Genetic Variants Associated With Cardiac Structure and Function: A Meta-analysis and Replication of Genome-wide Association Data

• Published in: JAMA : the journal of the American Medical Association Vol. 302; no. 2; pp. 168 - 178
• Main Authors: Vasan, Ramachandran S, Glazer, Nicole L, Felix, Janine F, Lieb, Wolfgang, Wild, Philipp S, Felix, Stephan B, Watzinger, Norbert, Larson, Martin G, Smith, Nicholas L, Dehghan, Abbas, Großhennig, Anika, Schillert, Arne, Teumer, Alexander, Schmidt, Reinhold, Kathiresan, Sekar, Lumley, Thomas, Aulchenko, Yurii S, König, Inke R, Zeller, Tanja, Homuth, Georg, Struchalin, Maksim, Aragam, Jayashri, Bis, Joshua C, Rivadeneira, Fernando, Erdmann, Jeanette, Schnabel, Renate B, Dörr, Marcus, Zweiker, Robert, Lind, Lars, Rodeheffer, Richard J, Greiser, Karin Halina, Levy, Daniel, Haritunians, Talin, Deckers, Jaap W, Stritzke, Jan, Lackner, Karl J, Völker, Uwe, Ingelsson, Erik, Kullo, Iftikhar, Haerting, Johannes, O’Donnell, Christopher J, Heckbert, Susan R, Stricker, Bruno H, Ziegler, Andreas, Reffelmann, Thorsten, Redfield, Margaret M, Werdan, Karl, Mitchell, Gary F, Rice, Kenneth, Arnett, Donna K, Hofman, Albert, Gottdiener, John S, Uitterlinden, Andre G, Meitinger, Thomas, Blettner, Maria, Friedrich, Nele, Wang, Thomas J, Psaty, Bruce M, van Duijn, Cornelia M, Wichmann, H.-Erich, Munzel, Thomas F, Kroemer, Heyo K, Benjamin, Emelia J, Rotter, Jerome I, Witteman, Jacqueline C, Schunkert, Heribert, Schmidt, Helena, Völzke, Henry, Blankenberg, Stefan
• Format: Journal Article
• Language: English
• Published: Chicago, IL American Medical Association 08.07.2009
• Subjects: Adult; Aged; Aged, 80 and over; Aorta - anatomy & histology; Biological and medical sciences; Cardiovascular disease; Cardiovascular Diseases - epidemiology; Cardiovascular Diseases - genetics; Echocardiography; European Continental Ancestry Group; Female; General aspects; Genetics; Genome-Wide Association Study; Genotype; Heart Atria - anatomy & histology; Heart Ventricles - anatomy & histology; Humans; Male; Medical sciences; MEDICIN; Medicin och hälsovetenskap; MEDICINE; Meta-analysis; Middle Aged; Organ Size; Phenotype; Polymorphism, Single Nucleotide; Risk Factors; Studies; Systematic review; Ventricular Dysfunction, Left - genetics; Ventricular Function, Left - genetics; Medicine; Cardiac performance; Association; Genetic variant; Genetics; Replication; Genome; Metaanalysis
• ISSN: 0098-7484; 1538-3598; 1538-3598
• DOI: 10.1001/jama.2009.978-a

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 × 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.