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Hum Mol Genet. 2016 Oct 1;25(19):4350-4368. doi: 10.1093/hmg/ddw284. Epub 2016 Aug 29.

Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans.

Author information

1
California Pacific Medical Center Research Institute, San Francisco, CA, USA devans@psg.ucsf.edu. nsotoo@u.washington.edu.
2
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
3
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
4
Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
5
Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
6
Department of Pediatrics and Rady Children's Hospital, University of California at San Diego, School of Medicine, La Jolla, CA, USA.
7
Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
8
Center of Excellence in Minority Health and Health Disparities, Jackson State University, Jackson, MS, USA.
9
Department of Epidemiology and Biostatistics, Jackson State University School of Public Health (Initiative), Jackson, MS, USA.
10
Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
11
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
12
Department of Medicine and Cardiology, Tulane University, New Orleans, LA, USA.
13
Department of Statistics and Biostatistics and Department of Genetics, Rutgers University, Piscataway, NJ, USA.
14
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
15
Department of Epidemiology, Tulane University, New Orleans, LA, USA.
16
Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH, USA.
17
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
18
Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA.
19
California Pacific Medical Center Research Institute, San Francisco, CA, USA.
20
Division of Cardiovascular Medicine, University of Pennsylvania, Philadelphia, PA, USA.
21
Departments of Family Medicine and Epidemiology, Alpert Medical School, Brown University, Providence, RI, USA.
22
Department of Medicine, Division of Cardiovascular Disease, University of Mississippi Medical Center, Jackson, MS, USA.
23
Department of Epidemiology, University of Washington, Seattle, WA, USA.
24
Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA.
25
National Institutes of Health, National Human Genome Research Institute, Office of Population Genomics, Bethesda, MD, USA.
26
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ, USA.
27
Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
28
CARIM School for Cardiovascular Diseases, Maastricht Centre for Systems Biology (MaCSBio), Dept. of Biochemistry, Maastricht University, Maastricht, the Netherlands.
29
Cardiogenetics Lab, Institute of Cardiovascular and Cell Sciences, St George's University of London, UK.
30
Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA.
31
Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
32
Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University, Winston-Salem, NC, USA.
33
Department of Medicine, Division of Cardiology, University of Pittsburgh Medical Center Heart and Vascular Institute, University of Pittsburgh, Pittsburgh, PA, USA.
34
Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.
35
Program for Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.
36
Jackson Heart Study, University of Mississippi Medical Center, Jackson, MS, USA.
37
Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston,MA, USA.
38
Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, NC, USA.
39
Department of Health Services, University of Washington, Seattle, WA, USA.
40
Department of Medicine, Division of Sleep Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
41
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.
42
University Heart Center Hamburg and German Center for Cardiovascular Research, Hamburg, Germany.
43
J. Craig Venter Institute, San Diego, CA, USA.
44
Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA.
45
Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH, USA.
46
Epidemiological Cardiology Research Center (EPICARE), Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
47
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
48
Laboratory of Epidemiology and Population Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
49
Department of Pathology, University of California San Diego, La Jolla, CA, USA.
50
Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
51
Membership of the CHARGE QRS Consortium is provided in the acknowledgements and.
52
Department of Epidemiology, University of Washington, Seattle, WA, USA devans@psg.ucsf.edu. nsotoo@u.washington.edu.
53
Division of Cardiology, University of Washington, Seattle, WA, USA.

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.

PMID:
27577874
PMCID:
PMC5291202
DOI:
10.1093/hmg/ddw284
[Indexed for MEDLINE]
Free PMC Article

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