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Genome-wide association study reveals novel genetic loci: a new polygenic risk score for mitral valve prolapse

dc.rights.licenseopenen_US
dc.contributor.authorROSELLI, Carolina
dc.contributor.authorYU, Mengyao
dc.contributor.authorNAUFFAL, Victor
dc.contributor.authorGEORGES, Adrien
dc.contributor.authorYANG, Qiong
dc.contributor.authorLOVE, Katie
dc.contributor.authorWENG, Lu-Chen
dc.contributor.authorDELLING, Francesca N.
dc.contributor.authorMAURYA, Svetlana R.
dc.contributor.authorSCHROLKAMP, Maren
dc.contributor.authorTFELT-HANSEN, Jacob
dc.contributor.authorHAGEGE, Albert A.
dc.contributor.authorJEUNEMAITRE, Xavier
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorDEBETTE, Stephanie
dc.contributor.authorAMOUYEL, Philippe
dc.contributor.authorGUAN, Wyliena
dc.contributor.authorMUEHLSCHLEGEL, Jochen D.
dc.contributor.authorBODY, Simon C.
dc.contributor.authorSHAH, Svati
dc.contributor.authorSAMAD, Zainab
dc.contributor.authorKYRYACHENKO, Sergiy
dc.contributor.authorHAYNES, Carol
dc.contributor.authorRIENSTRA, Michiel
dc.contributor.authorLE TOURNEAU, Thierry
dc.contributor.authorPROBST, Vincent
dc.contributor.authorROUSSEL, Ronan
dc.contributor.authorWIJDH-DEN HAMER, Inez J.
dc.contributor.authorSILAND, Joylene E.
dc.contributor.authorKNOWLTON, Kirk U.
dc.contributor.authorJACQUES SCHOTT, Jean
dc.contributor.authorLEVINE, Robert A.
dc.contributor.authorBENJAMIN, Emelia J.
dc.contributor.authorVASAN, Ramachandran S.
dc.contributor.authorHORNE, Benjamin D.
dc.contributor.authorMUHLESTEIN, Joseph B.
dc.contributor.authorBENFARI, Giovanni
dc.contributor.authorENRIQUEZ-SARANO, Maurice
dc.contributor.authorNATALE, Andrea
dc.contributor.authorMOHANTY, Sanghamitra
dc.contributor.authorTRIVEDI, Chintan
dc.contributor.authorSHOEMAKER, Moore B.
dc.contributor.authorYONEDA, Zachary T.
dc.contributor.authorWELLS, Quinn S.
dc.contributor.authorBAKER, Michael T.
dc.contributor.authorFARBER-EGER, Eric
dc.contributor.authorMICHELENA, Hector I.
dc.contributor.authorLUNDBY, Alicia
dc.contributor.authorNORRIS, Russell A.
dc.contributor.authorSLAUGENHAUPT, Susan A.
dc.contributor.authorDINA, Christian
dc.contributor.authorLUBITZ, Steven A.
dc.contributor.authorBOUATIA-NAJI, Nabila
dc.contributor.authorELLINOR, Patrick T.
dc.contributor.authorMILAN, David J.
dc.date.accessioned2022-04-19T09:59:18Z
dc.date.available2022-04-19T09:59:18Z
dc.date.issued2022-03-04
dc.identifier.issn1522-9645 (Electronic) 0195-668X (Linking)en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/136656
dc.description.abstractEnAIMS: Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of >2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder. METHODS AND RESULTS: We performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. We identified 14 loci associated with MVP in our primary analysis and 2 additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes including LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. We created a polygenic risk score (PRS) for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors. CONCLUSION: We identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-beta signalling molecules and spectrin beta. We present the first PRS for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. These findings advance our understanding of this common valvular heart disease and may reveal novel therapeutic targets for intervention. KEY QUESTION: Expand our understanding of the genetic basis for mitral valve prolapse (MVP). Uncover relevant pathways and target genes for MVP pathophysiology. Leverage genetic data for MVP risk prediction. KEY FINDING: Sixteen genetic loci were significantly associated with MVP, including 13 novel loci. Interesting target genes at these loci included LTBP2, TGFB2, ALKP3, BAG3, RBM20, and SPTBN1. A risk score including clinical factors and a polygenic risk score, performed best at predicting MVP, with an area under the receiver operating characteristics curve of 0.677. TAKE-HOME MESSAGE: Mitral valve prolapse has a polygenic basis: many genetic variants cumulatively influence pre-disposition for disease. Disease risk may be modulated via changes to transforming growth factor-beta signalling, the cytoskeleton, as well as cardiomyopathy pathways. Polygenic risk scores could enhance the MVP risk prediction.
dc.language.isoENen_US
dc.subject.enGenome-wide association study
dc.subject.enMitral valve prolapse
dc.subject.enProteomics
dc.subject.enRNA-sequencing
dc.subject.enGenetic correlation
dc.subject.enPolygenic risk score
dc.title.enGenome-wide association study reveals novel genetic loci: a new polygenic risk score for mitral valve prolapse
dc.typeArticle de revueen_US
dc.identifier.doi10.1093/eurheartj/ehac049en_US
dc.subject.halSciences du Vivant [q-bio]/Santé publique et épidémiologieen_US
dc.identifier.pubmed35245370en_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.teamELEANOR_BPHen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.identifierhal-03644552
hal.version1
hal.date.transferred2022-04-19T09:59:23Z
hal.exporttrue
dc.rights.ccPas de Licence CCen_US
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