title: Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval.
abstract: Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.
authors: Department of Epidemiology, Bank of America Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors: C L
authors: CL
authors: Avery
authors: Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
authors: C M
authors: CM
authors: Sitlani
authors: McKusick-Nathans Institute of Genetic Medicine and Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: D E
authors: DE
authors: Arking
authors: Department of Epidemiology, The University of Alabama at Birmingham, Birmingham, AL, USA.
authors: D K
authors: DK
authors: Arnett
authors: Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
authors: J C
authors: JC
authors: Bis
authors: Division of Epidemiology and Center for Human Genetics, The University of Texas Health Science Center, Houston, TX, USA.
authors: E
authors: E
authors: Boerwinkle
authors: Department of Pharmacology and Therapeutics, University College Cork, Cork, UK.
authors: B M
authors: BM
authors: Buckley
authors: Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: Y-D
authors: YD
authors: Ida Chen
authors: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
authors: A J M
authors: AJ
authors: de Craen
authors: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: M
authors: M
authors: Eijgelsheim
authors: Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
authors: D
authors: D
authors: Enquobahrie
authors: California Pacific Medical Center Research Institute, San Francisco, CA, USA.
authors: D S
authors: DS
authors: Evans
authors: Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
authors: I
authors: I
authors: Ford
authors: Laboratory of Epidemiology, Demography, and Biometry, Intramural Research Program, National Institute on Aging, Bethesda, MD, USA.
authors: M E
authors: ME
authors: Garcia
authors: Icelandic Heart Association, Kopavogur, Iceland.
authors: V
authors: V
authors: Gudnason
authors: Laboratory of Epidemiology, Demography, and Biometry, Intramural Research Program, National Institute on Aging, Bethesda, MD, USA.
authors: T B
authors: TB
authors: Harris
authors: 1] Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA [2] Department of Epidemiology, University of Washington, Seattle, WA, USA.
authors: S R
authors: SR
authors: Heckbert
authors: Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA.
authors: H
authors: H
authors: Hochner
authors: 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands [2] Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands.
authors: A
authors: A
authors: Hofman
authors: Department of Medicine, University of California, San Francisco, CA, USA.
authors: W-C
authors: WC
authors: Hsueh
authors: 1] Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands [2] Centre for Medical Systems Biology, Leiden, The Netherlands.
authors: A
authors: A
authors: Isaacs
authors: Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
authors: J W
authors: JW
authors: Jukema
authors: THL-National Institute for Health and Welfare, Helsinki, Finland.
authors: P
authors: P
authors: Knekt
authors: 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands [2] Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: J A
authors: JA
authors: Kors
authors: 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands [2] Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands.
authors: B P
authors: BP
authors: Krijthe
authors: THL-National Institute for Health and Welfare, Helsinki, Finland.
authors: K
authors: K
authors: Kristiansson
authors: THL-National Institute for Health and Welfare, Helsinki, Finland.
authors: M
authors: M
authors: Laaksonen
authors: Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, NC, USA.
authors: Y
authors: Y
authors: Liu
authors: Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: X
authors: X
authors: Li
authors: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
authors: P W
authors: PW
authors: Macfarlane
authors: 1] Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA [2] Center for Human Genetic Research, Cardiovascular Research Center, Harvard Medical School, Boston, MA, USA [3] Massachusetts General Hospital, Boston, MA, USA.
authors: C
authors: C
authors: Newton-Cheh
authors: Division of Cardiology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
authors: M S
authors: MS
authors: Nieminen
authors: 1] Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands [2] Centre for Medical Systems Biology, Leiden, The Netherlands.
authors: B A
authors: BA
authors: Oostra
authors: 1] National Heart Lung and Blood Institute's Framingham Heart Study, Framingham, MA, USA [2] Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA.
authors: G M
authors: GM
authors: Peloso
authors: Division of Cardiology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
authors: K
authors: K
authors: Porthan
authors: Department of Biostatistics, University of Washington, Seattle, WA, USA.
authors: K
authors: K
authors: Rice
authors: 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands [2] Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands [3] Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: F F
authors: FF
authors: Rivadeneira
authors: Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: J I
authors: JI
authors: Rotter
authors: THL-National Institute for Health and Welfare, Helsinki, Finland.
authors: V
authors: V
authors: Salomaa
authors: BHF Glasgow Cardiovascular Research Centre, Faculty of Medicine, Glasgow, UK.
authors: N
authors: N
authors: Sattar
authors: 1] Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA [2] Department of Epidemiology, University of Washington, Seattle, WA, USA.
authors: D S
authors: DS
authors: Siscovick
authors: Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
authors: P E
authors: PE
authors: Slagboom
authors: Icelandic Heart Association, Kopavogur, Iceland.
authors: A V
authors: AV
authors: Smith
authors: Division of Cardiology, University of Washington, Seattle, WA, USA.
authors: N
authors: N
authors: Sotoodehnia
authors: Academic Section of Geriatric Medicine, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
authors: D J
authors: DJ
authors: Stott
authors: 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands [2] Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands [3] Department of Medical Informatics, Erasmus Medical Center, Rotterdam, The Netherlands [4] Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: B H
authors: BH
authors: Stricker
authors: Department of Epidemiology, Bank of America Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors: T
authors: T
authors: Stürmer
authors: Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
authors: S
authors: S
authors: Trompet
authors: 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands [2] Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands [3] Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
authors: A G
authors: AG
authors: Uitterlinden
authors: 1] Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands [2] Centre for Medical Systems Biology, Leiden, The Netherlands.
authors: C
authors: C
authors: van Duijn
authors: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
authors: R G J
authors: RG
authors: Westendorp
authors: 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands [2] Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands.
authors: J C
authors: JC
authors: Witteman
authors: 1] Department of Epidemiology, Bank of America Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA [2] Departments of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors: E A
authors: EA
authors: Whitsel
authors: 1] Cardiovascular Health Research Unit, University of Washington, Seattle, WA, USA [2] Department of Epidemiology, University of Washington, Seattle, WA, USA [3] Departments of Medicine, University of Washington, Seattle, WA, USA [4] Department of Health Services, University of Washington, Seattle, WA, USA [5] Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
authors: B M
authors: BM
authors: Psaty
mesh_terms: D003198:Computer Simulation; D003430:Cross-Sectional Studies; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics*; D004562:Electrocardiography; D059647:Gene-Environment Interaction; D055106:Genome-Wide Association Study; D006801:Humans; D016014:Linear Models; D008133:Long QT Syndrome / Q000235:genetics*; D008390:Markov Chains; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D019655:Quantitative Trait, Heritable; D044465:White People / Q000235:genetics