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.

Face shape differs in phylogenetically related populations

“…Craniofacial development is a complex process determined by genetic regulation and genetic variants influence facial morphology in the general population. 18,19 Thus, face shape difference between populations reflects underlying genetic differences. Therefore, our findings indicate that different baselines for face shape norms for individual populations should be applied when considering craniofacial conditions.…”

Growth hormone receptor gene variant and three-dimensional mandibular morphology

“…Moreover, these studies have used magnetic resonance imaging and laser scans to measure facial morphology. 27,28 The present study, to our knowledge, is the first to report a relationship between GHR gene variants and threedimensional mandibular morphology using CBCT imaging, which accurately measures not only soft tissues but also bone morphology, 29 and is therefore useful for examining the complex structure of the mandible.…”

Prenatal Methylmercury Exposure and Genetic Predisposition to Cognitive Deficit at Age 8 Years

“…Standard quality control methods were performed and have been previously described 19 resulting in a final sample of 8365 independent individuals with genotypic information. Genotypic data were subsequently imputed using MACH 20 and phased haplotype data from HapMap CEU (Rel22). Data from genotyped and imputed SNPs (using the most likely genotype) were extracted for 247 SNPs (See S1).…”