title: Genome-wide association study of three-dimensional facial morphology identifies a variant in PAX3 associated with nasion position.
abstract: Craniofacial morphology is highly heritable, but little is known about which genetic variants influence normal facial variation in the general population. We aimed to identify genetic variants associated with normal facial variation in a population-based cohort of 15-year-olds from the Avon Longitudinal Study of Parents and Children. 3D high-resolution images were obtained with two laser scanners, these were merged and aligned, and 22 landmarks were identified and their x, y, and z coordinates used to generate 54 3D distances reflecting facial features. 14 principal components (PCs) were also generated from the landmark locations. We carried out genome-wide association analyses of these distances and PCs in 2,185 adolescents and attempted to replicate any significant associations in a further 1,622 participants. In the discovery analysis no associations were observed with the PCs, but we identified four associations with the distances, and one of these, the association between rs7559271 in PAX3 and the nasion to midendocanthion distance (n-men), was replicated (p = 4 × 10(-7)). In a combined analysis, each G allele of rs7559271 was associated with an increase in n-men distance of 0.39 mm (p = 4 × 10(-16)), explaining 1.3% of the variance. Independent associations were observed in both the z (nasion prominence) and y (nasion height) dimensions (p = 9 × 10(-9) and p = 9 × 10(-10), respectively), suggesting that the locus primarily influences growth in the yz plane. Rare variants in PAX3 are known to cause Waardenburg syndrome, which involves deafness, pigmentary abnormalities, and facial characteristics including a broad nasal bridge. Our findings show that common variants within this gene also influence normal craniofacial development.
authors.affiliation: MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, UK. l.paternoster@bristol.ac.uk
authors.forename: Lavinia
authors.initials: L
authors.lastname: Paternoster
authors.forename: Alexei I
authors.initials: AI
authors.lastname: Zhurov
authors.forename: Arshed M
authors.initials: AM
authors.lastname: Toma
authors.forename: John P
authors.initials: JP
authors.lastname: Kemp
authors.forename: Beate
authors.initials: B
authors.lastname: St Pourcain
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
authors.forename: George
authors.initials: G
authors.lastname: McMahon
authors.forename: Wendy
authors.initials: W
authors.lastname: McArdle
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ring
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.forename: Stephen
authors.initials: S
authors.lastname: Richmond
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
mesh_terms: D000293:Adolescent; D000483:Alleles; D015331:Cohort Studies; D005147:Facial Bones / Q000033:anatomy & histology*; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D021621:Imaging, Three-Dimensional / Q000379:methods; D008137:Longitudinal Studies / Q000379:methods; D008297:Male; D009295:Nasal Bone / Q000033:anatomy & histology; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D014849:Waardenburg Syndrome / Q000235:genetics
chemical_list: D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors