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dc.titleExome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy
dc.contributor.authorEsslinger U.
dc.contributor.authorGarnier S.
dc.contributor.authorKorniat A.
dc.contributor.authorProust C.
dc.contributor.authorKararigas G.
dc.contributor.authorMüller-Nurasyid M.
dc.contributor.authorEmpana J.-P.
dc.contributor.authorMorley M.P.
dc.contributor.authorPerret C.
dc.contributor.authorStark K.
dc.contributor.authorBick A.G.
dc.contributor.authorPrasad S.K.
dc.contributor.authorKriebel J.
dc.contributor.authorLi J.
dc.contributor.authorTiret L.
dc.contributor.authorStrauch K.
dc.contributor.authorO'Regan D.P.
dc.contributor.authorMarguiles K.B.
dc.contributor.authorSeidman J.G.
dc.contributor.authorBoutouyrie P.
dc.contributor.authorLacolley P.
dc.contributor.authorJouven X.
dc.contributor.authorHengstenberg C.
dc.contributor.authorKomajda M.
dc.contributor.authorHakonarson H.
dc.contributor.authorIsnard R.
dc.contributor.authorArbustini E.
dc.contributor.authorGrallert H.
dc.contributor.authorCook S.A.
dc.contributor.authorSeidman C.E.
dc.contributor.authorRegitz-Zagrosek V.
dc.contributor.authorCappola T.P.
dc.contributor.authorCharron P.
dc.contributor.authorCambien F.
dc.contributor.authorVillard E.
dc.identifier.citationEsslinger 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.
dc.description.abstractAims 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.
dc.rightsCC0 1.0 Universal
dc.sourceUnpaywall 20191101
dc.subjectALPK3 gene
dc.subjectBAG3 gene
dc.subjectcomputer model
dc.subjectcongestive cardiomyopathy
dc.subjectcontrolled study
dc.subjectFHOD3 gene
dc.subjectFLNC gene
dc.subjectgene expression
dc.subjectgene function
dc.subjectgene identification
dc.subjectgene locus
dc.subjectgene mapping
dc.subjectgene mutation
dc.subjectgenetic susceptibility
dc.subjectgenome-wide association study
dc.subjectHSPB7 gene
dc.subjecthuman cell
dc.subjecthuman tissue
dc.subjectmajor clinical study
dc.subjectmissense mutation
dc.subjectMLIP gene
dc.subjectpopulation research
dc.subjectsingle nucleotide polymorphism
dc.subjectSLC39A8 gene
dc.subjectTTN gene
dc.subjectZBTB17 gene
dc.subjectcongestive cardiomyopathy
dc.subjectgenetic predisposition
dc.subjectCardiomyopathy, Dilated
dc.subjectGenetic Predisposition to Disease
dc.subjectMutation, Missense
dc.subjectPolymorphism, Single Nucleotide
dc.contributor.departmentDUKE-NUS MEDICAL SCHOOL
dc.description.sourcetitlePLoS ONE
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