Genome and Transcriptome-Wide Analyses Identify Multiple Candidate Genes and a Significant Polygenic Contribution in Bicuspid Aortic Valve
Abstract
BACKGROUND: Bicuspid aortic valve (BAV) is a frequent congenital heart defect with a high heritability. Despite this, only a limited number of genes have been associated with the disease, and the molecular mechanisms remain unexplained in most cases. This study aimed to further understand the genetic architecture of BAV. METHODS: A genome-wide association study meta-analysis including 9631 cases among 65 677 participants was performed. Genes were prioritized using transcriptomic analyses based on RNA sequencing in relevant tissues, including human fetal and adult aortic valves. The impact of the knockdown or knockout of 4 candidate genes on cardiac development was verified in zebrafish. A polygenic risk score was developed, its association with BAV was evaluated in an independent cohort, and its association with a wide range of phenotypes (n=976) was evaluated in UK Biobank (n=355 618 individuals). RESULTS: Thirty-six genomic loci were identified, including 32 that were not described previously. Among the prioritized genes, KANK2 and ERBB4 were identified as potentially causal through transcriptomic analyses, colocalization, and Mendelian randomization based on gene expression in human aortic valves (n=484), whereas PRDM6 and STRN were prioritized using similar analyses from aortic (n=326) and left ventricular tissues (n=326), respectively. Targeting 4 candidate genes ( WNT4 , LEF1 , STRN , and KANK2 ) in zebrafish led to disruption in cardiac development. A polygenic risk score was associated with an odds ratio of 2.07 (95% CI, 1.90–2.25; P =5.43×10 -62 ) per SD for BAV and significantly associated with thoracic aortic aneurysm and atrial fibrillation in UK Biobank. CONCLUSIONS: This study supports a significant polygenic contribution to BAV, where the combination of multiple common variants in genes involved in heart morphogenesis disrupts aortic valve development.
Article Details
Authors (95)
Sébastien Thériault
Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval (S.T., F.D., Z.L., H.D.M., P.P., Y.B., P.M.)
Jacob A. Holdcraft
Department of Biostatistics, School of Public Health, Boston University, MA (J.A.H., G.M.P.)
Dinara Sharipova
Department of Animal Physiology, Institute of Biochemistry and Biology, University of Potsdam, Germany (D.S., S.A.-S.).
Adèle Faucherre
Institut de Génomique Fonctionnelle, University of Montpellier, Centre national de la recherche scientifique, Institut national de la santé et de la recherche médicale, France (A. Faucherre, C.J.).
Radoslaw M. Debiec
Department of Cardiovascular Sciences, Leicester British Heart Foundation Centre of Research Excellence and National Institute for Health and Care Research Leicester Biomedical Research Centre, University of Leicester (R.M.D., P.S.B., C.P.N., A.P.B., N.J.S., T.R.W.).
Gina M. Peloso
Baravan Al-Kassou
Department of Medicine II, Heart Center Bonn (B.A.-K., G.N.), University of Bonn and University Hospital Bonn, Germany.
Sary Aranki
Brigham and Women’s Hospital, Boston, MA (S.A., M.D.F., S.G.).
Elena Ashikhmina Swan
Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, MN (E.A.S.).
Andrea Ballotta
Centro Cardiologico Monzino Istituto di Ricovero e Cura a Carattere Scientifico Via Parea, Milan University, Italy (A.B.).
Michele Bellino
University Study of Salerno, Italy (M. Bellino).
Hanna M. Björck
Anne Sophie Boureau
Nantes Université, CHU Nantes, Centre national de la recherche scientifique, Institut national de la santé et de la recherche médicale, L’Institut du Thorax, France (A.S.B., F.L., S.L.S., F.S., C.D., T.L.T., J.-J.S.).
Peter S. Braund
Department of Cardiovascular Sciences, Leicester British Heart Foundation Centre of Research Excellence and National Institute for Health and Care Research Leicester Biomedical Research Centre, University of Leicester (R.M.D., P.S.B., C.P.N., A.P.B., N.J.S., T.R.W.).
François Corriveau
Université Laval, Quebec City, Canada (F.C.).
François Dagenais
Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval (S.T., F.D., Z.L., H.D.M., P.P., Y.B., P.M.)
Lasse Folkersen
Nucleus Genomics, New York, NY (L.F.).
