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@article{Esslinger:2017:10.1371/journal.pone.0172995,
author = {Esslinger, U and Garnier, S and Korniat, A and Proust, C and Kararigas, G and Mueller-Nurasyid, M and Empana, J-P and Morley, MP and Perret, C and Stark, K and Bick, AG and Prasad, SK and Kriebel, J and Li, J and Tiret, L and Strauch, K and O'Regan, DP and Marguiles, KB and Seidman, JG and Boutouyrie, P and Lacolley, P and Jouven, X and Hengstenberg, C and Komajda, M and Hakonarson, H and Isnard, R and Arbustini, E and Grallert, H and Cook, SA and Seidman, CE and Regitz-Zagrosek, V and Cappola, TP and Charron, P and Cambien, F and Villard, E},
doi = {10.1371/journal.pone.0172995},
journal = {PLOS ONE},
title = {Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy},
url = {http://dx.doi.org/10.1371/journal.pone.0172995},
volume = {12},
year = {2017}
}

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TY  - JOUR
AB  - 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.
AU  - Esslinger,U
AU  - Garnier,S
AU  - Korniat,A
AU  - Proust,C
AU  - Kararigas,G
AU  - Mueller-Nurasyid,M
AU  - Empana,J-P
AU  - Morley,MP
AU  - Perret,C
AU  - Stark,K
AU  - Bick,AG
AU  - Prasad,SK
AU  - Kriebel,J
AU  - Li,J
AU  - Tiret,L
AU  - Strauch,K
AU  - O'Regan,DP
AU  - Marguiles,KB
AU  - Seidman,JG
AU  - Boutouyrie,P
AU  - Lacolley,P
AU  - Jouven,X
AU  - Hengstenberg,C
AU  - Komajda,M
AU  - Hakonarson,H
AU  - Isnard,R
AU  - Arbustini,E
AU  - Grallert,H
AU  - Cook,SA
AU  - Seidman,CE
AU  - Regitz-Zagrosek,V
AU  - Cappola,TP
AU  - Charron,P
AU  - Cambien,F
AU  - Villard,E
DO  - 10.1371/journal.pone.0172995
PY  - 2017///
SN  - 1932-6203
TI  - Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy
T2  - PLOS ONE
UR  - http://dx.doi.org/10.1371/journal.pone.0172995
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000396311700021&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - http://hdl.handle.net/10044/1/45990
VL  - 12
ER  -

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