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Title: Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy
Authors: Esslinger U.
Garnier S.
Korniat A.
Proust C.
Kararigas G.
Müller-Nurasyid M.
Empana J.-P.
Morley M.P.
Perret C.
Stark K.
Bick A.G.
Prasad S.K.
Kriebel J.
Li J.
Tiret L.
Strauch K.
O'Regan D.P.
Marguiles K.B.
Seidman J.G.
Boutouyrie P.
Lacolley P.
Jouven X.
Hengstenberg C.
Komajda M.
Hakonarson H.
Isnard R.
Arbustini E.
Grallert H.
Cook S.A. 
Seidman C.E.
Regitz-Zagrosek V.
Cappola T.P.
Charron P.
Cambien F.
Villard E.
Keywords: ALPK3 gene
BAG3 gene
computer model
congestive cardiomyopathy
controlled study
FHOD3 gene
FLNC gene
gene expression
gene function
gene identification
gene locus
gene mapping
gene mutation
genetic susceptibility
genome-wide association study
HSPB7 gene
human cell
human tissue
major clinical study
missense mutation
MLIP gene
population research
single nucleotide polymorphism
SLC39A8 gene
TTN gene
ZBTB17 gene
congestive cardiomyopathy
genetic predisposition
Cardiomyopathy, Dilated
Genetic Predisposition to Disease
Mutation, Missense
Polymorphism, Single Nucleotide
Issue Date: 2017
Citation: Esslinger U., Garnier S., Korniat A., Proust C., Kararigas G., Müller-Nurasyid M., Empana J.-P., Morley M.P., Perret C., Stark K., Bick A.G., Prasad S.K., Kriebel J., Li J., Tiret L., Strauch K., O'Regan D.P., Marguiles K.B., Seidman J.G., Boutouyrie P., Lacolley P., Jouven X., Hengstenberg C., Komajda M., Hakonarson H., Isnard R., Arbustini E., Grallert H., Cook S.A., Seidman C.E., Regitz-Zagrosek V., Cappola T.P., Charron P., Cambien F., Villard E. (2017). Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy. PLoS ONE 12 (3) : e0172995. ScholarBank@NUS Repository.
Rights: CC0 1.0 Universal
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 DCMassociated loci (Q-value0.01). 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 (MAF0.01) 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. © This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Source Title: PLoS ONE
ISSN: 19326203
DOI: 10.1371/journal.pone.0172995
Rights: CC0 1.0 Universal
Appears in Collections:Staff Publications

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