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Genetic Variants Associated With Cardiac Structure and FunctionA Meta-analysis and Replication of Genome-wide Association Data
Ramachandran S. Vasan, MD;
Nicole L. Glazer, PhD;
Janine F. Felix, MD, PhD;
Wolfgang Lieb, MD;
Philipp S. Wild, MD;
Stephan B Felix, MD;
Norbert Watzinger, MD;
Martin G. Larson, ScD;
Nicholas L. Smith, PhD;
Abbas Dehghan, MD, DSc;
Anika Großhennig, PhD;
Arne Schillert, PhD;
Alexander Teumer, Dipl-Math;
Reinhold Schmidt, MD;
Sekar Kathiresan, MD;
Thomas Lumley, PhD;
Yurii S. Aulchenko, PhD;
Inke R. König, PhD;
Tanja Zeller, PhD;
Georg Homuth, PhD;
Maksim Struchalin;
Jayashri Aragam, MD;
Joshua C. Bis, PhD;
Fernando Rivadeneira, MD, PhD;
Jeanette Erdmann, PhD;
Renate B. Schnabel, MD;
Marcus Dörr, MD;
Robert Zweiker, MD;
Lars Lind, MD, PhD;
Richard J. Rodeheffer, MD;
Karin Halina Greiser, MD;
Daniel Levy, MD;
Talin Haritunians, PhD;
Jaap W. Deckers, MD, PhD;
Jan Stritzke, MD;
Karl J. Lackner, PhD;
Uwe Völker, PhD;
Erik Ingelsson, MD, PhD;
Iftikhar Kullo, MD;
Johannes Haerting, PhD;
Christopher J. O’Donnell, MD;
Susan R. Heckbert, MD, PhD;
Bruno H. Stricker, MB, PhD;
Andreas Ziegler, PhD;
Thorsten Reffelmann, MD;
Margaret M. Redfield, MD;
Karl Werdan, MD;
Gary F. Mitchell, MD;
Kenneth Rice, PhD;
Donna K. Arnett, PhD;
Albert Hofman, MD, PhD;
John S. Gottdiener, MD;
Andre G. Uitterlinden, PhD;
Thomas Meitinger, MD;
Maria Blettner, PhD;
Nele Friedrich, PhD;
Thomas J. Wang, MD;
Bruce M. Psaty, MD;
Cornelia M. van Duijn, PhD;
H.-Erich Wichmann, MD, PhD;
Thomas F. Munzel, MD;
Heyo K. Kroemer, PhD;
Emelia J. Benjamin, MD, ScM;
Jerome I. Rotter, MD;
Jacqueline C. Witteman, PhD;
Heribert Schunkert, MD;
Helena Schmidt, MD, PhD;
Henry Völzke, MD;
Stefan Blankenberg, MD
JAMA. 2009;302(2):168-178.
Context Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease.
Objective To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples.
Design, Setting, and Participants Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10-7 to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort.
Main Outcome Measures Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size.
Results In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance).
Conclusions We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.
Author Affiliations: Framingham Heart Study: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham (Drs Vasan, Larson, Kathiresan, Aragam, Levy, O’Donnell, Mitchell, Wang, and Benjamin); Departments of Medicine, Preventive Medicine and Cardiology Sections, Boston University School of Medicine (Drs Vasan and Benjamin) and Department of Mathematics and Statistics, Boston University (Dr Larson), Boston, Massachusetts; and National Heart, Lung, and Blood Institute (Drs O’Donnell and Levy), Bethesda, Maryland. The Cardiovascular Health Study: Cardiovascular Health Research Unit and Department of Medicine (Drs Glazer, Bis, and Psaty), Departments of Biostatistics (Drs Lumley and Rice), Epidemiology (Drs Heckbert, Smith, and Psaty), and Health Services (Dr Psaty), University of Washington, Seattle; Seattle Epidemiologic Research and Information Center of the Department of Veterans Affairs Office of Research and Development (Dr Smith) and Center for Health Studies, Group Health (Dr Psaty), Seattle; Department of Epidemiology, University of Alabama at Birmingham (Dr Arnett); Division of Cardiology, University of Maryland Hospital, Baltimore (Dr Gottdiener); and Medical Genetics Institute, Cedars-Sinai Medical Center, West Los Angeles, California (Drs Haritunians and Rotter). Rotterdam Study: Departments of Epidemiology (Drs J. Felix, Dehghan, Aulchenko, Struchalin, Stricker, Hofman, van Duijn, and Witteman), Internal Medicine (Drs Rivadeneira and Uitterlinden), Cardiology (Dr Deckers), Erasmus MC Rotterdam, the Netherlands; Member of the Netherlands Consortium on Healthy Aging (Drs J. Felix and Witteman). MONICA/KORA: Medical Clinic 2 (Drs Lieb, Großhennig, Erdmann, Stritzke, and Schunkert) and Institute of Medical Biometry and Statistics (Drs Großhennig, König), University of Lübeck, Lübeck; Institutes of Epidemiology (Dr Wichmann) and Human Genetics (Dr Meitinger), Helmholtz Zentrum München, München; German Research Center for Environmental Health, Neuherberg and Ludwig Maximilians University (Dr Wichmann) and German Research Center for Environmental Health, Neuherberg, Technische Universität München (Dr Meitinger), Munich, Germany. Gutenberg Heart Study: Departments of Medicine II (Drs Wild, Zeller, Schnabel, Münzel, and Blankenberg), Clinical Chemistry and Laboratory Medicine (Dr Lackner), Institute of Medical Biometry, Epidemiology, and Informatics (Dr Blettner), Johannes Gutenberg-University, Mainz, and Institute for Medical Biometry and Statistics (Drs Schillert and Ziegler), University Lübeck, Germany. Study of Health in Pomerania: Department of Internal Medicine B (Drs S. Felix, Dörr, and Reffelmann), Interfaculty Institute for Genetics and Functional Genomics (Drs Teumer, Homuth, and Völker), Institute of Pharmacology (Dr Kroemer), and Institute for Community Medicine (Drs Friedrich and Völzke), Ernst-Moritz-Arndt-Universität, Greifswald, Germany (Drs S. Felix, Homuth, Dörr, Völker, Reffelmann, Friedrich, Kroemer, and Völzke and Mr Teumer). Austrian Stroke Prevention Study: Department of Internal Medicine, Division of Cardiology (Drs Watzinger and Zweiker), Department of Neurology (Dr R. Schmidt), and Institute for Molecular Biology and Biochemistry (Dr H. Schmidt), Medical University Graz, Graz, Austria. PIVUS Study: Department of Medical Sciences, Uppsala University, Uppsala (Dr Lind) and Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm (Dr Ingelsson). Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota (Drs Rodeheffer, Kullo, and Redfield). CARLA Study: Institute of Medical Epidemiology, Biostatistics and Informatics (Drs Greiser and Haerting) and Martin-Luther-University, Halle-Wittenberg, Halle (Saale), Germany; and Center for Population Studies, National Heart, Lung, and Blood Institute, Bethesda, Maryland (Dr Levy).
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