Format

Send to

Choose Destination
PLoS One. 2017 Mar 15;12(3):e0172995. doi: 10.1371/journal.pone.0172995. eCollection 2017.

Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy.

Author information

1
Sorbonne Universités, UPMC Univ Paris 06, INSERM UMR-S1166, Team Genomics & Pathophysiology of Cardiovascular Diseases, Paris, France.
2
ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
3
Institute of Gender in Medicine and Center for Cardiovascular Research, Charite University Hospital, and DZHK, Berlin, Germany.
4
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
5
Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany.
6
DZHK (German Centre for Cardiovascular Research), Partnersite Munich Heart Alliance, Munich, Germany.
7
INSERM, UMR-S970, Department of Epidemiology, Paris, France.
8
Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
9
Penn Cardiovascular Institute and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
10
Department of Genetic Epidemiology, University of Regensburg, Regensburg, Germany.
11
Department of Medecine and Genetics Harvard Medical School, Boston, MA, United States of America.
12
Royal Brompton Hospital, London, United Kingdom.
13
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
14
Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
15
German Center for Diabetes Research, Neuherberg, Germany.
16
Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America.
17
Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
18
Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London, United Kingdom.
19
Howard Hughes Medical Institute, Chevy Chase, MD, United States of America.
20
AP-HP, Georges Pompidou European Hospital, Pharmacology Department, Paris, France.
21
INSERM U1116, Université de Lorraine, Nancy, France.
22
AP-HP, Georges Pompidou European Hospital, Cardiology Department, Paris, France.
23
Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.
24
AP-HP, Pitié-Salpêtrière Hospital, Cardiology Department, Paris, France.
25
AP-HP, Hôpital Pitié-Salpêtrière, Centre de Référence des Maladies Cardiaques Héréditaires, Paris, France.
26
IRCCS Fondazione Policlinico San Matteo, Pavia, Italy.
27
National Heart Centre Singapore, Singapore.
28
National Heart and Lung Institute, Imperial College London, London, United Kingdom.
29
Duke-NUS, Singapore.
30
Université de Versailles-Saint Quentin, AP-HP, Hôpital Ambroise Paré, Boulogne-Billancourt, France.

Abstract

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.

PMID:
28296976
PMCID:
PMC5351854
DOI:
10.1371/journal.pone.0172995
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center