title: Genetic association analyses highlight biological pathways underlying mitral valve prolapse.
abstract: Nonsyndromic mitral valve prolapse (MVP) is a common degenerative cardiac valvulopathy of unknown etiology that predisposes to mitral regurgitation, heart failure and sudden death. Previous family and pathophysiological studies suggest a complex pattern of inheritance. We performed a meta-analysis of 2 genome-wide association studies in 1,412 MVP cases and 2,439 controls. We identified 6 loci, which we replicated in 1,422 cases and 6,779 controls, and provide functional evidence for candidate genes. We highlight LMCD1 (LIM and cysteine-rich domains 1), which encodes a transcription factor and for which morpholino knockdown of the ortholog in zebrafish resulted in atrioventricular valve regurgitation. A similar zebrafish phenotype was obtained with knockdown of the ortholog of TNS1, which encodes tensin 1, a focal adhesion protein involved in cytoskeleton organization. We also showed expression of tensin 1 during valve morphogenesis and describe enlarged posterior mitral leaflets in Tns1(-/-) mice. This study identifies the first risk loci for MVP and suggests new mechanisms involved in mitral valve regurgitation, the most common indication for mitral valve repair.
authors: INSERM Unité Mixte de Recherche (UMR) 1087, Centre National de la Recherche Scientifique (CNRS) UMR 6291, Institut du Thorax, Nantes, France.|Centre Hospitalier Universitaire (CHU) Nantes, Université de Nantes, Nantes, France.
authors: Christian
authors: http://orcid.org/0000-0002-7722-7348
authors: C
authors: Dina
authors: INSERM UMR 970, Paris Cardiovascular Research Center, Paris, France.|Paris Descartes University, Paris Sorbonne Cité, Paris, France.
authors: Nabila
authors: N
authors: Bouatia-Naji
authors: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
authors: Nathan
authors: N
authors: Tucker
authors: Framingham Heart Study, Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, US National Institutes of Health, Framingham, Massachusetts, USA.|Department of Medicine (Cardiovascular Division), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors: Francesca N
authors: FN
authors: Delling
authors: Department of Regenerative Medicine and Cell Biology, Cardiovascular Developmental Biology Center, Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina, USA.
authors: Katelynn
authors: K
authors: Toomer
authors: Department of Cardiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
authors: Ronen
authors: R
authors: Durst
authors: INSERM UMR 970, Paris Cardiovascular Research Center, Paris, France.|Paris Descartes University, Paris Sorbonne Cité, Paris, France.
authors: Maelle
authors: M
authors: Perrocheau
authors: Hospital Universitario Montepríncipe, Universidad Centro de Estudios Universitarios (CEU) San Pablo, Madrid, Spain.|Centro Nacional de Investigaciones Cardiovasculares, Carlos III (CNIC), Madrid, Spain.
authors: Leticia
authors: L
authors: Fernandez-Friera
authors: Hospital Universitario Montepríncipe, Universidad Centro de Estudios Universitarios (CEU) San Pablo, Madrid, Spain.|Centro Nacional de Investigaciones Cardiovasculares, Carlos III (CNIC), Madrid, Spain.
authors: Jorge
authors: http://orcid.org/0000-0002-4227-7062
authors: J
authors: Solis
authors: INSERM Unité Mixte de Recherche (UMR) 1087, Centre National de la Recherche Scientifique (CNRS) UMR 6291, Institut du Thorax, Nantes, France.|Centre Hospitalier Universitaire (CHU) Nantes, Université de Nantes, Nantes, France.
authors: Thierry
authors: T
authors: Le Tourneau
authors: Framingham Heart Study, Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, US National Institutes of Health, Framingham, Massachusetts, USA.|Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.
authors: Ming-Huei
authors: MH
authors: Chen
authors: INSERM Unité Mixte de Recherche (UMR) 1087, Centre National de la Recherche Scientifique (CNRS) UMR 6291, Institut du Thorax, Nantes, France.|Centre Hospitalier Universitaire (CHU) Nantes, Université de Nantes, Nantes, France.
authors: Vincent
authors: V
authors: Probst
authors: Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Quebec City, Quebec, Canada.
authors: Yohan
authors: Y
authors: Bosse
authors: Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Quebec City, Quebec, Canada.
authors: Philippe
authors: P
authors: Pibarot
authors: Centre National de Génotypage, Evry, France.
authors: Diana
authors: D
authors: Zelenika
authors: Centre National de Génotypage, Evry, France.|Génome Québec, Montreal, Quebec, Canada.
authors: Mark
authors: M
authors: Lathrop
authors: Paris Descartes University, Paris Sorbonne Cité, Paris, France.|Paris 13 University, Sorbonne Paris Cité, Bobigny, France.|INSERM U1153, Institut National de Recherche en Agronomie (INRA) U1125, Nutritional Epidemiology Research Unit, Epidemiology and Biostatistics Center, Bobigny, France.|Assistance Publique-Hôpitaux de Paris (AP-HP), Department of Public Health, Avicenne Hospital, Bobigny, France.|Paris Diderot University, Paris, France.
