Journal
PLOS ONE
Volume 12, Issue 3, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0172995
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Funding
- Leducq Transatlantic Network
- BestAgeing FP7 European Community project
- Conny Maeva Charitable Foundation
- British Heart Foundation, UK [PG/12/27/29489]
- NMRC Singapore
- Medical Research Council, UK
- Tanoto Foundation
- National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust, Biomedical Research Unit in Cardiovascular Disease at Royal Brompton Harefield NHS Foundation Trust and Imperial College London
- National Research Agency (ANR)
- Research Foundation for Hypertension (FRHTA)
- Research Institute in Public Health (IRESP)
- Region Ile de France (DIM)
- ANR [ANR-09-GENO-010]
- Helmholtz Zentrum Munchen German Research Center of Environmental Health - German Federal Ministry of Education and Research
- State of Bavaria
- Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universitat, as part of LM Uinnovativ
- NIH [R01HL105993, R01HL088577]
- Howard Hughes Medical Institute
- National Institutes of Health
- British Heart Foundation [PG/12/27/29489] Funding Source: researchfish
- Rosetrees Trust [M232-CD1] Funding Source: researchfish
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Aims Dilated cardiomyopathy (DCM) is an important cause of heart failure with a strong familial component. We performed an exome-wide array-based association study (EWAS) to assess the contribution of missense variants to sporadic DCM. Methods and results 116,855 single nucleotide variants (SNVs) were analyzed in 2796 DCM patients and 6877 control subjects from 6 populations of European ancestry. We confirmed two previously identified associations with SNVs in BAG3 and ZBTB17 and discovered six novel DCM-associated loci (Q-value<0.01). The lead-SNVs at novel loci are common and located in TTN, SLC39A8, MLIP, FLNC, ALPK3 and FHOD3. In silico fine mapping identified HSPB7 as the most likely candidate at the ZBTB17 locus. Rare variant analysis (MAF<0.01) demonstrated significant association for TTN variants only (P = 0.0085). All candidate genes but one (SLC39A8) exhibit preferential expression in striated muscle tissues and mutations in TTN, BAG3, FLNC and FHOD3 are known to cause familial cardiomyopathy. We also investigated a panel of 48 known cardiomyopathy genes. Collectively, rare (n = 228, P = 0.0033) or common (n = 36, P = 0.019) variants with elevated in silico severity scores were associated with DCM, indicating that the spectrum of genes contributing to sporadic DCM extends beyond those identified here. Conclusion We identified eight loci independently associated with sporadic DCM. The functions of the best candidate genes at these loci suggest that proteostasis regulation might play a role in DCM pathophysiology.
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