Journal
CIRCULATION-CARDIOVASCULAR GENETICS
Volume 6, Issue 1, Pages 37-46Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGENETICS.111.962365
Keywords
echocardiography; ethnic; genome-wide association studies; left atrium genetics; left ventricular mass genetics
Funding
- National Institutes of Health (NIH)/National Institute on Minority Health and Health Disparities (NIMHD) [P20]
- Novartis
- Celgene Corp
- Global Iron Summit
- NIH [HL 100245, R01 HL09257, RC1 HD101056, R01 HL102214, R01 AG028321]
- Candidate Gene Association Resource Study, Exome Sequencing Project
- ARIC, NIH
- NIH
- National Heart, Lung, and Blood Institute [HL 087652]
- University of North Carolina at Chapel Hill [N01-HC-55015]
- Baylor Medical College [N01-HC-55016]
- University of Mississippi Medical Center [N01-HC-55021]
- University of Minnesota [N01-HC-55019, N01-HC-48048]
- Johns Hopkins University [N01-HC-55020, N01-HC-85081, N01 HC-15103]
- University of Texas, Houston [N01-HC-55017]
- University of North Carolina, Forsyth County [N01-HC-55018]
- University of Washington [N01-HC-85079, N01 HC-55222, U01 HL080295, N01-HC-95159]
- Wake Forest University [N01-HC-85080, N01-HC-45205]
- University of Pittsburgh [N01-HC-85082]
- University of California, Davis [N01-HC-85083]
- University of California, Irvine [N01-HC-85084, N01-HC-45134, N01-HC-95100]
- New England Medical Center [N01-HC-85085]
- University of Vermont [N01-HC-85086]
- Georgetown University [N01-HC-35129]
- University of Wisconsin [N01-HC-75150]
- Geisinger Clinic [N01-HC-45133]
- Case Western Reserve University [RO1 HL46380-01-16]
- University of Illinois [N01-HB-72982, N01-HB-97062]
- Howard University [N01-HB-72991, N01-HB-97061]
- University of Miami [N01-HB-72992, N01-HB-97064]
- Duke University [N01-HB-72993]
- George Washington University [N01-HB-72994]
- University of Tennessee [N01-HB-72995, N01-HB-97070]
- Yale University [N01-HB-72996, N01-HB-97072]
- Children's Hospital-Philadelphia [N01-HB-72997, N01-HB-97056]
- University of Chicago [N01-HB-72998, N01-HB-97053]
- Medical College of Georgia [N01-HB-73000, N01-HB-97060]
- Washington University [N01-HB-73001, N01-HB-97071]
- Jewish Hospital and Medical Center of Brooklyn [N01-HB-73002]
- Trustees of Health and Hospitals of the City of Boston, Inc. [N01-HB-73003]
- Children's Hospital-Oakland [N01-HB-73004, N01-HB-97054]
- University of Mississippi [N01-HB-73005, N01-HC-95171]
- St. Luke's Hospital-New York [N01-HB-73006]
- Alta Bates-Herrick Hospital [N01-HB-97051]
- Columbia University [N01-HB-97058]
- St. Jude's Children's Research Hospital [N01-HB-97066]
- Research Foundation, State University of New York-Albany [N01-HB-97068, N01-HB-97069]
- New England Research Institute [N01-HB-97073]
- Interfaith Medical Center-Brooklyn [N01-HB-97085]
- University of Alabama at Birmingham [N01-HC-48047, N01-HC-95095]
- Northwestern University [N01-HC-48049]
- Kaiser Foundation Research Institute [N01-HC-48050]
- Tufts-New England Medical Center [N01-HC-45204]
- Harbor-UCLA Research and Education Institute [N01-HC-05187]
- Boston University [N01-HC-25195]
- Jackson State University [N01-HC-95170]
- Tougaloo College [N01-HC-95172]
- Regents of the University of California [N01-HC-95160]
- [R01 HD067264]
- [RC4 AG039029]
- [R01 HL101161-01-A1]
- [R01 DK077950-03]
- [RC1 HL100185]
- [P60 MD002249]
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Background-Using data from 4 community-based cohorts of African Americans, we tested the association between genome-wide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study. Methods and Results-Among 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genome-wide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0x10(-7)). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43x10(-7)) for left ventricular mass, rs7213314 in WIPI1 (P=1.68x10(-7)) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57x10(-8)) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02x10(-7)) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN. Conclusions-In the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes. (Circ Cardiovasc Genet. 2013;6:37-46.)
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