A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy
French Institute of Health and Medical Research1, Pierre-and-Marie-Curie University2, University Hospital Regensburg3, University of Lübeck4, Imperial College London5, National Institutes of Health6, Charité7, Umeå University8, University of Hull9, Centre national de la recherche scientifique10, University of Mainz11, University of Leicester12
01 May 2011-Vol. 32, Iss: 9, pp 1065-1076
TL;DR: The results show that rare mutations in BAG3 contribute to monogenic forms of the disease, while common variant(s) in the same gene are implicated in sporadic DCM.
Abstract: Aims: Dilated cardiomyopathy (DCM) is a major cause of heart failure with a high familial recurrence risk. So far, the genetics of DCM remains largely unresolved. We conducted the first genome-wide ...
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TL;DR: In insights into the role of alcohol consumption in the genetic architecture of hypertension, a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions is conducted.
Abstract: Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.
1,218 citations
Cites background from "A genome-wide association study ide..."
...A GWAS identified association of BAG3 with dilated cardiomyopathy[65], and suggestive association with alcohol dependence[44]....
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TL;DR: Reassessment of assumptions about the complexity of the genomic and phenomic architecture of DCM is warranted, which will require comprehensive genomic studies in much larger cohorts of rigorously phenotyped probands and family members than previously examined.
Abstract: Remarkable progress has been made in understanding the genetic basis of dilated cardiomyopathy (DCM). Rare variants in >30 genes, some also involved in other cardiomyopathies, muscular dystrophy, or syndromic disease, perturb a diverse set of important myocardial proteins to produce a final DCM phenotype. Large, publicly available datasets have provided the opportunity to evaluate previously identified DCM-causing mutations, and to examine the population frequency of sequence variants similar to those that have been observed to cause DCM. The frequency of these variants, whether associated with dilated or hypertrophic cardiomyopathy, is greater than estimates of disease prevalence. This mismatch might be explained by one or more of the following possibilities: that the penetrance of DCM-causing mutations is lower than previously thought, that some variants are noncausal, that DCM prevalence is higher than previously estimated, or that other more-complex genomics underlie DCM. Reassessment of our assumptions about the complexity of the genomic and phenomic architecture of DCM is warranted. Much about the genomic basis of DCM remains to be investigated, which will require comprehensive genomic studies in much larger cohorts of rigorously phenotyped probands and family members than previously examined.
728 citations
Heidelberg University1, University Hospital Heidelberg2, Saarland University3, Princeton University4, Siemens5, French Institute of Health and Medical Research6, University College London7, Aarhus University Hospital8, Umeå University9, University of Milan10, University of Pavia11, University of Southern Denmark12
TL;DR: This is to the authors' knowledge, the first study that comprehensively investigated the genetics of DCM in a large-scale cohort and across a broad gene panel of the known DCM genes and underline the high analytical quality and feasibility of Next-Generation Sequencing in clinical genetic diagnostics.
Abstract: Aim: We were able to show that targeted Next-Generation Sequencing is well suited to be applied in clinical routine diagnostics, substantiating the ongoing paradigm shift from low- to high-throughp ...
444 citations
Cites methods from "A genome-wide association study ide..."
...7%), family-based whole exome sequencing or alternative approaches should be applied to identify possible genetic defects in so far unknown disease genes, with BAG3 being one recent example.(22,23)...
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TL;DR: Relatively few clinical clues guide the diagnosis of inherited DCM, but emerging evidence supports the use of genetic testing to identify those patients at risk for faster disease progression, congestive heart failure, and arrhythmia.
Abstract: Genetic mutations account for a significant percentage of cardiomyopathies, which are a leading cause of congestive heart failure. In hypertrophic cardiomyopathy (HCM), cardiac output is limited by the thickened myocardium through impaired filling and outflow. Mutations in the genes encoding the thick filament components myosin heavy chain and myosin binding protein C (MYH7 and MYBPC3) together explain 75% of inherited HCMs, leading to the observation that HCM is a disease of the sarcomere. Many mutations are “private” or rare variants, often unique to families. In contrast, dilated cardiomyopathy (DCM) is far more genetically heterogeneous, with mutations in genes encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium-handling proteins. DCM is characterized by enlarged ventricular dimensions and impaired systolic and diastolic function. Private mutations account for most DCMs, with few hotspots or recurring mutations. More than 50 single genes are linked to inherited DCM, including many genes that also link to HCM. Relatively few clinical clues guide the diagnosis of inherited DCM, but emerging evidence supports the use of genetic testing to identify those patients at risk for faster disease progression, congestive heart failure, and arrhythmia.
372 citations
Cites background from "A genome-wide association study ide..."
