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Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23

dc.rights.licenseopenen_US
dc.contributor.authorGARNIER, Sophie
dc.contributor.authorASSENBERG, Magdalena
dc.contributor.authorWEISS, Stefan
dc.contributor.authorMOKRY, Michal
dc.contributor.authorREGITZ-ZAGROSEK, Vera
dc.contributor.authorHENGSTENBERG, Christian
dc.contributor.authorCAPPOLA, Thomas P.
dc.contributor.authorISNARD, Richard
dc.contributor.authorARBUSTINI, Eloisa
dc.contributor.authorCOOK, Stuart A.
dc.contributor.authorVAN SETTEN, Jessica
dc.contributor.authorCALIS, Jorg J. A.
dc.contributor.authorHAKONARSON, Hakon
dc.contributor.authorMORLEY, Michael P.
dc.contributor.authorSTARK, Klaus
dc.contributor.authorPRASAD, Sanjay K.
dc.contributor.authorLI, Jin
dc.contributor.authorO'REGAN, Declan P.
dc.contributor.authorGRASSO, Maurizia
dc.contributor.authorMULLER-NURASYID, Martina
dc.contributor.authorMEITINGER, Thomas
dc.contributor.authorEMPANA, Jean-Philippe
dc.contributor.authorSTRAUCH, Konstantin
dc.contributor.authorWALDENBERGER, Melanie
dc.contributor.authorMARGUILES, Kenneth B.
dc.contributor.authorSEIDMAN, Christine E.
dc.contributor.authorKARARIGAS, Georgios
dc.contributor.authorMEDER, Benjamin
dc.contributor.authorHAAS, Jan
dc.contributor.authorBOUTOUYRIE, Pierre
dc.contributor.authorLACOLLEY, Patrick
dc.contributor.authorJOUVEN, Xavier
dc.contributor.authorERDMANN, Jeanette
dc.contributor.authorBLANKENBERG, Stefan
dc.contributor.authorWICHTER, Thomas
dc.contributor.authorRUPPERT, Volker
dc.contributor.authorTAVAZZI, Luigi
dc.contributor.authorDUBOURG, Olivier
dc.contributor.authorROIZES, Gerard
dc.contributor.authorDORENT, Richard
dc.contributor.authorDE GROOTE, Pascal
dc.contributor.authorFAUCHIER, Laurent
dc.contributor.authorTROCHU, Jean-Noel
dc.contributor.authorAUPETIT, Jean-Francois
dc.contributor.authorBILINSKA, Zofia T.
dc.contributor.authorGERMAIN, Marine
dc.contributor.authorVOLKER, Uwe
dc.contributor.authorHEMERICH, Daiane
dc.contributor.authorRAJI, Ibticem
dc.contributor.authorBACQ-DAIAN, Delphine
dc.contributor.authorPROUST, Carole
dc.contributor.authorREMIOR, Paloma
dc.contributor.authorGOMEZ-BUENO, Manuel
dc.contributor.authorLEHNERT, Kristin
dc.contributor.authorMAAS, Renee
dc.contributor.authorOLASO, Robert
dc.contributor.authorSARIPELLA, Ganapathi Varma
dc.contributor.authorFELIX, Stephan B.
dc.contributor.authorMCGINN, Steven
dc.contributor.authorDUBOSCQ-BIDOT, Laetitia
dc.contributor.authorVAN MIL, Alain
dc.contributor.authorBESSE, Celine
dc.contributor.authorFONTAINE, Vincent
dc.contributor.authorBLANCHE, Helene
dc.contributor.authorADER, Flavie
dc.contributor.authorKEATING, Brendan
dc.contributor.authorCURJOL, Angelique
dc.contributor.authorBOLAND, Anne
dc.contributor.authorKOMAJDA, Michel
dc.contributor.authorCAMBIEN, Francois
dc.contributor.authorDELEUZE, Jean-Francois
dc.contributor.authorDORR, Marcus
dc.contributor.authorASSELBERGS, Folkert W.
dc.contributor.authorVILLARD, Eric
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorTREGOUET, David-Alexandre
dc.contributor.authorCHARRON, Philippe
dc.date.accessioned2021-05-07T13:54:21Z
dc.date.available2021-05-07T13:54:21Z
dc.date.issued2021-03-03
dc.identifier.issn1522-9645 (Electronic) 0195-668X (Linking)en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/27214
dc.description.abstractEnAIMS : Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure. METHODS AND RESULTS : We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10-11 and 7.7 × 10-4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10-8 and 1.4 × 10-3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 27% increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene. CONCLUSION : This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.
dc.description.sponsorshipMedical Genomicsen_US
dc.language.isoENen_US
dc.subject.enDilated cardiomyopathy
dc.subject.enHeart failure
dc.subject.enGWAS
dc.subject.enImputation
dc.subject.en4C-sequencing
dc.subject.enGenetic risk score
dc.title.enGenome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23
dc.typeArticle de revueen_US
dc.identifier.doi10.1093/eurheartj/ehab030en_US
dc.subject.halSciences du Vivant [q-bio]/Santé publique et épidémiologieen_US
dc.identifier.pubmed33677556en_US
bordeaux.journalEuropean Heart Journalen_US
bordeaux.hal.laboratoriesBordeaux Population Health Research Center (BPH) - UMR 1219en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.teamVINTAGEen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.identifier.funderIDAssistance publique-Hôpitaux de Parisen_US
bordeaux.identifier.funderIDFondation Leducqen_US
bordeaux.identifier.funderIDSociété Française de Cardiologieen_US
bordeaux.identifier.funderIDDeutsche Forschungsgemeinschaften_US
bordeaux.identifier.funderIDHelmholtz Zentrum Münchenen_US
bordeaux.identifier.funderIDUniversité de Bordeauxen_US
bordeaux.identifier.funderIDMedical Research Councilen_US
bordeaux.identifier.funderIDBritish Heart Foundationen_US
hal.identifierhal-03220966
hal.version1
hal.date.transferred2021-05-07T13:54:29Z
hal.exporttrue
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