Genome-wide association study reveals novel genetic loci: a new polygenic risk score for mitral valve prolapse-Reference-Cited by-同舟云学术

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

Published:2022-03-04 Issue:17 Volume:43 Page:1668-1680
ISSN:0195-668X
Container-title:European Heart Journal
language:en
Short-container-title:

Author:

Roselli Carolina¹²^ORCID,Yu Mengyao³,Nauffal Victor¹⁴^ORCID,Georges Adrien³^ORCID,Yang Qiong⁵^ORCID,Love Katie⁶^ORCID,Weng Lu Chen¹⁶^ORCID,Delling Francesca N⁷^ORCID,Maurya Svetlana R⁸^ORCID,Schrölkamp Maren⁸^ORCID,Tfelt-Hansen Jacob⁹¹⁰^ORCID,Hagège Albert³¹¹,Jeunemaitre Xavier³¹¹,Debette Stéphanie¹²¹³^ORCID,Amouyel Philippe¹⁴^ORCID,Guan Wyliena¹⁶¹⁵^ORCID,Muehlschlegel Jochen D¹⁶^ORCID,Body Simon C¹⁷^ORCID,Shah Svati¹⁸¹⁹^ORCID,Samad Zainab¹⁹²⁰,Kyryachenko Sergiy³^ORCID,Haynes Carol¹⁸^ORCID,Rienstra Michiel²^ORCID,Le Tourneau Thierry²¹²²^ORCID,Probst Vincent²¹,Roussel Ronan²³²⁴,Wijdh-Den Hamer Inez J²⁵^ORCID,Siland Joylene E²^ORCID,Knowlton Kirk U²⁶²⁷,Jacques Schott Jean²¹^ORCID,Levine Robert A²⁸^ORCID,Benjamin Emelia J²⁹³⁰³¹^ORCID,Vasan Ramachandran S⁵²⁹³²^ORCID,Horne Benjamin D²⁶³³^ORCID,Muhlestein Joseph B²⁶³⁴^ORCID,Benfari Giovanni³⁵^ORCID,Enriquez-Sarano Maurice³⁵^ORCID,Natale Andrea³⁶,Mohanty Sanghamitra³⁶,Trivedi Chintan³⁶,Shoemaker Moore B³⁷,Yoneda Zachary T³⁷^ORCID,Wells Quinn S³⁸³⁹⁴⁰,Baker Michael T³⁸^ORCID,Farber-Eger Eric³⁸^ORCID,Michelena Hector I³⁵,Lundby Alicia⁸⁴¹,Norris Russell A⁴²^ORCID,Slaugenhaupt Susan A⁴³,Dina Christian²¹^ORCID,Lubitz Steven A¹⁶¹⁵^ORCID,Bouatia-Naji Nabila³^ORCID,Ellinor Patrick T¹⁶¹⁵^ORCID,Milan David J⁶⁴⁴

Affiliation:

1. Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard , Cambridge, MA 02142 , USA

2. Department of Cardiology, University of Groningen, University Medical Center Groningen , Groningen , The Netherlands

3. Université de Paris, PARCC, Inserm , F-75015 Paris , France

4. Division of Cardiovascular Medicine, Brigham and Women’s Hospital , Boston, MA , USA

5. School of Public Health, Boston University , Boston, MA , USA

6. Cardiovascular Research Center, Massachusetts General Hospital , Boston, MA , USA

7. Division of Cardiology, University of California San Francisco , San Francisco, CA , USA

8. Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen , København 2200 , Denmark

9. Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital , Copenhagen , Denmark

10. Department of Forensic Medicine, Faculty of Medical Sciences, University of Copenhagen , Copenhagen , Denmark

11. Assistance Publique–Hôpitaux de Paris, Departments of Cardiology and Genetics, Hôpital Européen Georges Pompidou , 75015 Paris , France

12. Bordeaux Population Health Research Center, Inserm Center U1219, University of Bordeaux , Bordeaux , France

13. Department of Neurology, Bordeaux University Hospital, Inserm U1219 , Bordeaux , France

14. Univ. Lille, Inserm, Centre Hosp. Univ Lille, Institut Pasteur de Lille, UMR1167 – RID-AGE- Risk factors and molecular determinants of aging-related diseases , F-59000 Lille , France

15. Demoulas Center for Cardiac Arrhythmias, Massachusetts General Hospital , Boston, MA , USA

16. Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital , Boston, MA , USA

17. Department of Anesthesiology, Boston University School of Medicine , Boston, MA , USA

18. Duke Molecular Physiology Institute, Duke University , Durham, NC , USA

19. Division of Cardiology, Department of Medicine, Duke University School of Medicine , Durham, NC , USA

20. Department of Medicine, Aga Khan University , Karachi , Pakistan

21. l’institut du thorax, INSERM, CNRS, Univ Nantes, CHU Nantes , Nantes , France

22. l’institut du thorax, CHU Nantes , Nantes , France

23. Cordeliers Research Centre, ImMeDiab Team, INSERM, Université de Paris , Paris , France

24. Hôpital Bichat-Claude-Bernard, APHP, Department of Diabetology , Paris , France

25. Department of Cardiothoracic Surgery, University of Groningen, University Medical Center Groningen , Groningen , The Netherlands

26. Intermountain Medical Center Heart Institute , Salt Lake City, UT , USA

27. Division of Cardiovascular Medicine, Department of Medicine, University of California San Diego , San Diego, CA , USA

28. Cardiac Ultrasound Laboratory, Harvard Medical School, Massachusetts General Hospital , Boston, MA , USA

29. National Heart, Lung, and Blood Institute’s and Boston University’s, The Framingham Heart Study , Framingham, MA , USA

30. Section of Cardiovascular Medicine, Boston University School of Medicine , Boston, MA , USA

31. Department of Epidemiology, Boston University School of Public Health , Boston, MA , USA

32. School of Medicine, Boston University , Boston, MA , USA

33. Division of Cardiovascular Medicine, Department of Medicine, Stanford University , Stanford, CA , USA

34. Cardiology Division, Department of Internal Medicine, University of Utah , Salt Lake City, UT , USA

35. Department of Cardiovascular Medicine, Mayo Clinic , Rochester, MN , USA

36. Texas Cardiac Arrhythmia Institute, St David’s Medical Center , Austin, TX , USA

37. Department of Medicine, Division of Cardiovascular Diseases, Vanderbilt University Medical Center , Nashville, TN , USA

38. Department of Medicine, Vanderbilt University Medical Center , Nashville, TN , USA

39. Department of Pharmacology, Vanderbilt University Medical Center , Nashville, TN , USA

40. Department of Biomedical Informatics, Vanderbilt University Medical Center , Nashville, TN , USA

41. The Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen , København 2200 , Denmark

42. Cardiovascular Developmental Biology Center, Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina , Charleston, SC , USA

43. Center for Genomic Medicine and Department of Neurology, Massachusetts General Hospital Research Institute and Harvard Medical School , Boston, MA , USA

44. Leducq Foundation , Boston, MA 02110 , USA

Abstract

Abstract 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.

Funder

Abbott

Biosense Webster

Baylis

Boston Scientific

Biotronik

Medtronic

Sanofi

Novo Nordisk

Merck

Eli Lilly

Astra-Zeneca