authors: Serge
authors: S
authors: Hercberg
authors: Paris Diderot University, Paris, France.|INSERM UMRS 1138, Centre de Recherche des Cordeliers, Paris, France.|AP-HP, Department of Endocrinology, Diabetes and Nutrition, Fibrosis, Inflammation, Remodeling in Cardiovascular, Respiratory and Renal Diseases (FIRE) Department Hospital University, Bichat Hospital, Paris, France.
authors: Ronan
authors: R
authors: Roussel
authors: Framingham Heart Study, Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, US National Institutes of Health, Framingham, Massachusetts, USA.|Department of Medicine (Cardiovascular Division), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors: Emelia J
authors: http://orcid.org/0000-0003-4076-2336
authors: EJ
authors: Benjamin
authors: INSERM, Clinical Investigation Centre (CIC) 0203, University Hospital of Pontchaillou, Rennes, France.|Department of Endocrinology, University Hospital, Rennes, France.
authors: Fabrice
authors: F
authors: Bonnet
authors: Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, California, USA.
authors: Su Hao
authors: SH
authors: Lo
authors: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
authors: Elena
authors: E
authors: Dolmatova
authors: INSERM Unité Mixte de Recherche (UMR) 1087, Centre National de la Recherche Scientifique (CNRS) UMR 6291, Institut du Thorax, Nantes, France.
authors: Floriane
authors: F
authors: Simonet
authors: INSERM Unité Mixte de Recherche (UMR) 1087, Centre National de la Recherche Scientifique (CNRS) UMR 6291, Institut du Thorax, Nantes, France.|Centre Hospitalier Universitaire (CHU) Nantes, Université de Nantes, Nantes, France.
authors: Simon
authors: S
authors: Lecointe
authors: INSERM Unité Mixte de Recherche (UMR) 1087, Centre National de la Recherche Scientifique (CNRS) UMR 6291, Institut du Thorax, Nantes, France.|Centre Hospitalier Universitaire (CHU) Nantes, Université de Nantes, Nantes, France.
authors: Florence
authors: F
authors: Kyndt
authors: INSERM Unité Mixte de Recherche (UMR) 1087, Centre National de la Recherche Scientifique (CNRS) UMR 6291, Institut du Thorax, Nantes, France.|Centre Hospitalier Universitaire (CHU) Nantes, Université de Nantes, Nantes, France.
authors: Richard
authors: R
authors: Redon
authors: INSERM Unité Mixte de Recherche (UMR) 1087, Centre National de la Recherche Scientifique (CNRS) UMR 6291, Institut du Thorax, Nantes, France.|Centre Hospitalier Universitaire (CHU) Nantes, Université de Nantes, Nantes, France.
authors: Hervé
authors: H
authors: Le Marec
authors: CNRS UMR 8199, Lille Pasteur Institute, Lille 2 University, European Genomic Institute for Diabetes (EGID), Lille, France.|Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, UK.
authors: Philippe
authors: P
authors: Froguel
authors: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
authors: Patrick T
authors: http://orcid.org/0000-0002-2067-0533
authors: PT
authors: Ellinor
authors: Framingham Heart Study, Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, US National Institutes of Health, Framingham, Massachusetts, USA.
authors: Ramachandran S
authors: RS
authors: Vasan
authors: INSERM UMR 970, Paris Cardiovascular Research Center, Paris, France.|Paris Descartes University, Paris Sorbonne Cité, Paris, France.|AP-HP, Department of Pathology, Hôpital Européen Georges Pompidou, Paris, France.
authors: Patrick
authors: P
authors: Bruneval
authors: Department of Regenerative Medicine and Cell Biology, Cardiovascular Developmental Biology Center, Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina, USA.
authors: Roger R
authors: RR
authors: Markwald
authors: Department of Regenerative Medicine and Cell Biology, Cardiovascular Developmental Biology Center, Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina, USA.
authors: Russell A
authors: RA
authors: Norris
authors: Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, USA.
authors: David J
authors: DJ
authors: Milan
authors: Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors: Susan A
authors: SA
authors: Slaugenhaupt
authors: Cardiac Ultrasound Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors: Robert A
authors: RA
authors: Levine
authors: INSERM Unité Mixte de Recherche (UMR) 1087, Centre National de la Recherche Scientifique (CNRS) UMR 6291, Institut du Thorax, Nantes, France.|Centre Hospitalier Universitaire (CHU) Nantes, Université de Nantes, Nantes, France.
authors: Jean-Jacques
authors: JJ
authors: Schott
authors: INSERM UMR 970, Paris Cardiovascular Research Center, Paris, France.|AP-HP, Department of Cardiology, Hôpital Européen Georges Pompidou, Paris, France.
authors: Albert A
authors: AA
authors: Hagege
authors: INSERM UMR 970, Paris Cardiovascular Research Center, Paris, France.|Paris Descartes University, Paris Sorbonne Cité, Paris, France.|AP-HP, Department of Genetics, Hôpital Européen Georges Pompidou, Paris, France.
authors: Xavier
authors: http://orcid.org/0000-0001-5925-381X
authors: X
authors: Jeunemaitre
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D055106:Genome-Wide Association Study; D006801:Humans; D051379:Mice; D008945:Mitral Valve Prolapse / Q000235:genetics*