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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, 6 Jean-Philippe Empana 7 Michael Morley 8 Claire Perret 1 Klaus Stark 9 Alexander Bick 10 Sanjay Prasad 11 Jennifer Kriebel 3, 12 Jin Li 13 Laurence Tiret 1 Konstantin Strauch 3, 4 Declan O'Regan 14 Kenneth Marguiles 8 Jonathan Seidman 15, 10 Pierre Boutouyrie 7, 16 Patrick Lacolley 17 Xavier Jouven 7 Christian Hengstenberg 5, 6, 18 Michel Komajda 1, 19 Hakon Hakonarson 13 Richard Isnard 1, 19 Eloisa Arbustini 20 Harald Grallert 3, 12 Stuart Cook 21, 14, 22 Christine Seidman 10, 23 Vera Regitz-Zagrosek 2 Thomas Cappola 8 Philippe Charron 1, 19, 24 François Cambien 1 Eric Villard 1, 19
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.
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Submitted on : Sunday, February 13, 2022 - 10:15:38 PM
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Ulrike Esslinger, Sophie Garnier, Agathe Korniat, Carole Proust, Georgios Kararigas, et al.. Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy. PLoS ONE, Public Library of Science, 2017, 12 (3), pp.e0172995. ⟨10.1371/journal.pone.0172995⟩. ⟨hal-03571195⟩

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