Genetic Control of Left Atrial Gene Expression Yields Insights Into the Genetic Susceptibility for Atrial Fibrillation
Document Type
Article
Publication Date
3-1-2018
Publication Title
Circulation. Genomic and precision medicine
Disciplines
Biology
Abstract
BACKGROUND: Genome-wide association studies have identified 23 loci for atrial fibrillation (AF), but the mechanisms responsible for these associations, as well as the causal genes and genetic variants, remain undefined. METHODS: To identify the effect of common genetic variants on gene expression that might explain the mechanisms linking genome-wide association loci with AF risk, we performed RNA sequencing of left atrial appendages from a biracial cohort of 265 subjects. RESULTS: Combining gene expression data with genome-wide single nucleotide polymorphism data, we found that approximately two-thirds of the expressed genes were regulated in cis by common genetic variants at a false discovery rate of <0.05, defined as cis-expression quantitative trait loci. Twelve of 23 reported AF genome-wide association loci displayed genome-wide significant cis-expression quantitative trait loci, at PRRX1 (chromosome 1q24), SNRNP27 (1q24), CEP68 (2p14), FKBP7 (2q31), KCNN2 (5q22), FAM13B (5q31), CAV1 (7q31), ASAH1 (8p22), MYOZ1 (10q22), C11ORF45 (11q24), TBX5 (12q24), and SYNE2 (14q23), suggesting that altered expression of these genes plays a role in AF susceptibility. Allelic expression imbalance was used as an independent method to characterize the cis-control of gene expression. One thousand two hundred forty-eight of 5153 queried genes had cis-single nucleotide polymorphisms that significantly regulated allelic expression at a false discovery rate of <0.05. CONCLUSIONS: We provide a genome-wide catalog of the genetic control of gene expression in human left atrial appendage. These data can be used to confirm the relevance of genome-wide association loci and to direct future functional studies to identify the genes and genetic variants responsible for complex diseases such as AF.
DOI
10.1161/CIRCGEN.118.002107
Recommended Citation
Hsu, Jeffrey; Gore-Panter, Shamone; Tchou, Gregory; Castel, Laurie; Lovano, Beth; Moravec, Christine S.; Pettersson, Gosta B.; Roselli, Eric E.; and Gillinov, A. Marc, "Genetic Control of Left Atrial Gene Expression Yields Insights Into the Genetic Susceptibility for Atrial Fibrillation" (2018). Biological, Geological, and Environmental Faculty Publications. 145.
https://engagedscholarship.csuohio.edu/scibges_facpub/145
Volume
11
Issue
3
Comments
This study was supported by the National Institutes of Health (NIH) grants R01 HL 090620 and R01 HL 111314 to Drs Chung, Wagoner, Barnard, and Smith, the NIH National Center for Research Resources for Case Western Reserve University and Cleveland Clinic Clinical and Translational Science Award UL1-RR024989, the Cleveland Clinic Department of Cardiovascular Medicine philanthropy research funds, and the Tomsich Atrial Fibrillation Research Fund. Dr Hsu was supported by the NIH training grant T32 GM 088088. Dr Smith was supported by the Geoffrey Gund Endowed Chair for Cardiovascular Research.