title: A genome-wide association study identifies multiple loci for variation in human ear morphology.
abstract: Here we report a genome-wide association study for non-pathological pinna morphology in over 5,000 Latin Americans. We find genome-wide significant association at seven genomic regions affecting: lobe size and attachment, folding of antihelix, helix rolling, ear protrusion and antitragus size (linear regression P values 2 × 10(-8) to 3 × 10(-14)). Four traits are associated with a functional variant in the Ectodysplasin A receptor (EDAR) gene, a key regulator of embryonic skin appendage development. We confirm expression of Edar in the developing mouse ear and that Edar-deficient mice have an abnormally shaped pinna. Two traits are associated with SNPs in a region overlapping the T-Box Protein 15 (TBX15) gene, a major determinant of mouse skeletal development. Strongest association in this region is observed for SNP rs17023457 located in an evolutionarily conserved binding site for the transcription factor Cartilage paired-class homeoprotein 1 (CART1), and we confirm that rs17023457 alters in vitro binding of CART1.
authors.affiliation: Department of Genetics, Evolution and Environment, UCL Genetics Institute, University College London, London WC1E 6BT, UK.
authors.forename: Kaustubh
authors.initials: K
authors.lastname: Adhikari
authors.affiliation: Department of Genetics, Evolution and Environment, UCL Genetics Institute, University College London, London WC1E 6BT, UK.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Reales
authors.affiliation: Centre for Cardiovascular Genetics, BHF Laboratories, Institute Cardiovascular Sciences, University College London, Rayne Building, London WC1E 6JF, UK.
authors.forename: Andrew J P
authors.initials: AJ
authors.lastname: Smith
authors.affiliation: Department of Genetics, Evolution and Environment, UCL Genetics Institute, University College London, London WC1E 6BT, UK.
authors.forename: Esra
authors.initials: E
authors.lastname: Konka
authors.affiliation: Centre for Cardiovascular Genetics, BHF Laboratories, Institute Cardiovascular Sciences, University College London, Rayne Building, London WC1E 6JF, UK.
authors.forename: Jutta
authors.initials: J
authors.lastname: Palmen
authors.affiliation: Centro Nacional Patagónico, CONICET, Puerto Madryn U9129ACD, Argentina.
authors.forename: Mirsha
authors.initials: M
authors.lastname: Quinto-Sanchez
authors.affiliation: 1] Department of Genetics, Evolution and Environment, UCL Genetics Institute, University College London, London WC1E 6BT, UK [2] National Institute of Anthropology and History, Mexico City 4510, Mexico.
authors.forename: Victor
authors.initials: V
authors.lastname: Acuña-Alonzo
authors.affiliation: GENMOL (Genética Molecular), Universidad de Antioquia, Medellín 5001000, Colombia.
authors.forename: Claudia
authors.initials: C
authors.lastname: Jaramillo
authors.affiliation: GENMOL (Genética Molecular), Universidad de Antioquia, Medellín 5001000, Colombia.
authors.forename: William
authors.initials: W
authors.lastname: Arias
authors.affiliation: Instituto de Alta Investigación, Universidad de Tarapacá, Programa de Genética Humana ICBM Facultad de Medicina Universidad de Chile and Centro de Investigaciones del Hombre en el Desierto, Arica 1000000, Chile.
authors.forename: Macarena
authors.initials: M
authors.lastname: Fuentes
authors.affiliation: Instituto de Alta Investigación, Universidad de Tarapacá, Programa de Genética Humana ICBM Facultad de Medicina Universidad de Chile and Centro de Investigaciones del Hombre en el Desierto, Arica 1000000, Chile.
authors.forename: María
authors.initials: M
authors.lastname: Pizarro
authors.affiliation: 1] National Institute of Anthropology and History, Mexico City 4510, Mexico [2] Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM-Instituto Nacional de Medicina Genómica, Mexico City 4510, Mexico.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Barquera Lozano
authors.affiliation: 1] National Institute of Anthropology and History, Mexico City 4510, Mexico [2] Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM-Instituto Nacional de Medicina Genómica, Mexico City 4510, Mexico.
authors.forename: Gastón
authors.initials: G
authors.lastname: Macín Pérez
authors.affiliation: Facultad de Medicina, UNAM, Mexico City 4510, Mexico.
authors.forename: Jorge
authors.initials: J
authors.lastname: Gómez-Valdés
authors.affiliation: Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM-Instituto Nacional de Medicina Genómica, Mexico City 4510, Mexico.
authors.forename: Hugo
authors.initials: H
authors.lastname: Villamil-Ramírez
authors.affiliation: Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre 91501-970, Brazil.
