John R. Shaffer, Ekaterina Orlova, Myoung Keun Lee, Elizabeth J. Leslie, Zachary D. Raffensperger, Carrie L. Heike, Michael L. Cunningham, Jacqueline T. Hecht, Chung How Kau, Nichole L. Nidey, Lina M. