Title |
Fine-mapping, novel loci identification, and SNP association transferability in a genome-wide association study of QRS duration in African Americans
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Published in |
Human Molecular Genetics, August 2016
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DOI | 10.1093/hmg/ddw284 |
Pubmed ID | |
Authors |
Daniel S. Evans, Christy L. Avery, Mike A. Nalls, Guo Li, John Barnard, Erin N. Smith, Toshiko Tanaka, Anne M. Butler, Sarah G. Buxbaum, Alvaro Alonso, Dan E. Arking, Gerald S. Berenson, Joshua C. Bis, Steven Buyske, Cara L. Carty, Wei Chen, Mina K. Chung, Steven R. Cummings, Rajat Deo, Charles B. Eaton, Ervin R. Fox, Susan R. Heckbert, Gerardo Heiss, Lucia A. Hindorff, Wen-Chi Hsueh, Aaron Isaacs, Yalda Jamshidi, Kathleen F. Kerr, Felix Liu, Yongmei Liu, Kurt K. Lohman, Jared W. Magnani, Joseph F. Maher, Reena Mehra, Yan A. Meng, Solomon K. Musani, Christopher Newton-Cheh, Kari E. North, Bruce M. Psaty, Susan Redline, Jerome I. Rotter, Renate B. Schnabel, Nicholas J. Schork, Ralph V. Shohet, Andrew B. Singleton, Jonathan D. Smith, Elsayed Z. Soliman, Sathanur R. Srinivasan, Herman A. Taylor, David R. Van Wagoner, James G. Wilson, Taylor Young, Zhu-Ming Zhang, Alan B. Zonderman, Michele K. Evans, Luigi Ferrucci, Sarah S. Murray, Gregory J. Tranah, Eric A. Whitsel, Alex P. Reiner, CHARGE QRS Consortium, Nona Sotoodehnia |
Abstract |
The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with QRS duration at 22 loci among those of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a 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=4x10(-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=1.1x10(-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=4.9x10(-8)) and chromosome 1 near CD1E and SPTA1 (rs7547997, P=7.9x10(-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=9.9x10(-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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 2 | 33% |
Netherlands | 1 | 17% |
United Kingdom | 1 | 17% |
Unknown | 2 | 33% |
Demographic breakdown
Type | Count | As % |
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Scientists | 3 | 50% |
Members of the public | 3 | 50% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Unknown | 66 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 11 | 17% |
Researcher | 9 | 14% |
Student > Bachelor | 8 | 12% |
Professor > Associate Professor | 7 | 11% |
Other | 6 | 9% |
Other | 12 | 18% |
Unknown | 13 | 20% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 16 | 24% |
Medicine and Dentistry | 10 | 15% |
Agricultural and Biological Sciences | 7 | 11% |
Psychology | 3 | 5% |
Nursing and Health Professions | 2 | 3% |
Other | 10 | 15% |
Unknown | 18 | 27% |