Titre :

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

Auteur(s) :

Roselli, Carolina [Auteur]
Yu, Mengyao [Auteur]
Paris-Centre de Recherche Cardiovasculaire [PARCC (UMR_S 970/ U970)]
Nauffal, Victor [Auteur]
Georges, Adrien [Auteur]
Paris-Centre de Recherche Cardiovasculaire [PARCC (UMR_S 970/ U970)]
Yang, Qiong [Auteur]
Love, Katie [Auteur]
Weng, Lu-Chen [Auteur]
Delling, Francesca N. [Auteur]
Maurya, Svetlana R. [Auteur]
Schrolkamp, Maren [Auteur]
Tfelt-Hansen, Jacob [Auteur]
Hagege, Albert A. [Auteur]
Paris-Centre de Recherche Cardiovasculaire [PARCC (UMR_S 970/ U970)]
Jeunemaitre, Xavier [Auteur]
Paris-Centre de Recherche Cardiovasculaire [PARCC (UMR_S 970/ U970)]
Debette, Stephanie [Auteur]
Bordeaux population health [BPH]
Amouyel, Philippe [Auteur]
Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE]
Guan, Wyliena [Auteur]
Muehlschlegel, Jochen D. [Auteur]
Body, Simon C. [Auteur]
Shah, Svati [Auteur]
Samad, Zainab [Auteur]
Kyryachenko, Sergiy [Auteur]
Paris-Centre de Recherche Cardiovasculaire [PARCC (UMR_S 970/ U970)]
Haynes, Carol [Auteur]
Rienstra, Michiel [Auteur]
Le Tourneau, Thierry [Auteur]
Probst, Vincent [Auteur]
Roussel, Ronan [Auteur]
Centre de Recherche des Cordeliers [CRC (UMR_S_1138 / U1138)]
Wijdh-den Hamer, Inez J. [Auteur]
Siland, Joylene E. [Auteur]
Knowlton, Kirk U. [Auteur]
Jacques Schott, Jean [Auteur]
Levine, Robert A. [Auteur]
Benjamin, Emelia J. [Auteur]
Vasan, Ramachandran S. [Auteur]
Horne, Benjamin D. [Auteur]
Muhlestein, Joseph B. [Auteur]
Benfari, Giovanni [Auteur]
Enriquez-Sarano, Maurice [Auteur]
Natale, Andrea [Auteur]
Mohanty, Sanghamitra [Auteur]
Trivedi, Chintan [Auteur]
Shoemaker, Moore B. [Auteur]
Yoneda, Zachary T. [Auteur]
Wells, Quinn S. [Auteur]
Baker, Michael T. [Auteur]
Farber-Eger, Eric [Auteur]
Michelena, Hector I. [Auteur]
Lundby, Alicia [Auteur]
Norris, Russell A. [Auteur]
Slaugenhaupt, Susan A. [Auteur]
Dina, Christian [Auteur]
Lubitz, Steven A. [Auteur]
Bouatia-Naji, Nabila [Auteur]
Paris-Centre de Recherche Cardiovasculaire [PARCC (UMR_S 970/ U970)]
Ellinor, Patrick T. [Auteur]
Milan, David J. [Auteur]

Titre de la revue :

European Heart Journal

Éditeur :

Oxford University Press (OUP)

Date de publication :

2022-03-04

ISSN :

0195-668X

Mot(s)-clé(s) en anglais :

Genome-wide association study
Mitral valve prolapse
Proteomics
RNA-sequencing
Genetic correlation
Polygenic risk score

Discipline(s) HAL :

Sciences du Vivant [q-bio]/Santé publique et épidémiologie

Résumé en anglais : [en]

AIMS: 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 ...
Lire la suite >AIMS: 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.Lire moins >

Langue :

Anglais

Comité de lecture :

Oui

Audience :

Internationale

Vulgarisation :

Non

Collections :

• Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement (RID-AGE) - U1167

Source :

Harvested from HAL