...A genomewide association study identified a region that included the HSPB7 gene and the CLCNKA gene (56, 57)....
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References
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TL;DR: LocusZoom is a web-based plotting tool that provides fast visual display of GWAS results in a publication-ready format that visually displays regional information such as the strength and extent of the association signal relative to genomic position, local linkage disequilibrium (LD) and recombination patterns and the positions of genes in the region.
Abstract: Summary: Genome-wide association studies (GWAS) have revealed hundreds of loci associated with common human genetic diseases and traits. We have developed a web-based plotting tool that provides fast visual display of GWAS results in a publication-ready format. LocusZoom visually displays regional information such as the strength and extent of the association signal relative to genomic position, local linkage disequilibrium (LD) and recombination patterns
2,454 citations
TL;DR: This document, The European Society of Cardiology Working Group on Myocardial and Pericardial Diseases presents an update of the existing classification scheme, to help clinicians look beyond generic diagnostic labels in order to reach more specific diagnoses.
Abstract: In biology, classification systems are used to promote understanding and systematic discussion through the use of logical groups and hierarchies In clinical medicine, similar principles are used to standardise the nomenclature of disease For more than three decades, heart muscle diseases have been classified into primary or idiopathic myocardial diseases (cardiomyopathies) and secondary disorders that have similar morphological appearances, but which are caused by an identifiable pathology such as coronary artery disease or myocardial infiltration (specific heart muscle diseases) In this document, The European Society of Cardiology Working Group on Myocardial and Pericardial Diseases presents an update of the existing classification scheme The aim is to help clinicians look beyond generic diagnostic labels in order to reach more specific diagnoses
2,370 citations
"A genome-wide association study ide..." refers background in this paper
...Idiopathic dilated cardiomyopathy (DCM) is a form of heart failure (HF) defined by the presence of left ventricular dilatation and left ventricular systolic dysfunction in the absence of an obvious aetiology, such as coronary artery disease (CAD), hypertension, valvular disease, or congenital defect.(1) –3 Dilated cardiomyopathy is a major cause of systolic HF and the main indication for heart transplantation....
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TL;DR: A World Wide Web server is presented to predict the effect of an nsSNP on protein structure and function and the dependence of selective pressure on the structural and functional properties of proteins is studied.
Abstract: Human single nucleotide polymorphisms (SNPs) represent the most frequent type of human population DNA variation. One of the main goals of SNP research is to understand the genetics of the human phenotype variation and especially the genetic basis of human complex diseases. Non-synonymous coding SNPs (nsSNPs) comprise a group of SNPs that, together with SNPs in regulatory regions, are believed to have the highest impact on phenotype. Here we present a World Wide Web server to predict the effect of an nsSNP on protein structure and function. The prediction method enabled analysis of the publicly available SNP database HGVbase, which gave rise to a dataset of nsSNPs with predicted functionality. The dataset was further used to compare the effect of various structural and functional characteristics of amino acid substitutions responsible for phenotypic display of nsSNPs. We also studied the dependence of selective pressure on the structural and functional properties of proteins. We found that in our dataset the selection pressure against deleterious SNPs depends on the molecular function of the protein, although it is insensitive to several other protein features considered. The strongest selective pressure was detected for proteins involved in transcription regulation.
2,276 citations
"A genome-wide association study ide..." refers background in this paper
...The cysteine to arginine substitution at Position 151 of the BAG3 protein is predicted to be probably damaging by the Polyphen tool.(27) As rs2234962 could tag functional SNPs absent from the genotyping array used in our study, we examined the LD of this SNP with other variants in the region and observed that only two SNPs in HapMap release 22 were in tight LD (r(2) ....
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TL;DR: Several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease are identified.
Abstract: A b s t r ac t Background Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease. Methods We first identified chromosomal loci that were strongly associated with coronary ar- tery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI (Myocardial Infarction) Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single- nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P 80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). Conclusions We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease.
2,000 citations
01 Nov 2005
TL;DR: The HapMap Web site at http://www.hapmap.org is the primary portal to genotype data produced as part of the International Haplotype Map Project.
Abstract: The HapMap Web site at http://www.hapmap.org is the primary portal to genotype data produced as part of the International Haplotype Map Project. In phase I of the project, >1.1 million SNPs were genotyped in 270 individuals from four worldwide populations. The HapMap Web site provides researchers with a number of tools that allow them to analyze the data as well as download data for local analyses. This paper presents step-by-step guides to using those tools, including guides for retrieving genotype and frequency data, picking tag-SNPs for use in association studies, viewing haplotypes graphically, and examining marker-to-marker LD patterns.
1,367 citations