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Original Article

Genetic Control of Left Atrial Gene Expression Yields Insights into the Genetic Susceptibility for Atrial Fibrillation

Jeffrey Hsu, Shamone Gore-Panter, Gregory Tchou, Laurie Castel, Beth Lovano, Christine S. Moravec, Gosta B. Pettersson, Eric E. Roselli, A. Marc Gillinov, Kenneth R. McCurry, Nicholas G. Smedira, John Barnard, David R. Van Wagoner, Mina K. Chung, Jonathan D. Smith
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https://doi.org/10.1161/CIRCGEN.118.002107
Circ Genom Precis Med. 2018;11:e002107
Originally published March 15, 2018
Jeffrey Hsu
From the Departments of Cellular and Molecular Medicine (J.H., G.T., J.D.S.), Quantitative Health Sciences (J.B.), Molecular Cardiology (S.G.-P., L.C., B.L., C.S.M., D.R.V.W., M.K.C.), Cardiovascular Medicine (C.S.M., D.R.V.W., M.K.C., J.D.S.), and Cardiothoracic Surgery (G.B.P., E.E.R., A.M.G., K.R.M., N.G.S.), Cleveland Clinic, Cleveland, OH.
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Shamone Gore-Panter
From the Departments of Cellular and Molecular Medicine (J.H., G.T., J.D.S.), Quantitative Health Sciences (J.B.), Molecular Cardiology (S.G.-P., L.C., B.L., C.S.M., D.R.V.W., M.K.C.), Cardiovascular Medicine (C.S.M., D.R.V.W., M.K.C., J.D.S.), and Cardiothoracic Surgery (G.B.P., E.E.R., A.M.G., K.R.M., N.G.S.), Cleveland Clinic, Cleveland, OH.
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Gregory Tchou
From the Departments of Cellular and Molecular Medicine (J.H., G.T., J.D.S.), Quantitative Health Sciences (J.B.), Molecular Cardiology (S.G.-P., L.C., B.L., C.S.M., D.R.V.W., M.K.C.), Cardiovascular Medicine (C.S.M., D.R.V.W., M.K.C., J.D.S.), and Cardiothoracic Surgery (G.B.P., E.E.R., A.M.G., K.R.M., N.G.S.), Cleveland Clinic, Cleveland, OH.
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Laurie Castel
From the Departments of Cellular and Molecular Medicine (J.H., G.T., J.D.S.), Quantitative Health Sciences (J.B.), Molecular Cardiology (S.G.-P., L.C., B.L., C.S.M., D.R.V.W., M.K.C.), Cardiovascular Medicine (C.S.M., D.R.V.W., M.K.C., J.D.S.), and Cardiothoracic Surgery (G.B.P., E.E.R., A.M.G., K.R.M., N.G.S.), Cleveland Clinic, Cleveland, OH.
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Beth Lovano
From the Departments of Cellular and Molecular Medicine (J.H., G.T., J.D.S.), Quantitative Health Sciences (J.B.), Molecular Cardiology (S.G.-P., L.C., B.L., C.S.M., D.R.V.W., M.K.C.), Cardiovascular Medicine (C.S.M., D.R.V.W., M.K.C., J.D.S.), and Cardiothoracic Surgery (G.B.P., E.E.R., A.M.G., K.R.M., N.G.S.), Cleveland Clinic, Cleveland, OH.
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Christine S. Moravec
From the Departments of Cellular and Molecular Medicine (J.H., G.T., J.D.S.), Quantitative Health Sciences (J.B.), Molecular Cardiology (S.G.-P., L.C., B.L., C.S.M., D.R.V.W., M.K.C.), Cardiovascular Medicine (C.S.M., D.R.V.W., M.K.C., J.D.S.), and Cardiothoracic Surgery (G.B.P., E.E.R., A.M.G., K.R.M., N.G.S.), Cleveland Clinic, Cleveland, OH.
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Gosta B. Pettersson
From the Departments of Cellular and Molecular Medicine (J.H., G.T., J.D.S.), Quantitative Health Sciences (J.B.), Molecular Cardiology (S.G.-P., L.C., B.L., C.S.M., D.R.V.W., M.K.C.), Cardiovascular Medicine (C.S.M., D.R.V.W., M.K.C., J.D.S.), and Cardiothoracic Surgery (G.B.P., E.E.R., A.M.G., K.R.M., N.G.S.), Cleveland Clinic, Cleveland, OH.
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Eric E. Roselli
From the Departments of Cellular and Molecular Medicine (J.H., G.T., J.D.S.), Quantitative Health Sciences (J.B.), Molecular Cardiology (S.G.-P., L.C., B.L., C.S.M., D.R.V.W., M.K.C.), Cardiovascular Medicine (C.S.M., D.R.V.W., M.K.C., J.D.S.), and Cardiothoracic Surgery (G.B.P., E.E.R., A.M.G., K.R.M., N.G.S.), Cleveland Clinic, Cleveland, OH.
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A. Marc Gillinov
From the Departments of Cellular and Molecular Medicine (J.H., G.T., J.D.S.), Quantitative Health Sciences (J.B.), Molecular Cardiology (S.G.-P., L.C., B.L., C.S.M., D.R.V.W., M.K.C.), Cardiovascular Medicine (C.S.M., D.R.V.W., M.K.C., J.D.S.), and Cardiothoracic Surgery (G.B.P., E.E.R., A.M.G., K.R.M., N.G.S.), Cleveland Clinic, Cleveland, OH.
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Kenneth R. McCurry
From the Departments of Cellular and Molecular Medicine (J.H., G.T., J.D.S.), Quantitative Health Sciences (J.B.), Molecular Cardiology (S.G.-P., L.C., B.L., C.S.M., D.R.V.W., M.K.C.), Cardiovascular Medicine (C.S.M., D.R.V.W., M.K.C., J.D.S.), and Cardiothoracic Surgery (G.B.P., E.E.R., A.M.G., K.R.M., N.G.S.), Cleveland Clinic, Cleveland, OH.
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Nicholas G. Smedira
From the Departments of Cellular and Molecular Medicine (J.H., G.T., J.D.S.), Quantitative Health Sciences (J.B.), Molecular Cardiology (S.G.-P., L.C., B.L., C.S.M., D.R.V.W., M.K.C.), Cardiovascular Medicine (C.S.M., D.R.V.W., M.K.C., J.D.S.), and Cardiothoracic Surgery (G.B.P., E.E.R., A.M.G., K.R.M., N.G.S.), Cleveland Clinic, Cleveland, OH.
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John Barnard
From the Departments of Cellular and Molecular Medicine (J.H., G.T., J.D.S.), Quantitative Health Sciences (J.B.), Molecular Cardiology (S.G.-P., L.C., B.L., C.S.M., D.R.V.W., M.K.C.), Cardiovascular Medicine (C.S.M., D.R.V.W., M.K.C., J.D.S.), and Cardiothoracic Surgery (G.B.P., E.E.R., A.M.G., K.R.M., N.G.S.), Cleveland Clinic, Cleveland, OH.
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David R. Van Wagoner
From the Departments of Cellular and Molecular Medicine (J.H., G.T., J.D.S.), Quantitative Health Sciences (J.B.), Molecular Cardiology (S.G.-P., L.C., B.L., C.S.M., D.R.V.W., M.K.C.), Cardiovascular Medicine (C.S.M., D.R.V.W., M.K.C., J.D.S.), and Cardiothoracic Surgery (G.B.P., E.E.R., A.M.G., K.R.M., N.G.S.), Cleveland Clinic, Cleveland, OH.
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Mina K. Chung
From the Departments of Cellular and Molecular Medicine (J.H., G.T., J.D.S.), Quantitative Health Sciences (J.B.), Molecular Cardiology (S.G.-P., L.C., B.L., C.S.M., D.R.V.W., M.K.C.), Cardiovascular Medicine (C.S.M., D.R.V.W., M.K.C., J.D.S.), and Cardiothoracic Surgery (G.B.P., E.E.R., A.M.G., K.R.M., N.G.S.), Cleveland Clinic, Cleveland, OH.
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Jonathan D. Smith
From the Departments of Cellular and Molecular Medicine (J.H., G.T., J.D.S.), Quantitative Health Sciences (J.B.), Molecular Cardiology (S.G.-P., L.C., B.L., C.S.M., D.R.V.W., M.K.C.), Cardiovascular Medicine (C.S.M., D.R.V.W., M.K.C., J.D.S.), and Cardiothoracic Surgery (G.B.P., E.E.R., A.M.G., K.R.M., N.G.S.), Cleveland Clinic, Cleveland, OH.
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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.

