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.

Figure 1. Nine facial landmarks extracted via image registration tools from 3D MRIs.

An MRI of one of the authors (MK) is used for illustration. A, with the landmark for left zygion (ZygL) highlighted, where a clipping plane was used to uncover the bone; B, with the landmarks for left (EyeL) and right pupils (EyeR) highlighted, where a clipping plane was used to uncover the vitreous humor; C, with the four nasal landmarks highlighted, including the left alare, nasion (Nsn), pronasale (Prn), and subnasale (Sbn).

Figure 2. Facial landmarks from 3D MRI in all 5,388 individuals from the discovery cohorts RS1, RS2, QTIMS, SHIP, and SHIP-TREND.

A, all raw landmarks before un-scaled PS; and B, after un-scaled PS.

Figure 3. Quantile-Quantile (Q-Q) plots for the GWAS.

Quantile-Quantile plots for the GWAS of (A) AlrL-Prn, (B) EyeL-Nsn, (C) EyeL-EyeR, and (D) ZygR-Nsn.

Figure 4. Five genomic regions harboring SNPs reaching genome-wide significant associations with facial shape phenotypes in a meta-analysis of five GWAS in discovery cohorts.

The association signals (the −log10 P-values) are plotted against physical positions of each SNP in a 400 kb region centered by the most significantly associated SNP (NCBI build 36.3). Known genes in the region are aligned at the bottom. A. 1p36.23-p33 associated with AlrL-Prn, candidate gene PRDM16; B. 2q35 associated with EyeR-Nsn, candidate gene PAX3; C. 3q28 associated with EyeR-EyeL, candidate gene TP63. D. 5q35.1 associated with EyeL-Nsn, candidate gene C5orf50; E. 10q24.associated with EyeL-Nsn, candidate gene COL17A1.

Figure 5. Facial landmarks from 2D portrait photos.

Eight facial landmarks extracted from a 2D portrait photo of one of the authors (MK) to illustrate facial shape phenotyping in the 2D portrait photos (A). Landmark configurations in 2D photos from 3,503 individuals from the replication cohorts BLTS and TwinsUK before (B), and after (C) full PS. Note that raw landmarks in B appeared to be upset-down of a face, which were rotated by 180° in C.