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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

Citation

Evans, Daniel S.; Avery, Christy L.; Nalls, Mike A.; Li, Guo; Barnard, John; Smith, Erin N.; Tanaka, Toshiko; Butler, Anne M.; Buxbaum, Sarah G.; & Alonso, Alvaro, et al. (2016). Fine-Mapping, Novel Loci Identification, and SNP Association Transferability in a Genome-Wide Association Study of QRS Duration in African Americans. Human Molecular Genetics, 25(19), 4350-4368. PMCID: PMC5291202

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 x 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 x 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 x 10-8) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 x 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 x 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.

URL

http://dx.doi.org/10.1093/hmg/ddw284

Reference Type

Journal Article

Year Published

2016

Journal Title

Human Molecular Genetics

Author(s)

Evans, Daniel S.
Avery, Christy L.
Nalls, Mike A.
Li, Guo
Barnard, John
Smith, Erin N.
Tanaka, Toshiko
Butler, Anne M.
Buxbaum, Sarah G.
Alonso, Alvaro
Arking, Dan E.
Berenson, Gerald S.
Bis, Joshua C.
Buyske, Steven G.
Carty, Cara L.
Chen, Wei
Chung, Mina K.
Cummings, Steven R.
Deo, Rajat
Eaton, Charles B.
Fox, Ervin R.
Heckbert, Susan R.
Heiss, Gerardo M.
Hindorff, Lucia A.
Hsueh, Wen-Chi
Isaacs, Aaron J.
Jamshidi, Yalda
Kerr, Kathleen F.
Liu, Felix
Liu, Yongmei
Lohman, Kurt K.
Magnani, Jared W.
Maher, Joseph F.
Mehra, Reena
Meng, Yan A.
Musani, Solomon K.
Newton-Cheh, Christopher H.
North, Kari E.
Psaty, Bruce M.
Redline, Susan S.
Rotter, Jerome I.
Schnabel, Renate B.
Schork, Nicholas J.
Shohet, Ralph V.
Singleton, Andrew B.
Smith, Jonathan D.
Soliman, Elsayed Z.
Srinivasan, Sathanur R.
Taylor, Herman A., Jr.
Van Wagoner, David R.
Wilson, James G.
Young, Taylor R.
Zhang, Zhu-Ming
Zonderman, Alan B.
Evans, Michele K.
Ferrucci, Luigi
Murray, Sarah S.
Tranah, Gregory J.
Whitsel, Eric A.
Reiner, Alexander P.

PMCID

PMC5291202