkins University
6 University of Texas
7 Harbor UCLA Medical Center [Torrance, Ca.]
8 NHLBI - National Heart, Lung, and Blood Institute [Bethesda]
9 National Heart, Lung and Blood Institute
10 Erasmus University Rotterdam
11 Icelandic Heart Association
12 University of Iceland [Reykjavik]
13 University of Michigan [Ann Arbor]
14 Ontario Institute for Cancer Research
15 UWA - The University of Western Australia
16 Samuel Lunenfeld Research Institute
17 Saw Swee Hock School of Public Health
18 NUS - National University of Singapore
19 NUHS - National University Health System [Singapore]
20 SERI - Singapore Eye Research Institute [Singapore]
21 SIB - Swiss Institute of Bioinformatics [Lausanne]
22 Department of Medical Genetics
23 University of Groningen [Groningen]
24 University of Oxford
25 QMUL - Queen Mary University of London
26 GIS - Genome Institute of Singapore
27 Hospital del Mar Medical Research Institute
28 Institute of metabolic Science, MRC Epidemiology Unit
29 Fimlab Laboratories
30 University of Tampere
31 Centre for Molecular Epidemiology
32 University of Tartu
33 Human Genomics Laboratory
34 CIBERESP - Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública = Consortium for Biomedical Research of Epidemiology and Public Health
35 German Research Center for Environmental Health - Helmholtz Center München (GmbH)
36 Laboratory of Epidemiology, Demography, and Biometry
37 CRESS (U1153 / UMR_A_1125 / UMR_S_1153) - Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité
38 Sir Charles Gairdner Hospital
39 School of Medicine and Pharmacology
40 Institute of Public Health, Department of Public Health and Primary Care
41 Department of Mathematics
42 Northwestern University [Evanston]
43 VU - Vrije Universiteit Amsterdam [Amsterdam]
44 Universiteit Leiden = Leiden University
45 Group Health Cooperative
46 Medical Genetics Institute
47 Department of Clinical Physiology and Nuclear Medicine
48 Research Centre of Applied and Preventive Cardiovascular Medicine
49 Department of Biostatistics [Oslo]
50 CNR - National Research Council of Italy | Consiglio Nazionale delle Ricerche
51 Netherlands Consortium for Healthy Aging
52 BU - Boston University [Boston]
53 Interfaculty Institute for Genetics and Functional Genomics
54 Institute for Community Medicine
55 Duke University [Durham]
2 University of Washington [Seattle]
3 Brigham and Women's Hospital [Boston]
4 HUG - Hôpitaux Universitaires de Genève
5 JHU - Johns Hopkins University
6 University of Texas
7 Harbor UCLA Medical Center [Torrance, Ca.]
8 NHLBI - National Heart, Lung, and Blood Institute [Bethesda]
9 National Heart, Lung and Blood Institute
10 Erasmus University Rotterdam
11 Icelandic Heart Association
12 University of Iceland [Reykjavik]
13 University of Michigan [Ann Arbor]
14 Ontario Institute for Cancer Research
15 UWA - The University of Western Australia
16 Samuel Lunenfeld Research Institute
17 Saw Swee Hock School of Public Health
18 NUS - National University of Singapore
19 NUHS - National University Health System [Singapore]
20 SERI - Singapore Eye Research Institute [Singapore]
21 SIB - Swiss Institute of Bioinformatics [Lausanne]
22 Department of Medical Genetics
23 University of Groningen [Groningen]
24 University of Oxford
25 QMUL - Queen Mary University of London
26 GIS - Genome Institute of Singapore
27 Hospital del Mar Medical Research Institute
28 Institute of metabolic Science, MRC Epidemiology Unit
29 Fimlab Laboratories
30 University of Tampere
31 Centre for Molecular Epidemiology
32 University of Tartu
33 Human Genomics Laboratory
34 CIBERESP - Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública = Consortium for Biomedical Research of Epidemiology and Public Health
35 German Research Center for Environmental Health - Helmholtz Center München (GmbH)
36 Laboratory of Epidemiology, Demography, and Biometry
37 CRESS (U1153 / UMR_A_1125 / UMR_S_1153) - Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité
38 Sir Charles Gairdner Hospital
39 School of Medicine and Pharmacology
40 Institute of Public Health, Department of Public Health and Primary Care
41 Department of Mathematics
42 Northwestern University [Evanston]
43 VU - Vrije Universiteit Amsterdam [Amsterdam]
44 Universiteit Leiden = Leiden University
45 Group Health Cooperative
46 Medical Genetics Institute
47 Department of Clinical Physiology and Nuclear Medicine
48 Research Centre of Applied and Preventive Cardiovascular Medicine
49 Department of Biostatistics [Oslo]
50 CNR - National Research Council of Italy | Consiglio Nazionale delle Ricerche
51 Netherlands Consortium for Healthy Aging
52 BU - Boston University [Boston]
53 Interfaculty Institute for Genetics and Functional Genomics
54 Institute for Community Medicine
55 Duke University [Durham]
Jeannette Simino
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Georg B. Ehret
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Shih-Jen Hwang
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Albert V. Smith
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Peng Chen
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- ORCID : 0000-0001-9934-3481
Serge Hercberg
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- ORCID : 0000-0002-3168-1350
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Jianjun Liu
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- ORCID : 0000-0002-3255-3019
Murielle Bochud
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Catharina A. Hartman
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Edward G. Lakatta
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Pierre Meneton
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- IdHAL : pierre-meneton
- ORCID : 0000-0003-4611-1892
Rainer Rettig
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E. Shyong Tai
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- PersonId : 800995
- ORCID : 0000-0003-2929-8966
Yik-Ying Teo
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Pim van Der Harst
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Myriam Fornage
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Vilmundur Gudnason
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Daniel Levy
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Walter Palmas
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Cornelia M. van Duijn
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Aravinda Chakravarti
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Dabeeru C. Rao
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Résumé
Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p <= 5 x 10(-8)) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 x 10(-4)) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.