title: The genetic component of bicuspid aortic valve and aortic dilation. An exome-wide association study.
abstract: Bicuspid aortic valve is the most common cardiovascular congenital malformation affecting 2% of the general population. The incidence of life-threatening complications, the high heritability, and familial clustering rates support the interest in identifying risk or protective genetic factors. The main objective of the present study was to identify population-based genetic variation associated with bicuspid aortic valve and concomitant ascending aortic dilation.
  
  
  
  A cross-sectional exome-wide association study was conducted in 565 Spanish cases and 484 controls. Single-marker and gene-based association analyses enriched for low frequency and rare genetic variants were performed on this discovery stage cohort and for the subsets of cases with and without ascending aortic dilation. Discovery-stage association signals and additional markers indirectly associated with bicuspid aortic valve, were genotyped in a replication cohort that comprised 895 Caucasian cases and 1483 controls.
  
  
  
  Although none of the association signals were consistent across series, the involvement of HMCN2 in calcium metabolism and valve degeneration caused by calcium deposit, and a nominal but not genome-wide significant association, supported it as an interesting gene for follow-up studies on the genetic susceptibility to bicuspid aortic valve.
  
  
  
  The absence of a genome-wide significant association signal shows this valvular malformation may be more genetically complex than previously believed. Exhaustive phenotypic characterization, even larger datasets, and collaborative efforts are needed to detect the combination of rare variants conferring risk which, along with specific environmental factors, could be causing the development of this disease.
authors.affiliation: Xenética de Enfermidades Cardiovasculares e Oftalmolóxicas, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain; Grupo de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela - Universidade de Santiago de Compostela - Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.
authors.forename: Marina
authors.initials: M
authors.lastname: Gago-Díaz
authors.affiliation: Xenética de Enfermidades Cardiovasculares e Oftalmolóxicas, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain; Grupo de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela - Universidade de Santiago de Compostela - Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain. Electronic address: maria.brion@usc.es.
authors.forename: María
authors.initials: M
authors.lastname: Brion
authors.affiliation: Servicio de Cardiología, Hospital Universitario Virgen Macarena, Sevilla, Spain.
authors.forename: Pastora
authors.initials: P
authors.lastname: Gallego
authors.affiliation: Servicio de Cardioloxía, Complexo Hospitalario Universitario de Vigo, Vigo, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Calvo
authors.affiliation: Servicio de Cardiología, Hospital Universitario Virgen de la Victoria, Málaga, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Robledo-Carmona
authors.affiliation: Servicio de Cardiología, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Saura
authors.affiliation: Servicio de Cardiología, Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Violeta
authors.initials: V
authors.lastname: Sánchez
authors.affiliation: Servicio de Cardiología, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Bermejo
authors.affiliation: Servicio de Cardiología, Hospital Clínico Universitario de Valladolid, Valladolid, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Sevilla
authors.affiliation: Cardiovascular Research Center and Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States; The Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Newton-Cheh
authors.affiliation: Grupo de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago de Compostela - Universidade de Santiago de Compostela - Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain; Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Carracedo
authors.affiliation: The Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, United States; Anesthesia and Pain Management, Brigham and Women's Hospital, Boston, MA, United States.
authors.forename: J Daniel
authors.initials: JD
authors.lastname: Muehlschlegel
authors.affiliation: Servei de Cardiologia, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: García-Dorado
authors.affiliation: The Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, United States; Anesthesia and Pain Management, Brigham and Women's Hospital, Boston, MA, United States.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Body
authors.affiliation: Servei de Cardiologia, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Artur
authors.initials: A
authors.lastname: Evangelista
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D001018:Aortic Diseases / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D001021:Aortic Valve / Q000002:abnormalities* / Q000473:pathology; D000082882:Bicuspid Aortic Valve Disease; D015415:Biomarkers; D016022:Case-Control Studies; D015897:Comorbidity; D003430:Cross-Sectional Studies; D004108:Dilatation, Pathologic / Q000235:genetics*; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006349:Heart Valve Diseases / Q000235:genetics* / Q000473:pathology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D013030:Spain / Q000453:epidemiology
chemical_list: D015415:Biomarkers
keywords: Aortic dilation; Bicuspid aortic valve; Complex trait; Exome-wide association study; Genetics