authors.forename: Tábita
authors.initials: T
authors.lastname: Hunemeier
authors.affiliation: 1] Centro Nacional Patagónico, CONICET, Puerto Madryn U9129ACD, Argentina [2] Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre 91501-970, Brazil.
authors.forename: Virginia
authors.initials: V
authors.lastname: Ramallo
authors.affiliation: Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre 91501-970, Brazil.
authors.forename: Caio C
authors.initials: CC
authors.lastname: Silva de Cerqueira
authors.affiliation: Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima 31, Peru.
authors.forename: Malena
authors.initials: M
authors.lastname: Hurtado
authors.affiliation: Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima 31, Peru.
authors.forename: Valeria
authors.initials: V
authors.lastname: Villegas
authors.affiliation: Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima 31, Peru.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Granja
authors.affiliation: Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima 31, Peru.
authors.forename: Carla
authors.initials: C
authors.lastname: Gallo
authors.affiliation: Laboratorios de Investigación y Desarrollo, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima 31, Peru.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Poletti
authors.affiliation: Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre 91501-970, Brazil.
authors.forename: Lavinia
authors.initials: L
authors.lastname: Schuler-Faccini
authors.affiliation: Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre 91501-970, Brazil.
authors.forename: Francisco M
authors.initials: FM
authors.lastname: Salzano
authors.affiliation: Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre 91501-970, Brazil.
authors.forename: Maria-Cátira
authors.initials: MC
authors.lastname: Bortolini
authors.affiliation: Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM-Instituto Nacional de Medicina Genómica, Mexico City 4510, Mexico.
authors.forename: Samuel
authors.initials: S
authors.lastname: Canizales-Quinteros
authors.affiliation: Instituto de Alta Investigación, Universidad de Tarapacá, Programa de Genética Humana ICBM Facultad de Medicina Universidad de Chile and Centro de Investigaciones del Hombre en el Desierto, Arica 1000000, Chile.
authors.forename: Francisco
authors.initials: F
authors.lastname: Rothhammer
authors.affiliation: GENMOL (Genética Molecular), Universidad de Antioquia, Medellín 5001000, Colombia.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Bedoya
authors.affiliation: Departamento de Zoología y Antropología Física, Universidad Complutense de Madrid, Madrid 28040, Spain.
authors.forename: Rosario
authors.initials: R
authors.lastname: Calderón
authors.affiliation: Departamento de Antropología, Facultad de Ciencias Sociales y Humanas, Universidad de Antioquia, Medellín 5001000, Colombia.
authors.forename: Javier
authors.initials: J
authors.lastname: Rosique
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian EH25 9RG, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Cheeseman
authors.affiliation: 1] UCL Ear Institute, University College London, London WC1X 8EE, UK [2] Royal National Throat Nose and Ear Hospital, London WC1X 8EE, UK.
authors.forename: Mahmood F
authors.initials: MF
authors.lastname: Bhutta
authors.affiliation: 1] Department of Genetics, Evolution and Environment, UCL Genetics Institute, University College London, London WC1E 6BT, UK [2] Centre for Cardiovascular Genetics, BHF Laboratories, Institute Cardiovascular Sciences, University College London, Rayne Building, London WC1E 6JF, UK.
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.affiliation: Centro Nacional Patagónico, CONICET, Puerto Madryn U9129ACD, Argentina.
authors.forename: Rolando
authors.initials: R
authors.lastname: Gonzalez-José
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian EH25 9RG, UK.
authors.forename: Denis
authors.initials: D
authors.lastname: Headon
authors.affiliation: 1] Department of Genetics, Evolution and Environment, UCL Genetics Institute, University College London, London WC1E 6BT, UK [2] Schools of BioSciences and Mathematics &Statistics, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Balding
authors.affiliation: Department of Genetics, Evolution and Environment, UCL Genetics Institute, University College London, London WC1E 6BT, UK.
authors.forename: Andrés
authors.initials: A
authors.lastname: Ruiz-Linares
mesh_terms: D000293:Adolescent; D000328:Adult; D044467:American Indian or Alaska Native / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D054644:Ear Auricle / Q000033:anatomy & histology / Q000196:embryology*; D053339:Edar Receptor / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007843:Latin America; D008297:Male; D051379:Mice; D009024:Morphogenesis / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: C489985:ALX1 protein, human; C506008:EDAR protein, human; D053339:Edar Receptor; C506009:Edar protein, mouse; D018398:Homeodomain Proteins; D020825:T-Box Domain Proteins; C523795:TBX15 protein, human