title: Effects of long-term averaging of quantitative blood pressure traits on the detection of genetic associations.
abstract: Blood pressure (BP) is a heritable, quantitative trait with intraindividual variability and susceptibility to measurement error. Genetic studies of BP generally use single-visit measurements and thus cannot remove variability occurring over months or years. We leveraged the idea that averaging BP measured across time would improve phenotypic accuracy and thereby increase statistical power to detect genetic associations. We studied systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) averaged over multiple years in 46,629 individuals of European ancestry. We identified 39 trait-variant associations across 19 independent loci (p < 5 × 10(-8)); five associations (in four loci) uniquely identified by our LTA analyses included those of SBP and MAP at 2p23 (rs1275988, near KCNK3), DBP at 2q11.2 (rs7599598, in FER1L5), and PP at 6p21 (rs10948071, near CRIP3) and 7p13 (rs2949837, near IGFBP3). Replication analyses conducted in cohorts with single-visit BP data showed positive replication of associations and a nominal association (p < 0.05). We estimated a 20% gain in statistical power with long-term average (LTA) as compared to single-visit BP association studies. Using LTA analysis, we identified genetic loci influencing BP. LTA might be one way of increasing the power of genetic associations for continuous traits in extant samples for other phenotypes that are measured serially over time.
authors: Departments of Internal Medicine and Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: sganesh@umich.edu.
authors: Santhi K
authors: SK
authors: Ganesh
authors: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA; Harvard Medical School, Boston MA, 02115, USA.
authors: Daniel I
authors: DI
authors: Chasman
authors: Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA 01702, USA; Department of Mathematics, Boston University, Boston, MA 02215, USA.
authors: Martin G
authors: MG
authors: Larson
authors: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Torrance, CA 90502, USA; Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
authors: Xiuqing
authors: X
authors: Guo
authors: Department of Epidemiology, Erasmus University Medical Center, 's-Gravendijkwal 230, 3015 Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus University Medical Center, 's-Gravendijkwal 230, 3015 Rotterdam, the Netherlands.
authors: Germain
authors: G
authors: Verwoert
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
authors: Joshua C
authors: JC
authors: Bis
authors: Research Center for Human Genetics, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors: Xiangjun
authors: X
authors: Gu
authors: Icelandic Heart Association, 201 Kopavogur, Iceland; Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
authors: Albert V
authors: AV
authors: Smith
authors: Departments of Internal Medicine and Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Min-Lee
authors: ML
authors: Yang
authors: Department of Cardiology, Peking University First Hospital, Beijing 100034, China.
authors: Yan
authors: Y
authors: Zhang
authors: 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, 1211 Geneva, Switzerland.
authors: Georg
authors: G
authors: Ehret
authors: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.
authors: Lynda M
authors: LM
authors: Rose
authors: Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA 01702, USA; Center for Population Studies, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
authors: Shih-Jen
authors: SJ
authors: Hwang
authors: Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA.
authors: George J
authors: GJ
authors: Papanicolau
authors: Department of Internal Medicine, Erasmus University Medical Center, 's-Gravendijkwal 230, 3015 Rotterdam, the Netherlands.
authors: Eric J
authors: EJ
authors: Sijbrands
authors: Department of Biostatistics, University of Washington, Seattle, WA 98195, USA.
authors: Kenneth
authors: K
authors: Rice
authors: Icelandic Heart Association, 201 Kopavogur, Iceland.
authors: Gudny
authors: G
authors: Eiriksdottir
authors: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns-Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors: Vasyl
authors: V
authors: Pihur
authors: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA; Harvard Medical School, Boston MA, 02115, USA.
authors: Paul M
authors: PM
authors: Ridker
authors: Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA 01702, USA; Divisions of Epidemiology and Cardiology, Department of Medicine, Boston University School for Medicine, Boston, MA 02118, USA.
authors: Ramachandran S
authors: RS
authors: Vasan
authors: Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Christopher
authors: C
authors: Newton-Cheh
authors: Medical Genetics Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors: Leslie J
authors: LJ
authors: Raffel
authors: Department of Epidemiology, Erasmus University Medical Center, 's-Gravendijkwal 230, 3015 Rotterdam, the Netherlands.
authors: Najaf
authors: N
authors: Amin
authors: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Torrance, CA 90502, USA; Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
authors: Jerome I
authors: JI
authors: Rotter
authors: Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors: Kiang
authors: K
authors: Liu
authors: Laboratory of Epidemiology and Population Science, National Institute on Aging, Bethesda, MD 20892, USA.
authors: Lenore J
authors: LJ
authors: Launer
authors: Department of Cardiology, Peking University Third Hospital, Beijing 100191, China.
authors: Ming
authors: M
authors: Xu
authors: Clinical Pharmacology and the Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London EC1M 6BQ, UK.
authors: Mark
authors: M
authors: Caulfield
authors: Human Genetics Center, University of Texas Health Sciences Center at Houston, Houston, TX 77030, USA.
authors: Alanna C
authors: AC
authors: Morrison
authors: Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA 01702, USA; Cardiovascular Epidemiology and Human Genomics Branch, National Heart, Lung, and Blood Institute, Bethesda, MD 02892, USA.
authors: Andrew D
authors: AD
authors: Johnson
authors: Department of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA.
authors: Dhananjay
authors: D
authors: Vaidya
authors: Department of Epidemiology, Erasmus University Medical Center, 's-Gravendijkwal 230, 3015 Rotterdam, the Netherlands.
authors: Abbas
authors: A
authors: Dehghan
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
authors: Guo
authors: G
authors: Li
authors: Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.
authors: Claude
authors: C
authors: Bouchard
authors: Laboratory of Epidemiology and Population Science, National Institute on Aging, Bethesda, MD 20892, USA.
authors: Tamara B
authors: TB
authors: Harris
authors: Departments of Internal Medicine and Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
authors: He
authors: H
authors: Zhang
authors: Human Genetics Center, University of Texas Health Sciences Center at Houston, Houston, TX 77030, USA.
authors: Eric
authors: E
authors: Boerwinkle
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA; Department of Epidemiology, University of Washington, Seattle, WA 98101, USA.
authors: David S
authors: DS
authors: Siscovick
authors: Department of Cardiology, Peking University Third Hospital, Beijing 100191, China.
authors: Wei
authors: W
authors: Gao
authors: Department of Epidemiology, Erasmus University Medical Center, 's-Gravendijkwal 230, 3015 Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus University Medical Center, 's-Gravendijkwal 230, 3015 Rotterdam, the Netherlands; Netherlands Consortium for Healthy Aging, Netherlands Genomics Initiative, 2593 the Hague, the Netherlands.
authors: Andre G
authors: AG
authors: Uitterlinden
authors: Department of Epidemiology, Erasmus University Medical Center, 's-Gravendijkwal 230, 3015 Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus University Medical Center, 's-Gravendijkwal 230, 3015 Rotterdam, the Netherlands.
authors: Fernando
authors: F
authors: Rivadeneira
authors: Department of Epidemiology, Erasmus University Medical Center, 's-Gravendijkwal 230, 3015 Rotterdam, the Netherlands.
authors: Albert
authors: A
authors: Hofman
authors: Departments of Internal Medicine and Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Cristen J
authors: CJ
authors: Willer
authors: Department of Epidemiology, Erasmus University Medical Center, 's-Gravendijkwal 230, 3015 Rotterdam, the Netherlands.
authors: Oscar H
authors: OH
authors: Franco
authors: Department of Cardiology, Peking University First Hospital, Beijing 100034, China.
authors: Yong
authors: Y
authors: Huo
authors: Department of Epidemiology, Erasmus University Medical Center, 's-Gravendijkwal 230, 3015 Rotterdam, the Netherlands.
authors: Jacqueline C M
authors: JC
authors: Witteman
authors: Clinical Pharmacology and the Genome Centre, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK; NIHR Barts Cardiovascular Biomedical Research Unit, Queen Mary University of London, London EC1M 6BQ, UK.
authors: Patricia B
authors: PB
authors: Munroe
authors: Icelandic Heart Association, 201 Kopavogur, Iceland; Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
authors: Vilmundur
authors: V
authors: Gudnason
authors: Department of Medicine, Columbia University, New York, NY 10032, USA.
authors: Walter
authors: W
authors: Palmas
authors: Department of Epidemiology, Erasmus University Medical Center, 's-Gravendijkwal 230, 3015 Rotterdam, the Netherlands; Netherlands Consortium for Healthy Aging, Netherlands Genomics Initiative, 2593 the Hague, the Netherlands; Centre for Medical Systems Biology, Netherlands Genomics Initiative, 2593 the Hague, the Netherlands.
authors: Cornelia
authors: C
authors: van Duijn
authors: Research Center for Human Genetics, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors: Myriam
authors: M
authors: Fornage
authors: Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA 01702, USA; Center for Population Studies, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA; Boston University School of Medicine, Boston, MA 02118, USA.
authors: Daniel
authors: D
authors: Levy
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA; Department of Epidemiology, University of Washington, Seattle, WA 98101, USA; Group Health Research Institute, Group Health Cooperative, Seattle, WA 98101, USA.
authors: Bruce M
authors: BM
authors: Psaty
authors: 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.
authors: Aravinda
authors: A
authors: Chakravarti
mesh_terms: D001794:Blood Pressure / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D008137:Longitudinal Studies; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci