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.

Figure 1

Aligning the 3D Facial Images into Three Reference Planes

Figure 2

Position and Definition of the 22 Landmarks and 54 Parameters Analyzed in the Genome-wide Association Discovery Phase Parameters with pairs of numbers denote the direct 3D distance between pairs of landmarks. Those with “xz,” “xy,” or “yz” denote the prominence of the landmark from the xz, xy, or xz planes. ^∗ “men” (point 22) denotes the midendocanthion or midintercanthal point (the midpoint between left and right endocanthi); this point does not lie on the facial surface.

Figure 3

Deconstruction of the 3D n-men Phenotype into Its Constituent One-Dimensional Distances The midendocanthion is defined as the midpoint between the left and right endocanthi and is therefore not a surface point. The 3D nasion-midendocanthion (n-men) distance was deconstructed into the three 1D distances: the x (the lateral distance between the nasion and midendocanthion—a measure of how off-center the nasion is relative to the midendocanthion), the y (the vertical distance between the nasion and midendocanthion), and the z (the prominence of the nasion relative to the midendocanthion). The 2D yz distance was also constructed as was the angle between the yz and z components.

Figure 4

Association Plot of the Region Surrounding PAX3 for the Nasion-to-Midendocanthion Distance in the Discovery Phase (A) The discovery results. (B) Evidence of a second independent signal in the region—results after adjusting for the top hit (rs7559271) in the discovery data. Produced with LocusZoom. Linkage disequilibrium (r²) is illustrated by color of the points (see key).