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

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.

SUBMITTER: Vasan RS

PROVIDER: S-EPMC2975567 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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

Vasan Ramachandran S RS Glazer Nicole L NL Felix Janine F JF Lieb Wolfgang W Wild Philipp S PS Felix Stephan B SB Watzinger Norbert N Larson Martin G MG Smith Nicholas L NL Dehghan Abbas A Grosshennig Anika A Schillert Arne A Teumer Alexander A Schmidt Reinhold R Kathiresan Sekar S Lumley Thomas T Aulchenko Yurii S YS König Inke R IR Zeller Tanja T Homuth Georg G Struchalin Maksim M Aragam Jayashri J Bis Joshua C JC Rivadeneira Fernando F Erdmann Jeanette J Schnabel Renate B RB Dörr Marcus M Zweiker Robert R Lind Lars L Rodeheffer Richard J RJ Greiser Karin Halina KH Levy Daniel D Haritunians Talin T Deckers Jaap W JW Stritzke Jan J Lackner Karl J KJ Völker Uwe U Ingelsson Erik E Kullo Iftikhar I Haerting Johannes J O'Donnell Christopher J CJ Heckbert Susan R SR Stricker Bruno H BH Ziegler Andreas A Reffelmann Thorsten T Redfield Margaret M MM Werdan Karl K Mitchell Gary F GF Rice Kenneth K Arnett Donna K DK Hofman Albert A Gottdiener John S JS Uitterlinden Andre G AG Meitinger Thomas T Blettner Maria M Friedrich Nele N Wang Thomas J TJ Psaty Bruce M BM van Duijn Cornelia M CM Wichmann H-Erich HE Munzel Thomas F TF Kroemer Heyo K HK Benjamin Emelia J EJ Rotter Jerome I JI Witteman Jacqueline C JC Schunkert Heribert H Schmidt Helena H Völzke Henry H Blankenberg Stefan S

JAMA 20090701 2

<h4>Context</h4>Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease.<h4>Objective</h4>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.<h4>Design, setting, and participants</h4>Within each of 5 community-based cohorts com ...[more]

PMID: 19584346

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Project description:BackgroundEndometriosis is a heritable common gynaecological condition influenced by multiple genetic and environmental factors. Genome-wide association studies (GWASs) have proved successful in identifying common genetic variants of moderate effects for various complex diseases. To date, eight GWAS and replication studies from multiple populations have been published on endometriosis. In this review, we investigate the consistency and heterogeneity of the results across all the studies and their implications for an improved understanding of the aetiology of the condition.MethodsMeta-analyses were conducted on four GWASs and four replication studies including a total of 11 506 cases and 32 678 controls, and on the subset of studies that investigated associations for revised American Fertility Society (rAFS) Stage III/IV including 2859 cases. The datasets included 9039 cases and 27 343 controls of European (Australia, Belgium, Italy, UK, USA) and 2467 cases and 5335 controls of Japanese ancestry. Fixed and Han and Elkin random-effects models, and heterogeneity statistics (Cochran's Q test), were used to investigate the evidence of the nine reported genome-wide significant loci across datasets and populations.ResultsMeta-analysis showed that seven out of nine loci had consistent directions of effect across studies and populations, and six out of nine remained genome-wide significant (P < 5 × 10(-8)), including rs12700667 on 7p15.2 (P = 1.6 × 10(-9)), rs7521902 near WNT4 (P = 1.8 × 10(-15)), rs10859871 near VEZT (P = 4.7 × 10(-15)), rs1537377 near CDKN2B-AS1 (P = 1.5 × 10(-8)), rs7739264 near ID4 (P = 6.2 × 10(-10)) and rs13394619 in GREB1 (P = 4.5 × 10(-8)). In addition to the six loci, two showed borderline genome-wide significant associations with Stage III/IV endometriosis, including rs1250248 in FN1 (P = 8 × 10(-8)) and rs4141819 on 2p14 (P = 9.2 × 10(-8)). Two independent inter-genic loci, rs4141819 and rs6734792 on chromosome 2, showed significant evidence of heterogeneity across datasets (P < 0.005). Eight of the nine loci had stronger effect sizes among Stage III/IV cases, implying that they are likely to be implicated in the development of moderate to severe, or ovarian, disease. While three out of nine loci were inter-genic, the remaining were in or near genes with known functions of biological relevance to endometriosis, varying from roles in developmental pathways to cellular growth/carcinogenesis.ConclusionsOur meta-analysis shows remarkable consistency in endometriosis GWAS results across studies, with little evidence of population-based heterogeneity. They also show that the phenotypic classifications used in GWAS to date have been limited. Stronger associations with Stage III/IV disease observed for most loci emphasize the importance for future studies to include detailed sub-phenotype information. Functional studies in relevant tissues are needed to understand the effect of the variants on downstream biological pathways.

Project description:BACKGROUND:Using data from 4 community-based cohorts of African Americans, we tested the association between genome-wide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study. METHODS AND RESULTS:Among 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genome-wide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0?×10(-7)). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43×10(-7)) for left ventricular mass, rs7213314 in WIPI1 (P=1.68×10(-7)) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57×10(-8)) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02×10(-7)) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN. CONCLUSIONS:In the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.

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

Publications

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

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