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

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

doi:10.1093/eurheartj/ehac049

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

Eur Heart J. 2022 May 1;43(17):1668-1680. doi: 10.1093/eurheartj/ehac049.

Authors

Carolina Roselli^{1

2}, Mengyao Yu³, Victor Nauffal^{1

4}, Adrien Georges³, Qiong Yang⁵, Katie Love⁶, Lu-Chen Weng^{1

6}, Francesca N Delling⁷, Svetlana R Maurya⁸, Maren Schrölkamp⁸, Jacob Tfelt-Hansen^{9

10}, Albert Hagège^{3

11}, Xavier Jeunemaitre^{3

11}, Stéphanie Debette^{12

13}, Philippe Amouyel¹⁴, Wyliena Guan^{1

6

15}, Jochen D Muehlschlegel¹⁶, Simon C Body¹⁷, Svati Shah^{18

19}, Zainab Samad^{19

20}, Sergiy Kyryachenko³, Carol Haynes¹⁸, Michiel Rienstra², Thierry Le Tourneau^{21

22}, Vincent Probst²¹, Ronan Roussel^{23

24}, Inez J Wijdh-Den Hamer²⁵, Joylene E Siland², Kirk U Knowlton^{26

27}, Jean Jacques Schott²¹, Robert A Levine²⁸, Emelia J Benjamin^{29

30

31}, Ramachandran S Vasan^{5

29

32}, Benjamin D Horne^{26

33}, Joseph B Muhlestein^{26

34}, Giovanni Benfari³⁵, Maurice Enriquez-Sarano³⁵, Andrea Natale³⁶, Sanghamitra Mohanty³⁶, Chintan Trivedi³⁶, Moore B Shoemaker³⁷, Zachary T Yoneda³⁷, Quinn S Wells^{38

39

40}, Michael T Baker³⁸, Eric Farber-Eger³⁸, Hector I Michelena³⁵, Alicia Lundby^{8

41}, Russell A Norris⁴², Susan A Slaugenhaupt⁴³, Christian Dina²¹, Steven A Lubitz^{1

6

15}, Nabila Bouatia-Naji³, Patrick T Ellinor^{1

6

15}, David J Milan^{6

44}

Affiliations

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

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.

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

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural

MeSH terms

Adult
Genetic Loci / genetics
Genome-Wide Association Study
Humans
Latent TGF-beta Binding Proteins / genetics
Mitral Valve Prolapse* / genetics
Proteomics
Risk Factors

Substances

LTBP2 protein, human
Latent TGF-beta Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding