Format

Send to

Choose Destination
Am J Hum Genet. 2014 Jul 3;95(1):24-38. doi: 10.1016/j.ajhg.2014.05.010. Epub 2014 Jun 19.

Gene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia.

Author information

1
Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: jeannette@wubios.wustl.edu.
2
Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110, USA.
3
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
4
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02115, USA.
5
Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Cardiology, Department of Specialties of Internal Medicine, Geneva University Hospitals, Geneva 1211, Switzerland.
6
Research Center for Human Genetics, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX 77030, USA.
7
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
8
Framingham Heart Study, Framingham, MA 01702, USA; Center for Population Studies, National Heart, Lung, and Blood Institute, Framingham, MA 01702, USA.
9
Department of Internal Medicine, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.
10
Icelandic Heart Association, 201 Kopavogur, Iceland; Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
11
Department of Internal Medicine, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands; Department of Epidemiology, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.
12
Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
13
Centre for Genetic Origins of Health and Disease, University of Western Australia, Nedlands, WA 6009, Australia; Genetic Epidemiology and Biostatistics Platform, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Samuel Lunenfeld Research Institute, Toronto, ON M5T 3L9, Canada.
14
Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597, Singapore; Saw Swee Hock School of Public Health, National University Health System, Singapore 117597, Singapore.
15
Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597, Singapore; Saw Swee Hock School of Public Health, National University Health System, Singapore 117597, Singapore; Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; Department of Ophthalmology, National University Health System, Singapore 119228, Singapore; Singapore Eye Research Institute, Singapore 168751, Singapore; Centre for Quantitative Medicine, Office of Clinical Sciences, Duke-NUS Graduate Medical School, Singapore 169857, Singapore.
16
Department of Medical Genetics, University of Lausanne, 1005 Lausanne, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
17
Department of Cardiology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
18
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK.
19
Clinical Pharmacology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
20
Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597, Singapore; Saw Swee Hock School of Public Health, National University Health System, Singapore 117597, Singapore; Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; Department of Ophthalmology, National University Health System, Singapore 119228, Singapore; Division of Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore; Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; Department of Paediatrics, National University Health System, Singapore 119074, Singapore.
21
Cardiovascular Epidemiology and Genetics, IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain.
22
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK.
23
Department of Clinical Chemistry, Fimlab Laboratories, Tampere 30101, Finland; Department of Clinical Chemistry, University of Tampere School of Medicine, Tampere 33101, Finland.
24
Department of Epidemiology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
25
Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA; Centre for Molecular Epidemiology, National University of Singapore, Singapore 119260, Singapore.
26
Human Molecular Genetics Group, Institute of Molecular and Cell Biology, University of Tartu, Tartu 51010, Estonia.
27
Department of Epidemiology, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands.
28
Human Genetics Center, University of Texas Health Sciences Center, Houston, TX 77225, USA.
29
Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.
30
Icelandic Heart Association, 201 Kopavogur, Iceland.
31
Cardiovascular Epidemiology and Genetics, IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain; Epidemiology and Public Health Network (CIBERESP), 08036 Barcelona, Spain.
32
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany.
33
Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, NIH, Bethesda, MD 20892, USA.
34
U557 Institut National de la Santé et de la Recherche Médicale, U1125 Institut National de la Recherche Agronomique, Université Paris 13, 93000 Bobigny, France.
35
Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia; School of Medicine and Pharmacology, University of Western Australia, Nedlands, WA 6009, Australia.
36
Framingham Heart Study, Framingham, MA 01702, USA; Cardiovascular Epidemiology and Human Genomics Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892, USA.
37
Department of Clinical Physiology, Tampere University Hospital, Tampere 33521, Finland; Department of Clinical Physiology, University of Tampere School of Medicine, Tampere 33521, Finland.
38
Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge CB2 2SR, UK.
39
Framingham Heart Study, Framingham, MA 01702, USA; Department of Mathematics, Boston University, Boston, MA 02215, USA.
40
Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597, Singapore; Saw Swee Hock School of Public Health, National University Health System, Singapore 117597, Singapore; Division of Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore.
41
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
42
Department of Internal Medicine, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
43
