TY - JOUR
T1 - Genome-wide association study reveals novel genetic loci
T2 - A new polygenic risk score for mitral valve prolapse
AU - Roselli, Carolina
AU - Yu, Mengyao
AU - Nauffal, Victor
AU - Georges, Adrien
AU - Yang, Qiong
AU - Love, Katie
AU - Weng, Lu Chen
AU - Delling, Francesca N.
AU - Maurya, Svetlana R.
AU - Schrölkamp, Maren
AU - Tfelt-Hansen, Jacob
AU - Hagège, Albert
AU - Jeunemaitre, Xavier
AU - Debette, Stephanie
AU - Amouyel, Philippe
AU - Guan, Wyliena
AU - Muehlschlegel, Jochen D.
AU - Body, Simon C.
AU - Shah, Svati
AU - Samad, Zainab
AU - Kyryachenko, Sergiy
AU - Haynes, Carol
AU - Rienstra, Michiel
AU - Le Tourneau, Thierry
AU - Probst, Vincent
AU - Roussel, Ronan
AU - Wijdh-Den Hamer, Inez J.
AU - Siland, Joylene E.
AU - Knowlton, Kirk U.
AU - Jacques Schott, Jean
AU - Levine, Robert A.
AU - Benjamin, Emelia J.
AU - Vasan, Ramachandran S.
AU - Horne, Benjamin D.
AU - Muhlestein, Joseph B.
AU - Benfari, Giovanni
AU - Enriquez-Sarano, Maurice
AU - Natale, Andrea
AU - Mohanty, Sanghamitra
AU - Trivedi, Chintan
AU - Shoemaker, Moore B.
AU - Yoneda, Zachary T.
AU - Wells, Quinn S.
AU - Baker, Michael T.
AU - Farber-Eger, Eric
AU - Michelena, Hector I.
AU - Lundby, Alicia
AU - Norris, Russell A.
AU - Slaugenhaupt, Susan A.
AU - Dina, Christian
AU - Lubitz, Steven A.
AU - Bouatia-Naji, Nabila
AU - Ellinor, Patrick T.
AU - Milan, David J.
N1 - Publisher Copyright:
© 2022 The Author(s).
PY - 2022/5/1
Y1 - 2022/5/1
N2 - 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-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.
AB - 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-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.
KW - Genetic correlation
KW - Genome-wide association study
KW - Mitral valve prolapse
KW - Polygenic risk score
KW - Proteomics
KW - RNA-sequencing
UR - http://www.scopus.com/inward/record.url?scp=85129781030&partnerID=8YFLogxK
U2 - 10.1093/eurheartj/ehac049
DO - 10.1093/eurheartj/ehac049
M3 - Article
C2 - 35245370
AN - SCOPUS:85129781030
SN - 0195-668X
VL - 43
SP - 1668
EP - 1680
JO - European Heart Journal
JF - European Heart Journal
IS - 17
ER -