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

TitleFine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans.
Publication TypeJournal Article
Year of Publication2016
AuthorsEvans DS, Avery CL, Nalls MA, Li G, Barnard J, Smith EN, Tanaka T, Butler AM, Buxbaum SG, Alonso A, Arking DE, Berenson GS, Bis JC, Buyske S, Carty CL, Chen W, Chung MK, Cummings SR, Deo R, Eaton CB, Fox ER, Heckbert SR, Heiss G, Hindorff LA, Hsueh W-C, Isaacs A, Jamshidi Y, Kerr KF, Liu F, Liu Y, Lohman KK, Magnani JW, Maher JF, Mehra R, Meng YA, Musani SK, Newton-Cheh C, North KE, Psaty BM, Redline S, Rotter JI, Schnabel RB, Schork NJ, Shohet RV, Singleton AB, Smith JD, Soliman EZ, Srinivasan SR, Taylor HA, Van Wagoner DR, Wilson JG, Young T, Zhang Z-M, Zonderman AB, Evans MK, Ferrucci L, Murray SS, Tranah GJ, Whitsel EA, Reiner AP
Secondary AuthorsSotoodehnia N
Corporate AuthorsCHARGE QRS Consortium
JournalHum Mol Genet
Volume25
Issue19
Pagination4350-4368
Date Published2016 10 01
ISSN1460-2083
KeywordsAfrican Americans, Alleles, Cardiovascular Diseases, Electrocardiography, European Continental Ancestry Group, Female, Genome-Wide Association Study, Genotype, Heart Ventricles, Humans, Male, Myocardium, NAV1.5 Voltage-Gated Sodium Channel, Polymorphism, Single Nucleotide
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) 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). 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) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 10). 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), 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.

DOI10.1093/hmg/ddw284
Alternate JournalHum Mol Genet
PubMed ID27577874
PubMed Central IDPMC5291202
Grant ListHHSN268201100010C / HL / NHLBI NIH HHS / United States
U54 NS056883 / NS / NINDS NIH HHS / United States
HHSN268201100002I / HL / NHLBI NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
U01 HG007417 / HG / NHGRI NIH HHS / United States
R01 HL103612 / HL / NHLBI NIH HHS / United States
HHSN268201100001I / HL / NHLBI NIH HHS / United States
HHSN268201100009I / HL / NHLBI NIH HHS / United States
U01 HG007419 / HG / NHGRI NIH HHS / United States
Z01 AG000513 / / Intramural NIH HHS / United States
N01HC95160 / HL / NHLBI NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
R01 HL046380 / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
N01 AG062101 / AG / NIA NIH HHS / United States
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