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

• Type of Material: Article
• Authors: Daniel S. Evans, California Pacific Medical Center Research Institute; Christy L. Avery, University of North Carolina; Mike A. Nalls, National Institutes of Health; Guo Li, University of Washington; John Barnard, Cleveland Clinic; Erin N. Smith, University of California San Diego; Toshiko Tanaka, National Institutes of Health; Anne M. Butler, University of North Carolina; Sarah G. Buxbaum, Jackson State University; Alvaro Alonso, Emory University; Dan E. Arking, Johns Hopkins University; Gerald S. Berenson, Tulane University; Joshua C. Bis, University of Washington; Steven Buyske, Rutgers University; Cara L. Carly, Fred Hutchinson Cancer Research Center; Wei Chen, Tulane University; Mina K. Chung, Cleveland Clinic; Steven R. Cummings, California Pacific Medical Center Research Institute; Rajat Deo, University of Pennsylvania; Charles B. Eaton, Brown University; Ervin R. Fox, University of Mississippi Medical Center; Susan R. Heckbert, University of Washington; Gerardo Heiss, University of North Carolina, Chapel Hill; Lucia A. Hindorff, National Human Genome Research Institute; Wen-Chi Hsueh, National Institutes of Health; Aaron Isaacs, Erasmus University Medical Center; Yalda Jamshidi, St George's University of London; Kathleen F. Kerr, University of Washington; Felix Liu, University of California, San Francisco; Yongmei Liu, Wake Forest University; Kurt K. Lohman, Wake Forest University; Jared W. Magnani, University of Pittsburgh; Joseph F. Maher, University of Mississippi; Reena Mehra, Cleveland Clinic; Yan A. Meng, Broad Institute of Harvard and Massachusetts Institute of Technology; Solomon K. Musani, University of Mississippi; Christopher Newton-Cheh, Broad Institute of Harvard and Massachusetts Institute of Technology; Kari E. North, University of North Carolina, Chapel Hill; Bruce M. Psaty, University of Washington; Susan Redline, Brigham and Women's Hospital; Jerome I. Rotter, Harbor-UCLA Medical Center; Renate B. Schnabel, University Heart Center Hamburg and German Center for Cardiovascular Research; Nicholas J. Schork, J. Craig Venter Institute; Ralph V. Schohet, University of Hawaii; Andrew B. Singleton, National Institutes of Health; Jonathan D. Smith, Cleveland Clinic; Elsayed Z. Soliman, Wake Forest School of Medicine; Sathanur R. Srinivasan, Tulane University; Herman A. Taylor, Jr., University of Mississippi; David R. Van Wagoner, Cleveland Clinic; James G. Wilson, University of Mississippi; Taylor Young, Broad Institute of Harvard and Massachusetts Institute of Technology; Zhu-MIng Zhang, Wake Forest School of Medicine; Alan B. Zonderman, National Institutes of Health; Michelle K. Evans, National Institutes of Health; Luigi Ferucci, National Institutes of Health; Sarah S. Murray, University of California San Diego; Gregory J. Tranah, California Pacific Medical Center Research Institute; Eric A. Whitsel, University of North Carolina, Chapel Hill; Alex P. Reiner, Fred Hutchinson Cancer Research Center; Nona Sotoodehnia, University of Washington
• Language: English
• Date: 2016-10-01
• Publisher: Oxford University Press (OUP): Policy B - Oxford Open Option B
• Publication Version: Final Published Version
• Copyright Statement: © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: [e-mail].
• Final Published Version (URL): http://dx.doi.org/10.1093/hmg/ddw284
• Title of Journal or Parent Work: Human Molecular Genetics
• ISSN: 0964-6906
• Volume: 25
• Issue: 19
• Start Page: 4350
• End Page: 4368
• Grant/Funding Information: See publication for full funding statement.; As part of the National Heart, Lung, and Blood Institute (NHLBI)-sponsored Candidate gene Association Resource (CARe) project, the ARIC, JHS, MESA, and CFS studies contributed parent study data, ancillary study data, and DNA samples through the Broad Institute of Harvard and MIT (N01-HC-65226) to create a genotype/phenotype database for wide dissemination to the biomedical research community.; This work was supported by the National Institutes of Health [R01 HL088456 to N.S., R01 HL116747 to N.S., R01 HL111089 to N.S., R01 HL091244 to N.S., K99 HL098458 to C.L.A., 5T32CA009330-30 to A.M.B., R01 ES017794 to E.A.W., P20MD006899 to S.G.B., and U24AG051129 to D.S.E.], the Laughlin Family [to N.S.], and the German Research Foundation [SCHNA 1149/3-1 to R.B.S.].
• Keywords: Biochemistry & Molecular Biology; scn10a gene; Genes; GENETIC-VARIATION; Genome; Genome-wide association study; CARDIAC CONDUCTION; QRS complex duration; African American; PR INTERVAL; JACKSON HEART; Life Sciences & Biomedicine; HUMAN-POPULATIONS; Science & Technology; scn5a gene; Genetics & Heredity; COMMON VARIANTS; METAANALYSIS; RESTING HEART-RATE; VENTRICULAR CONDUCTION; Single nucleotide polymorphism; DESIGN
• Research Categories: Health Sciences, Epidemiology; Biology, Genetics; Health Sciences, Public Health

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.