  • alleles
  • atrial appendage
  • atrial fibrillation
  • genomics
  • quantitative trait loci
  • Received March 7, 2017.
  • Accepted January 23, 2018.
  • © 2018 American Heart Association, Inc.
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March 2018, Volume 11, Issue 3
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    Genetic Control of Left Atrial Gene Expression Yields Insights into the Genetic Susceptibility for Atrial Fibrillation
    Jeffrey Hsu, Shamone Gore-Panter, Gregory Tchou, Laurie Castel, Beth Lovano, Christine S. Moravec, Gosta B. Pettersson, Eric E. Roselli, A. Marc Gillinov, Kenneth R. McCurry, Nicholas G. Smedira, John Barnard, David R. Van Wagoner, Mina K. Chung and Jonathan D. Smith
    Circ Genom Precis Med. 2018;11:e002107, originally published March 15, 2018
    https://doi.org/10.1161/CIRCGEN.118.002107

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    Genetic Control of Left Atrial Gene Expression Yields Insights into the Genetic Susceptibility for Atrial Fibrillation
    Jeffrey Hsu, Shamone Gore-Panter, Gregory Tchou, Laurie Castel, Beth Lovano, Christine S. Moravec, Gosta B. Pettersson, Eric E. Roselli, A. Marc Gillinov, Kenneth R. McCurry, Nicholas G. Smedira, John Barnard, David R. Van Wagoner, Mina K. Chung and Jonathan D. Smith
    Circ Genom Precis Med. 2018;11:e002107, originally published March 15, 2018
    https://doi.org/10.1161/CIRCGEN.118.002107
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