Genetic variants associated with cardiac structure and function: A meta-analysis and replication of genome-wide association data

Ramachandran S. Vasan, Nicole L. Glazer, Janine F. Felix, Wolfgang Lieb, Philipp S. Wild, Stephan B. Felix, Norbert Watzinger, Martin G. Larson, Nicholas L. Smith, Abbas Dehghan, Anika Großhennig, Arne Schillert, Alexander Teumer, Reinhold Schmidt, Sekar Kathiresan, Thomas Lumley, Yurii S. Aulchenko, Inke R. König, Tanja Zeller, Georg HomuthMaksim Struchalin, Jayashri Aragam, Joshua C. Bis, Fernando Rivadeneira, Jeanette Erdmann, Renate B. Schnabel, Marcus Dörr, Robert Zweiker, Lars Lind, Richard J. Rodeheffer, Karin Halina Greiser, Daniel Levy, Talin Haritunians, Jaap W. Deckers, Jan Stritzke, Karl J. Lackner, Uwe Völker, Erik Ingelsson, Iftikhar Kullo, Johannes Haerting, Christopher J. O'Donnell, Susan R. Heckbert, Bruno H. Stricker, Andreas Ziegler, Thorsten Reffelmann, Margaret M. Redfield, Karl Werdan, Gary F. Mitchell, Kenneth Rice, Donna K. Arnett, Albert Hofman, John S. Gottdiener, Andre G. Uitterlinden, Thomas Meitinger, Maria Blettner, Nele Friedrich, Thomas J. Wang, Bruce M. Psaty, Cornelia M. Van Duijn, H. Erich Wichmann, Thomas F. Munzel, Heyo K. Kroemer, Emelia J. Benjamin, Jerome I. Rotter, Jacqueline C. Witteman, Heribert Schunkert, Helena Schmidt, Henry Völzke, Stefan Blankenberg

Research output: Contribution to journalArticle

149 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)168-178
Number of pages11
JournalJAMA - Journal of the American Medical Association
Volume302
Issue number2
DOIs
StatePublished - Jul 8 2009
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Vasan, R. S., Glazer, N. L., Felix, J. F., Lieb, W., Wild, P. S., Felix, S. B., Watzinger, N., Larson, M. G., Smith, N. L., Dehghan, A., Großhennig, A., Schillert, A., Teumer, A., Schmidt, R., Kathiresan, S., Lumley, T., Aulchenko, Y. S., König, I. R., Zeller, T., ... Blankenberg, S. (2009). Genetic variants associated with cardiac structure and function: A meta-analysis and replication of genome-wide association data. JAMA - Journal of the American Medical Association, 302(2), 168-178. https://doi.org/10.1001/jama.2009.978-a