Genome wide association analysis in dilated cardiomyopathy reveals two new key players in systolic heart failure on chromosomes 3p25.1 and 22q11.23

Garnier, Sophie; Harakaľová, Magdaléna; Stefan, W.; Michal, M.; Isnard, R.; Duboscq-Bidot, L.; Komajda, Michel; Cambien, F.; Deleuze, Jean‐François; Dörr, M; Asselbergs, F. W.; Villard, Eric; Trégouët, David‐Alexandre; Charron, P.

doi:10.1016/j.acvdsp.2021.04.147

Cited by 3 publications

(4 citation statements)

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“…The estimated proportion of variance in disease liability explained by common genetic variants, i.e. SNP-based heritability ( h 2 g ), was 5.4 ± 0.2% for HF; 6.1 ± 0.5% for non-ischaemic HF; 11.8 ± 2.6% for non-ischaemic HFrEF, and 1.8 ± 1.3% for non-ischaemic HFpEF ( Supplementary Figure 8 ) 6 . All HF phenotype pairs demonstrated positive genetic correlations, with estimates ranging from 0.42 (standard error, SE = 0.18) between ni-HFrEF and ni-HFpEF to 0.93 (SE = 0.15) between ni-HF and ni-HFpEF ( Supplementary Figure 9 ).…”

Section: Resultsmentioning

confidence: 99%

Mapping the aetiological foundations of the heart failure spectrum using human genetics

Henry,

Mo,

Finan

et al. 2023

Preprint

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Summary paragraphHeart failure (HF), a syndrome of symptomatic fluid overload due to cardiac dysfunction, is the most rapidly growing cardiovascular disorder. Despite recent advances, mortality and morbidity remain high and treatment innovation is challenged by limited understanding of aetiology in relation to disease subtypes. Here we harness the de-confounding properties of genetic variation to map causal biology underlying the HF phenotypic spectrum, to inform the development of more effective treatments. We report a genetic association analysis in 1.9 million ancestrally diverse individuals, including 153,174 cases of HF; 44,012 of non-ischaemic HF; 5,406 cases of non-ischaemic HF with reduced ejection fraction (HFrEF); and 3,841 cases of non-ischaemic HF with preserved ejection fraction (HFpEF). We identify 66 genetic susceptibility loci across HF subtypes, 37 of which have not previously been reported. We map the aetiologic contribution of risk factor traits and diseases as well as newly identified effector genes for HF, demonstrating differential risk factor effects on disease subtypes. Our findings highlight the importance of extra-cardiac tissues in HF, particularly the kidney and the vasculature in HFpEF. Pathways of cellular senescence and proteostasis are notably uncovered, includingIGFBP7as an effector gene for HFpEF. Using population approaches causally anchored in human genetics, we provide fundamental new insights into the aetiology of heart failure subtypes that may inform new approaches to prevention and treatment.

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Section: Resultsmentioning

confidence: 99%

Mapping the aetiological foundations of the heart failure spectrum using human genetics

Henry,

Mo,

Finan

et al. 2023

Preprint

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“…The current genome-wide association study (GWAS) meta-analysis included 14,255 cases and 1,199,156 controls of European ancestry from 16 studies in the HERMES Consortium (cohorts described in Supplementary Methods and Table S1 ). Genotyping for 15 of 16 studies were performed locally in each participating study using high-density genotyping arrays imputed against reference whole-genome sequencing panels from the Haplotype Reference Consortium (HRC) (14 studies), 1000 Genomes Project (Garnier et al 37 ), or population-specific reference panels (Estonian Biobank and deCODE) ( Supplementary Methods ). Genotyping for the Genomics England cohort was done using whole genome sequencing.…”

Section: Methodsmentioning

confidence: 99%

“…To define a genomic locus, conditionally independent genetic variants across both DCM GWAS and MTAG that are located within 500kb of each other were aggregated, and an additional 500kb were added to flank the variants at the extremes within each set. A genomic locus was considered novel if all conditionally independent variants within the locus are located ≥250kb away and not in LD ( R 2 ) with any sentinel variant with a P <5x10 −8 reported in previously published GWAS of DCM 8,37 .…”

Section: Methodsmentioning

confidence: 99%

Genome-wide association analysis reveals insights into the molecular etiology underlying dilated cardiomyopathy

Zheng,

Henry,

Cannie

et al. 2023

Preprint

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Dilated cardiomyopathy (DCM) is a clinical disorder characterised by reduced contractility of the heart muscle that is not explained by coronary artery disease or abnormal haemodynamic loading. Although Mendelian disease is well described, clinical testing yields a genetic cause in a minority of patients. The role of complex inheritance is emerging, however the common genetic architecture is relatively unexplored. To improve our understanding of the genetic basis of DCM, we perform a genome-wide association study (GWAS) meta-analysis comprising 14,255 DCM cases and 1,199,156 controls, and a multi-trait GWAS incorporating correlated cardiac magnetic resonance imaging traits of 36,203 participants. We identify 80 genetic susceptibility loci and prioritize 61 putative effector genes for DCM by synthesizing evidence from 8 gene prioritization strategies. Rare variant association testing identifies genes associated with DCM, includingMAP3K7, NEDD4L, andSSPN. Through integration with single-nuclei transcriptomics from 52 end-stage DCM patients and 18 controls, we identify cellular states, biological pathways, and intercellular communications driving DCM pathogenesis. Finally, we demonstrate that a polygenic score predicts DCM in the general population and modulates the penetrance of rare pathogenic and likely pathogenic variants in DCM-causing genes. Our findings may inform the design of novel clinical genetic testing strategies incorporating polygenic background and the genes and pathways identified may inform the development of targeted therapeutics.

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“…In one of the largest GWAS studies on DCM patients, two novel SNPs on chromosomes 3 and 21 were discovered to be linked to the DCM phenotype. 35 Liu et al, on the other hand, used RNA-seq to examine the SOX family gene expression levels in patients with DCM and HCM leading to heart failure. 36 They discovered an increase in this cohort's SOX4 and SOX8 gene levels.…”

Section: Genetic Variants Of Hereditary Cardiomyopathymentioning

confidence: 99%

Exploring Health Care Disparities in Genetic Testing and Research for Hereditary Cardiomyopathy: Current State and Future Perspectives

Huang,

Verma,

Mok

et al. 2024

Glob Med Genet

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Background Hereditary cardiomyopathies are commonly occurring myocardial conditions affecting heart structure and function with a genetic or familial association, but the etiology is often unknown. Cardiomyopathies are linked to significant mortality, requiring robust risk stratification with genetic testing and early diagnosis. Hypothesis We hypothesized that health care disparities exist in genetic testing for hereditary cardiomyopathies within clinical practice and research studies. Methods In a narrative fashion, we conducted a literature search with online databases such as PubMed/MEDLINE, Google Scholar, EMBASE, and Science Direct on papers related to hereditary cardiomyopathies. A comprehensive analysis of findings from articles in English on disparities in diagnostics and treatment was grouped into four categories. Results Racial and ethnic disparities in research study enrollment and health care delivery favor White populations and higher socioeconomic status, resulting in differences in the development and implementation of effective genetic screening. Such disparities have shown to be detrimental, as minorities often suffer from disease progression to heart failure and sudden cardiac death. Barriers related to clinical genetic testing included insurance-related issues and health illiteracy. The underrepresentation of minority populations extends to research methodologies, as testing in ethnic minorities resulted in a significantly lower detection rate and diagnostic yield, as well as a higher likelihood of misclassification of variants. Conclusions Prioritizing minority-based participatory research programs and screening protocols can address systemic disparities. Diversifying research studies can improve risk stratification strategies and impact clinical practice.

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Genome wide association analysis in dilated cardiomyopathy reveals two new key players in systolic heart failure on chromosomes 3p25.1 and 22q11.23

Cited by 3 publications

References 0 publications

Mapping the aetiological foundations of the heart failure spectrum using human genetics

Mapping the aetiological foundations of the heart failure spectrum using human genetics

Genome-wide association analysis reveals insights into the molecular etiology underlying dilated cardiomyopathy

Exploring Health Care Disparities in Genetic Testing and Research for Hereditary Cardiomyopathy: Current State and Future Perspectives

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