title: Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans.
abstract: The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 × 10-14) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 × 10-4). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 × 10-8) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 10-9). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 × 10-7), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved.
authors: California Pacific Medical Center Research Institute, San Francisco, CA, USA devans@psg.ucsf.edu. nsotoo@u.washington.edu.
authors: Daniel S
authors: DS
authors: Evans
authors: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
authors: Christy L
authors: CL
authors: Avery
authors: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors: Mike A
authors: MA
authors: Nalls
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
authors: Guo
authors: G
authors: Li
authors: Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors: John
authors: J
authors: Barnard
authors: Department of Pediatrics and Rady Children's Hospital, University of California at San Diego, School of Medicine, La Jolla, CA, USA.
authors: Erin N
authors: EN
authors: Smith
authors: Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
authors: Toshiko
authors: T
authors: Tanaka
authors: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
authors: Anne M
authors: AM
authors: Butler
authors: Center of Excellence in Minority Health and Health Disparities, Jackson State University, Jackson, MS, USA.|Department of Epidemiology and Biostatistics, Jackson State University School of Public Health (Initiative), Jackson, MS, USA.
authors: Sarah G
authors: SG
authors: Buxbaum
authors: Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
authors: Alvaro
authors: A
authors: Alonso
authors: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Dan E
authors: DE
authors: Arking
authors: Department of Medicine and Cardiology, Tulane University, New Orleans, LA, USA.
authors: Gerald S
authors: GS
authors: Berenson
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
authors: Joshua C
authors: JC
authors: Bis
authors: Department of Statistics and Biostatistics and Department of Genetics, Rutgers University, Piscataway, NJ, USA.
authors: Steven
authors: S
authors: Buyske
authors: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors: Cara L
authors: CL
authors: Carty
authors: Department of Epidemiology, Tulane University, New Orleans, LA, USA.
authors: Wei
authors: W
authors: Chen
authors: Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH, USA.|Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.|Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA.
authors: Mina K
authors: MK
authors: Chung
authors: California Pacific Medical Center Research Institute, San Francisco, CA, USA.
authors: Steven R
authors: SR
authors: Cummings
authors: Division of Cardiovascular Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Rajat
authors: R
authors: Deo
authors: Departments of Family Medicine and Epidemiology, Alpert Medical School, Brown University, Providence, RI, USA.
authors: Charles B
authors: CB
authors: Eaton
authors: Department of Medicine, Division of Cardiovascular Disease, University of Mississippi Medical Center, Jackson, MS, USA.
authors: Ervin R
authors: ER
authors: Fox
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.|Department of Epidemiology, University of Washington, Seattle, WA, USA.|Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
authors: Susan R
authors: SR
authors: Heckbert
authors: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
authors: Gerardo
authors: G
authors: Heiss
authors: National Institutes of Health, National Human Genome Research Institute, Office of Population Genomics, Bethesda, MD, USA.
authors: Lucia A
authors: LA
authors: Hindorff
authors: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, USA.
authors: Wen-Chi
authors: WC
authors: Hsueh
authors: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.|CARIM School for Cardiovascular Diseases, Maastricht Centre for Systems Biology (MaCSBio), Dept. of Biochemistry, Maastricht University, Maastricht, the Netherlands.
authors: Aaron
authors: A
authors: Isaacs
authors: Cardiogenetics Lab, Institute of Cardiovascular and Cell Sciences, St George's University of London, UK.
authors: Yalda
authors: Y
authors: Jamshidi
authors: Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA.
authors: Kathleen F
authors: KF
authors: Kerr
authors: Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
authors: Felix
authors: F
authors: Liu
authors: Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, NC, USA.
authors: Yongmei
authors: Y
authors: Liu
authors: Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, NC, USA.
authors: Kurt K
authors: KK
authors: Lohman
authors: Department of Medicine, Division of Cardiology, University of Pittsburgh Medical Center Heart and Vascular Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors: Jared W
authors: JW
authors: Magnani
authors: Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
authors: Joseph F
authors: JF
authors: Maher
authors: Program for Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.
authors: Reena
authors: R
authors: Mehra
authors: Jackson Heart Study, University of Mississippi Medical Center, Jackson, MS, USA.
authors: Yan A
authors: YA
authors: Meng
authors: Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston,MA, USA.
authors: Solomon K
authors: SK
authors: Musani
authors: Jackson Heart Study, University of Mississippi Medical Center, Jackson, MS, USA.|Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, NC, USA.
authors: Christopher
authors: C
authors: Newton-Cheh
authors: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.|Department of Health Services, University of Washington, Seattle, WA, USA.
authors: Kari E
authors: KE
authors: North
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.|Department of Epidemiology, University of Washington, Seattle, WA, USA.|Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.|Department of Medicine, Division of Sleep Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors: Bruce M
authors: BM
authors: Psaty
authors: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Departments of Medicine and Pediatrics, Harbor-UCLA Medical Center, Torrance, CA, USA.
authors: Susan
authors: S
authors: Redline
authors: University Heart Center Hamburg and German Center for Cardiovascular Research, Hamburg, Germany.
authors: Jerome I
authors: JI
authors: Rotter
authors: J. Craig Venter Institute, San Diego, CA, USA.
authors: Renate B
authors: RB
authors: Schnabel
authors: Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA.
authors: Nicholas J
authors: NJ
authors: Schork
authors: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH, USA.
authors: Ralph V
authors: RV
authors: Shohet
authors: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors: Andrew B
authors: AB
authors: Singleton
authors: Epidemiological Cardiology Research Center (EPICARE), Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors: Jonathan D
authors: JD
authors: Smith
authors: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
authors: Elsayed Z
authors: EZ
authors: Soliman
authors: Department of Epidemiology, Tulane University, New Orleans, LA, USA.
authors: Sathanur R
authors: SR
authors: Srinivasan
authors: Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
authors: Herman A
authors: HA
authors: Taylor
authors: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors: David R
authors: DR
authors: Van Wagoner
authors: Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
authors: James G
authors: JG
authors: Wilson
authors: Jackson Heart Study, University of Mississippi Medical Center, Jackson, MS, USA.
authors: Taylor
authors: T
authors: Young
authors: Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
authors: Zhu-Ming
authors: ZM
authors: Zhang
authors: Department of Pathology, University of California San Diego, La Jolla, CA, USA.
authors: Alan B
authors: AB
authors: Zonderman
authors: Department of Pathology, University of California San Diego, La Jolla, CA, USA.
authors: Michele K
authors: MK
authors: Evans
authors: Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
authors: Luigi
authors: L
authors: Ferrucci
authors: Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors: Sarah S
authors: SS
authors: Murray
authors: California Pacific Medical Center Research Institute, San Francisco, CA, USA.
authors: Gregory J
authors: GJ
authors: Tranah
authors: Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.|Membership of the CHARGE QRS Consortium is provided in the acknowledgements and.
authors: Eric A
authors: EA
authors: Whitsel
authors: Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.|Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors: Alex P
authors: AP
authors: Reiner
authors: Department of Epidemiology, University of Washington, Seattle, WA, USA devans@psg.ucsf.edu. nsotoo@u.washington.edu.|Division of Cardiology, University of Washington, Seattle, WA, USA.
authors: Nona
authors: N
authors: Sotoodehnia
mesh_terms: D001741:Black or African American / Q000235:genetics; D000483:Alleles; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D004562:Electrocardiography; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006352:Heart Ventricles / Q000503:physiopathology*; D006801:Humans; D008297:Male; D009206:Myocardium / Q000473:pathology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human