Amalia Forte
Michael D. Francke
Brigham and Women’s Hospital, Boston, MA (S.A., M.D.F., S.G.).
Alessandro Frigiola
Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Donato, San Donato Milanese, Italy (A. Frigiola, C.d.V., F.P.).
Svetlana Gorbatov
Brigham and Women’s Hospital, Boston, MA (S.A., M.D.F., S.G.).
Dongchuan Guo
Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston (D.G., D.M., D.R.M., S.K.P.).
Karam M. Habchi
New York-Presbyterian Weill Cornell Medical Center, New York, NY (K.M.H.).
Mahyar Heydarpour
Department of Medicine, Boston, MA (M.H.)
Eric M. Isselbacher
Department of Medicine, Harvard Medical School, Boston
Chris Jopling
Institut de Génomique Fonctionnelle, University of Montpellier, Centre national de la recherche scientifique, Institut national de la santé et de la recherche médicale, France (A. Faucherre, C.J.).
Fabien Laporte
Nantes Université, Centre Hospitalier Universitaire (CHU) Nantes, Centre National de la Recherche Scientifique (CNRS), INSERM, l’Institut du Thorax, Nantes, France
Solena Le Scouarnec
Nantes Université, CHU Nantes, Centre national de la recherche scientifique, Institut national de la santé et de la recherche médicale, L’Institut du Thorax, France (A.S.B., F.L., S.L.S., F.S., C.D., T.L.T., J.-J.S.).
Zhonglin Li
Peter Lichtner
Helmholtz Munich, Neuherberg, Germany (P.L., S.W.).
Carlo Maj
Center for Human Genetics
Hasanga D. Manikpurage
Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval (S.T., F.D., Z.L., H.D.M., P.P., Y.B., P.M.)
Christopher P. Nelson
Department of Cardiovascular Sciences, Leicester British Heart Foundation Centre of Research Excellence and National Institute for Health and Care Research Leicester Biomedical Research Centre, University of Leicester (R.M.D., P.S.B., C.P.N., A.P.B., N.J.S., T.R.W.).
Thy B. Nguyen
University of Colorado, Aurora (T.B.N.).
Russell A. Norris
Chin Siang Ong
Yale University School of Medicine, New Haven, CT (C.S.O.).
Philippe Pibarot
Laval University, Quebec, QC, Canada
Tanmoy Roychowdhury
Department of Internal Medicine, Division of Cardiology (T.R., I.S., C.J.W., B.Y.)
Berardo Sarubbi
Department of Biology and Koita Centre for Digital Health, Trivedi School of Biosciences, Ashoka University, Sonepat, India (T.R.).
Floriane Simonet
Nantes Université, CHU Nantes, Centre national de la recherche scientifique, Institut national de la santé et de la recherche médicale, L’Institut du Thorax, France (A.S.B., F.L., S.L.S., F.S., C.D., T.L.T., J.-J.S.).
Thoralf Sundt
Massachusetts General Hospital, Boston (E.M.I., T.S.).
Ida Surakka
Department of Internal Medicine, Division of Cardiology (T.R., I.S., C.J.W., B.Y.)
Idit Tessler
Sheba Medical center, Ramat Gan, Israel (I.T.).
Cristen J. Willer
Susanne Wittmann
Helmholtz Munich, Neuherberg, Germany (P.L., S.W.).
Bo Yang
Igor Berezovets
Department of Cardiac and Thoracic Vascular Surgery, University Heart Center Lübeck, University Medical Center Schleswig-Holstein, Germany (I.B., T.P., S.E.).
Stefanie A. Doppler
Department of Cardiovascular Surgery, Institute Insure (S.A.D., M.D., M.K.), German Heart Center Munich, School of Medicine and Health, Technical University of Munich University Hospital, Technical University of Munich.
Martina Dreßen
Department of Cardiovascular Surgery, Institute Insure (S.A.D., M.D., M.K.), German Heart Center Munich, School of Medicine and Health, Technical University of Munich University Hospital, Technical University of Munich.
Katharina Knoll
Department of Cardiovascular Diseases (K.K., H.S., T.T.), German Heart Center Munich, School of Medicine and Health, Technical University of Munich University Hospital, Technical University of Munich.
Thomas Puehler
Department of Cardiac and Thoracic Vascular Surgery, University Heart Center Lübeck, University Medical Center Schleswig-Holstein, Germany (I.B., T.P., S.E.).
Heribert Schunkert
DZHK Partner Site Munich, Munich Heart Alliance, Munich, Germany
Jean-François Avierinos
Service de Cardiologie, Assistance Publique - Hôpitaux de Marseille, Hôpital de la Timone, Marseille, France (J.-F.A.).
Malenka M. Bissell
Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, United Kingdom (M.M.B.).
Aidan P. Bolger
Department of Cardiovascular Sciences, Leicester British Heart Foundation Centre of Research Excellence and National Institute for Health and Care Research Leicester Biomedical Research Centre, University of Leicester (R.M.D., P.S.B., C.P.N., A.P.B., N.J.S., T.R.W.).
Yohan Bossé
Eduardo Bossone
Department of Public Health, Faculty of Medicine, University of Naples “Federico II,” Italy (E.B.).
María Brion
Rodolfo Citro
Department of Medicine and Health Science, University of Molise, Campobasso, Italy (R.C.).
Carlo de Vincentiis
Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Donato, San Donato Milanese, Italy (A. Frigiola, C.d.V., F.P.).
G. Michael Deeb
Department of Cardiac Surgery (G.M.D.)
Alessandro Della Corte
University of Campania L. Vanvitelli, Naples, Italy (A. Forte, A.D.C.).
Christian Dina
Ronen Durst
Cardiology Department, Hadassah Hebrew University Medical Center, Jerusalem, Israel (R.D., D.G.).
Stephan Ensminger
Per Eriksson
Arturo Evangelista
Anders Franco-Cereceda
Dan Gilon
Cardiology Department, Hadassah Hebrew University Medical Center, Jerusalem, Israel (R.D., D.G.).
Betti Giusti
Department of Experimental and Clinical Medicine, University of Florence, Italy (B.G., S.N.).
Simon L. Hetherington
Kettering General Hospital National Health Service Foundation Trust, Kettering, United Kingdom (S.L.H.).
Gordon S. Huggins
Tufts Medical Center, Boston, MA (G.S.H.).
Markus Krane
Department of Cardiovascular Surgery, Institute Insure (S.A.D., M.D., M.K.), German Heart Center Munich, School of Medicine and Health, Technical University of Munich University Hospital, Technical University of Munich.
Thierry Le Tourneau
Nantes Université, CHU Nantes, Centre national de la recherche scientifique, Institut national de la santé et de la recherche médicale, L’Institut du Thorax, France (A.S.B., F.L., S.L.S., F.S., C.D., T.L.T., J.-J.S.).
Giuseppe Limongelli
Patrick Mathieu
Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval (S.T., F.D., Z.L., H.D.M., P.P., Y.B., P.M.)
David Messika-Zeitoun
Department of Translational Medical Sciences, University of Campania Luigi Vanvitelli, Naples, Italy (G.L.).
Hector I. Michelena
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN (H.I.M.)
Dianna Milewicz
Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston (D.G., D.M., D.R.M., S.K.P.).
Jochen D. Muehlschlegel
David R. Murdock
Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston (D.G., D.M., D.R.M., S.K.P.).
Georg Nickenig
Stefano Nistri
Markus M. Nöthen
Francesca Pluchinotta
Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Donato, San Donato Milanese, Italy (A. Frigiola, C.d.V., F.P.).
Siddharth K Prakash
Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston (D.G., D.M., D.R.M., S.K.P.).
Nilesh J. Samani
Jean-Jacques Schott
Nantes Université, CHU Nantes, Centre national de la recherche scientifique, Institut national de la santé et de la recherche médicale, L’Institut du Thorax, France (A.S.B., F.L., S.L.S., F.S., C.D., T.L.T., J.-J.S.).
Tom R. Webb
Stéphane Zaffran
Aix Marseille Université, Institut national de la santé et de la recherche médicale, Marseille Medical Genetics, U1251, France (S.Z.).
Salim Abdelilah-Seyfried
Department of Animal Physiology, Institute of Biochemistry and Biology, University of Potsdam, Germany (D.S., S.A.-S.).
Kim Eagle
Michigan Medicine, University of Michigan, Ann Arbor (K.E.).
Johannes Schumacher
Teresa Trenkwalder
Department of Cardiovascular Diseases (K.K., H.S., T.T.), German Heart Center Munich, School of Medicine and Health, Technical University of Munich University Hospital, Technical University of Munich.
Simon C. Body
Department of Anesthesiology, Boston University, MA (S.C.B.).