title: A genome-wide association study identifies five loci influencing facial morphology in Europeans.
abstract: Inter-individual variation in facial shape is one of the most noticeable phenotypes in humans, and it is clearly under genetic regulation; however, almost nothing is known about the genetic basis of normal human facial morphology. We therefore conducted a genome-wide association study for facial shape phenotypes in multiple discovery and replication cohorts, considering almost ten thousand individuals of European descent from several countries. Phenotyping of facial shape features was based on landmark data obtained from three-dimensional head magnetic resonance images (MRIs) and two-dimensional portrait images. We identified five independent genetic loci associated with different facial phenotypes, suggesting the involvement of five candidate genes--PRDM16, PAX3, TP63, C5orf50, and COL17A1--in the determination of the human face. Three of them have been implicated previously in vertebrate craniofacial development and disease, and the remaining two genes potentially represent novel players in the molecular networks governing facial development. Our finding at PAX3 influencing the position of the nasion replicates a recent GWAS of facial features. In addition to the reported GWA findings, we established links between common DNA variants previously associated with NSCL/P at 2p21, 8q24, 13q31, and 17q22 and normal facial-shape variations based on a candidate gene approach. Overall our study implies that DNA variants in genes essential for craniofacial development contribute with relatively small effect size to the spectrum of normal variation in human facial morphology. This observation has important consequences for future studies aiming to identify more genes involved in the human facial morphology, as well as for potential applications of DNA prediction of facial shape such as in future forensic applications.
authors.affiliation: Department of Forensic Molecular Biology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Fan
authors.initials: F
authors.lastname: Liu
authors.forename: Fedde
authors.initials: F
authors.lastname: van der Lijn
authors.forename: Claudia
authors.initials: C
authors.lastname: Schurmann
authors.forename: Gu
authors.initials: G
authors.lastname: Zhu
authors.forename: M Mallar
authors.initials: MM
authors.lastname: Chakravarty
authors.forename: Pirro G
authors.initials: PG
authors.lastname: Hysi
authors.forename: Andreas
authors.initials: A
authors.lastname: Wollstein
authors.forename: Oscar
authors.initials: O
authors.lastname: Lao
authors.forename: Marleen
authors.initials: M
authors.lastname: de Bruijne
authors.forename: M Arfan
authors.initials: MA
authors.lastname: Ikram
authors.forename: Aad
authors.initials: A
authors.lastname: van der Lugt
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.forename: Wiro J
authors.initials: WJ
authors.lastname: Niessen
authors.forename: Georg
authors.initials: G
authors.lastname: Homuth
authors.forename: Greig
authors.initials: G
authors.lastname: de Zubicaray
authors.forename: Katie L
authors.initials: KL
authors.lastname: McMahon
authors.forename: Paul M
authors.initials: PM
authors.lastname: Thompson
authors.forename: Amro
authors.initials: A
authors.lastname: Daboul
authors.forename: Ralf
authors.initials: R
authors.lastname: Puls
authors.forename: Katrin
authors.initials: K
authors.lastname: Hegenscheid
authors.forename: Liisa
authors.initials: L
authors.lastname: Bevan
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Pausova
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Medland
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Wright
authors.forename: Carol
authors.initials: C
authors.lastname: Wicking
authors.forename: Stefan
authors.initials: S
authors.lastname: Boehringer
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Spector
authors.forename: Tomáš
authors.initials: T
authors.lastname: Paus
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.forename: Reiner
authors.initials: R
authors.lastname: Biffar
authors.forename: Manfred
authors.initials: M
authors.lastname: Kayser
mesh_terms: D001324:Autoantigens / Q000235:genetics*; D019521:Body Patterning / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005145:Face / Q000033:anatomy & histology*; D055106:Genome-Wide Association Study; D006801:Humans; D021621:Imaging, Three-Dimensional; D008279:Magnetic Resonance Imaging; D024041:Non-Fibrillar Collagens / Q000235:genetics*; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D044465:White People / Q000235:genetics; D000097805:Collagen Type XVII
chemical_list: D001324:Autoantigens; D004268:DNA-Binding Proteins; D024041:Non-Fibrillar Collagens; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000097805:Collagen Type XVII; C489409:PAX3 protein, human; C416371:PRDM16 protein, human; C115051:TP63 protein, human