Genome-Wide Association Study Reveals Multiple Loci Influencing Normal Human Facial Morphology

Abstract

Numerous lines of evidence point to a genetic basis for facial morphology in humans, yet little is known about how specific genetic variants relate to the phenotypic expression of many common facial features. We conducted genome-wide association meta-analyses of 20 quantitative facial measurements derived from the 3D surface images of 3118 healthy individuals of European ancestry belonging to two US cohorts. Analyses were performed on just under one million genotyped SNPs (Illumina OmniExpress+Exome v1.2 array) imputed to the 1000 Genomes reference panel (Phase 3). We observed genome-wide significant associations (p < 5 x 10-8) for cranial base width at 14q21.1 and 20q12, intercanthal width at 1p13.3 and Xq13.2, nasal width at 20p11.22, nasal ala length at 14q11.2, and upper facial depth at 11q22.1. Several genes in the associated regions are known to play roles in craniofacial development or in syndromes affecting the face: MAFB, PAX9, MIPOL1, ALX3, HDAC8, and PAX1. We also tested genotype-phenotype associations reported in two previous genome-wide studies and found evidence of replication for nasal ala length and SNPs in CACNA2D3 and PRDM16. These results provide further evidence that common variants in regions harboring genes of known craniofacial function contribute to normal variation in human facial features. Improved understanding of the genes associated with facial morphology in healthy individuals can provide insights into the pathways and mechanisms controlling normal and abnormal facial morphogenesis.

Fig 1. Set of 20 linear distance measurements used in the current study.

(A) Cranial base width, (B) Upper facial depth*, (C) Middle facial depth*, (D) Lower facial depth*, (E) Morphological facial height, (F) Upper facial height, (G) Lower facial height, (H) intercanthal width, (I) Outercanthal width, (J) Palpebral fissure length*, (K) Nasal width, (L) Subnasal width, (M) Nasal Protrusion, (N) Nasal ala length*, (O) Nasal height, (P) Nasal Bridge Length, (Q) Labial fissure length, (R) Philtrum length, (S) Upper lip height, and (T) Lower lip height. Measurements with an asterisk (*) are bilateral, but only the left side is shown in the figure.

Fig 2. LocusZoom plots showing genome-wide significant associations observed in the meta-analysis for cranial base width (Fig 1A).

(A) chromosome 14 and (B) chromosome 20. LocusZoom plots show the association (left y-axis; log10-transformed p-values) with facial traits. Genotyped SNPs are depicted by stars and imputed SNPs are depicted by circles. Shading of the points represent the linkage disequilibrium (r², based on the 1000 Genomes Project Europeans) between each SNP and the top SNP, indicated by purple shading. The blue overlay shows the recombination rate (right y-axis). Positions of genes are shown below the plot.

Fig 3. LocusZoom plots showing genome-wide significant associations observed in the meta-analysis for intercanthal width (Fig 1H).

(A) chromosome 1 and (B) chromosome X. LocusZoom plots show the association (left y-axis; log10-transformed p-values) with facial traits. Genotyped SNPs are depicted by stars and imputed SNPs are depicted by circles. Shading of the points represent the linkage disequilibrium (r², based on the 1000 Genomes Project Europeans) between each SNP and the top SNP, indicated by purple shading. The blue overlay shows the recombination rate (right y-axis). Positions of genes are shown below the plot.

Fig 4. LocusZoom plots showing genome-wide significant associations observed in the meta-analysis for nasal width (Fig 1K) and nasal ala length (Fig 1N).

(A) nasal width on chromosome 20 and (B) nasal ala length on chromosome 14. LocusZoom plots show the association (left y-axis; log10-transformed p-values) with facial traits. Genotyped SNPs are depicted by stars and imputed SNPs are depicted by circles. Shading of the points represent the linkage disequilibrium (r², based on the 1000 Genomes Project Europeans) between each SNP and the top SNP, indicated by purple shading. The blue overlay shows the recombination rate (right y-axis). Positions of genes are shown below the plot.

Fig 5. LocusZoom plot showing genome-wide significant association observed in the meta-analysis for upper facial depth (Fig 1B) on chromosome 11.

LocusZoom plots show the association (left y-axis; log10-transformed p-values) with facial traits. Genotyped SNPs are depicted by stars and imputed SNPs are depicted by circles. Shading of the points represent the linkage disequilibrium (r², based on the 1000 Genomes Project Europeans) between each SNP and the top SNP, indicated by purple shading. The blue overlay shows the recombination rate (right y-axis). Positions of genes are shown below the plot.