Genome-wide association study reveals novel genetic loci: a new polygenic risk score for mitral valve prolapse.
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Roselli Carolina, Yu Mengyao, Nauffal Victor, Georges Adrien, Yang Qiong, Love Katie, Weng Lu-Chen, Delling Francesca N, Maurya Svetlana R, Schrölkamp Maren, Tfelt-Hansen Jacob, Hagège Albert, Jeunemaitre Xavier, Debette Stéphanie, Amouyel Philippe, Guan Wyliena, Muehlschlegel Jochen D, Body Simon C, Shah Svati, Samad Zainab, Kyryachenko Sergiy, Haynes Carol, Rienstra Michiel, Le Tourneau Thierry, Probst Vincent, Roussel Ronan, Wijdh-Den Hamer Inez J, Siland Joylene E, Knowlton Kirk U, Jacques Schott Jean, Levine Robert A, Benjamin Emelia J, Vasan Ramachandran S, Horne Benjamin D, Muhlestein Joseph B, Benfari Giovanni, Enriquez-Sarano Maurice, Natale Andrea, Mohanty Sanghamitra, Trivedi Chintan, Shoemaker Moore B, Yoneda Zachary T, Wells Quinn S, Baker Michael T, Farber-Eger Eric, Michelena Hector I, Lundby Alicia, Norris Russell A, Slaugenhaupt Susan A, Dina Christian, Lubitz Steven A, Bouatia-Naji Nabila, Ellinor Patrick T, Milan David J
Аннотация
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-β signalling molecules and spectrin β. 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.