Division of Cardiovascular Sciences, National Heart, Lung, & Blood Institute, NIH, Bethesda, MD 20892, USA.
44
Department of Psychiatry/EMGO Institute/Neuroscience Campus, VU University Medical Centre, 1081 BT Amsterdam, the Netherlands; Department of Psychiatry, Leiden University Medical Centre, 2333 ZD Leiden, the Netherlands; Department of Psychiatry, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
45
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA; Department of Health Services, University of Washington, Seattle, WA 98195, USA; Group Health Research Institute, Group Health Cooperative, Seattle, WA 98101, USA.
46
Medical Genetics Institute, Cedars-Sinai Medical Center, Pacific Theatres, Los Angeles, CA 90048, USA.
47
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku 20521, Finland; Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20521, Finland.
48
Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
49
Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.
50
Istituto di Ricerca Genetica e Biomedica, CNR, Monserrato 09042, Italy.
51
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA.
52
Department of Internal Medicine, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands; Department of Epidemiology, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands; Netherland Genomics Inititiative, Netherlands Center for Healthy Aging, The Hague 2509, the Netherlands.
53
Department of Medicine, Johns Hopkins University, Baltimore, MD 21202, USA.
54
Department of Endocrinology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
55
Framingham Heart Study, Framingham, MA 01702, USA; Divisions of Epidemiology and Cardiology, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
56
Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; Department of Ophthalmology, National University Health System, Singapore 119228, Singapore; Singapore Eye Research Institute, Singapore 168751, Singapore; Neuroscience and Behavioural Disorders (NBD) Program, Duke-NUS Graduate Medical School, Singapore 169857, Singapore.
57
Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, 17487 Greifswald, Germany.
58
Institute for Community Medicine, University of Greifswald, 17487 Greifswald, Germany.
59
Department of Ophthalmology, Duke University Medical Center, Durham, NC 27710, USA; Division of Neuroscience, Duke-National University of Singapore, Singapore 169857, Singapore.
60
Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; Department of Ophthalmology, National University Health System, Singapore 119228, Singapore; Singapore Eye Research Institute, Singapore 168751, Singapore.
61
Institute of Social and Preventive Medicine, Lausanne University Hospital, 1010 Lausanne, Switzerland.
62
Interdisciplinary Center for Pathology of Emotions, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
63
Laboratory of Cardiovascular Science, National Institute on Aging, NIH, Bethesda, MD 21224, USA.
64
MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Genetics of Obesity and Related Metabolic Traits Program, The Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
65
U872 Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, Paris 75006, France.
66
Genetic Epidemiology and Biostatistics Platform, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Samuel Lunenfeld Research Institute, Toronto, ON M5T 3L9, Canada.
67
Institute of Physiology, University of Greifswald, 17495 Karlsburg, Germany.
68
Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597, Singapore; Saw Swee Hock School of Public Health, National University Health System, Singapore 117597, Singapore; Department of Medicine, National University Health System and Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore; Duke-National University of Singapore Graduate Medical School, Singapore 169857, Singapore.
69
Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597, Singapore; Saw Swee Hock School of Public Health, National University Health System, Singapore 117597, Singapore; Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore; Department of Statistics and Applied Probability, National University of Singapore, Singapore 117543, Singapore; Genome Institute of Singapore, A(∗)STAR, Singapore 138672, Singapore.
70
Department of Cardiology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands; Department of Genetics, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands; Durrer Center for Cardiogenetic Research, 3501 DG Utrecht, the Netherlands.
71
Department of Genetics, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
72
Research Center for Human Genetics, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX 77030, USA; Human Genetics Center, University of Texas Health Sciences Center, Houston, TX 77225, USA.
73
Framingham Heart Study, Framingham, MA 01702, USA; Center for Population Studies, National Heart, Lung, and Blood Institute, Framingham, MA 01702, USA; Boston University School of Medicine, Boston, MA 02118, USA.
74
Department of Medicine, Columbia University, New York, NY 10032, USA.
75
Department of Epidemiology, Erasmus University Medical Center, 3015 GE Rotterdam, the Netherlands; Netherland Genomics Inititiative, Netherlands Center for Healthy Aging, The Hague 2509, the Netherlands; Netherland Genomics Initiative, Centre for Medical Systems Biology, 2300 RC Leiden, the Netherlands.
76
Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: aravinda@jhmi.edu.
77
Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110, USA; Departments of Psychiatry, Genetics, and Mathematics, Washington University School of Medicine, St. Louis, MO 63110, USA.

Abstract

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 × 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 × 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.

PMID:
24954895
PMCID:
PMC4085636
DOI:
10.1016/j.ajhg.2014.05.010
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center