Esslinger, Ulrike and Garnier, Sophie and Korniat, Agathe and Proust, Carole and Kararigas, Georgios and Mueller-Nurasyid, Martina and Empana, Jean-Philippe and Morley, Michael P. and Perret, Claire and Stark, Klaus and Bick, Alexander G. and Prasad, Sanjay K. and Kriebel, Jennifer and Li, Jin and Tiret, Laurence and Strauch, Konstantin and O'Regan, Declan P. and Marguiles, Kenneth B. and Seidman, Jonathan G. and Boutouyrie, Pierre and Lacolley, Patrick and Jouven, Xavier and Hengstenberg, Christian and Komajda, Michel and Hakonarson, Hakon and Isnard, Richard and Arbustini, Eloisa and Grallert, Harald and Cook, Stuart A. and Seidman, Christine E. and Regitz-Zagrosek, Vera and Cappola, Thomas P. and Charron, Philippe and Cambien, Francois and Villard, Eric (2017) Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy. PLOS ONE, 12 (3): e0172995. ISSN 1932-6203,
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SKELETAL-MUSCLES; COMMON VARIANTS; HEART-FAILURE; P19CL6 CELLS; PROTEIN; MUTATIONS; HSPB7; FHOD3; DIFFERENTIATION; ARCHITECTURE; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Epidemiologie und Präventivmedizin > Lehrstuhl für Genetische Epidemiologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Dec 2018 13:00 |
| Last Modified: | 26 Feb 2019 09:41 |
| URI: | https://pred.uni-regensburg.de/id/eprint/219 |
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