Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy
Ulrike Esslinger
(1)
,
Sophie Garnier
(1)
,
Agathe Korniat
(1)
,
Carole Proust
(1)
,
Georgios Kararigas
(2)
,
Martina Müller-Nurasyid
(3, 4, 5)
,
Jean-Philippe Empana
(6)
,
Michael Morley
(7)
,
Claire Perret
(1)
,
Klaus Stark
(8)
,
Alexander Bick
(9)
,
Sanjay Prasad
(10)
,
Jennifer Kriebel
(3, 11)
,
Jin Li
(12)
,
Laurence Tiret
(1)
,
Konstantin Strauch
(3, 4)
,
Declan O'Regan
(13)
,
Kenneth Marguiles
(7)
,
Jonathan Seidman
(14, 9)
,
Pierre Boutouyrie
(6, 15)
,
Patrick Lacolley
(16)
,
Xavier Jouven
(6)
,
Christian Hengstenberg
(5, 17)
,
Michel Komajda
(1, 18)
,
Hakon Hakonarson
(12)
,
Richard Isnard
(1, 18)
,
Eloisa Arbustini
(19)
,
Harald Grallert
(3, 11)
,
Stuart Cook
(20, 13, 21)
,
Christine Seidman
(9, 22)
,
Vera Regitz-Zagrosek
(2)
,
Thomas Cappola
(7)
,
Philippe Charron
(1, 18, 23)
,
François Cambien
(1)
,
Eric Villard
(1, 18)
1
ICAN -
Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases
2 Charité - UniversitätsMedizin = Berlin University Medicine
3 HMGU - Helmholtz Zentrum München = German Research Center for Environmental Health
4 LMU - Ludwig Maximilian University [Munich] = Ludwig Maximilians Universität München
5 DZHK - German Center for Cardiovascular Research
6 PARCC (UMR_S 970/ U970) - Paris-Centre de Recherche Cardiovasculaire
7 University of Pennsylvania
8 University of Regensburg
9 HMS - Harvard Medical School [Boston]
10 Royal Brompton Hospital
11 DZD - German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg]
12 CHOP - Children’s Hospital of Philadelphia
13 Imperial College London
14 HHMI - Howard Hughes Medical Institute [Chevy Chase]
15 HEGP - Hôpital Européen Georges Pompidou [APHP]
16 DCAC - Défaillance Cardiovasculaire Aiguë et Chronique
17 TUM - Technische Universität Munchen - Technical University Munich - Université Technique de Munich
18 CHU Pitié-Salpêtrière [AP-HP]
19 Fondazione IRCCS Policlinico San Matteo [Pavia]
20 NHCS - National Heart Centre Singapore
21 Duke-NUS Medical School [Singapore]
22 HHMI - Howard Hughes Medical Institute [Boston]
23 Hôpital Ambroise Paré [AP-HP]
2 Charité - UniversitätsMedizin = Berlin University Medicine
3 HMGU - Helmholtz Zentrum München = German Research Center for Environmental Health
4 LMU - Ludwig Maximilian University [Munich] = Ludwig Maximilians Universität München
5 DZHK - German Center for Cardiovascular Research
6 PARCC (UMR_S 970/ U970) - Paris-Centre de Recherche Cardiovasculaire
7 University of Pennsylvania
8 University of Regensburg
9 HMS - Harvard Medical School [Boston]
10 Royal Brompton Hospital
11 DZD - German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg]
12 CHOP - Children’s Hospital of Philadelphia
13 Imperial College London
14 HHMI - Howard Hughes Medical Institute [Chevy Chase]
15 HEGP - Hôpital Européen Georges Pompidou [APHP]
16 DCAC - Défaillance Cardiovasculaire Aiguë et Chronique
17 TUM - Technische Universität Munchen - Technical University Munich - Université Technique de Munich
18 CHU Pitié-Salpêtrière [AP-HP]
19 Fondazione IRCCS Policlinico San Matteo [Pavia]
20 NHCS - National Heart Centre Singapore
21 Duke-NUS Medical School [Singapore]
22 HHMI - Howard Hughes Medical Institute [Boston]
23 Hôpital Ambroise Paré [AP-HP]
Sophie Garnier
- Fonction : Auteur
- PersonId : 934284
- IdHAL : sophie-garnier
- ORCID : 0000-0002-7492-1617
- IdRef : 031812910
Georgios Kararigas
- Fonction : Auteur
- PersonId : 784330
- ORCID : 0000-0002-8187-0176
Jean-Philippe Empana
- Fonction : Auteur
- PersonId : 760464
- ORCID : 0000-0002-1469-7772
- IdRef : 088628256
Klaus Stark
- Fonction : Auteur
- PersonId : 762616
- ORCID : 0000-0002-7832-1942
Patrick Lacolley
- Fonction : Auteur
- PersonId : 758275
- ORCID : 0000-0002-2938-1383
- IdRef : 09462447X
Christian Hengstenberg
- Fonction : Auteur
- PersonId : 762621
- ORCID : 0000-0002-8284-2994
Hakon Hakonarson
- Fonction : Auteur
- PersonId : 763145
- ORCID : 0000-0003-2814-7461
Richard Isnard
- Fonction : Auteur
- PersonId : 758420
- ORCID : 0000-0002-3439-8104
- IdRef : 050630733
Eloisa Arbustini
- Fonction : Auteur
- PersonId : 760654
- ORCID : 0000-0003-2948-7994
Vera Regitz-Zagrosek
- Fonction : Auteur
- PersonId : 761293
- ORCID : 0000-0002-3566-3467
Philippe Charron
- Fonction : Auteur
- PersonId : 766599
- IdHAL : philippe-charron
- ORCID : 0000-0002-1782-1118
- IdRef : 123379458
Eric Villard
- Fonction : Auteur
- PersonId : 1215042
- IdHAL : evillard
- ORCID : 0000-0001-9801-7297
- IdRef : 177061200
Résumé
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.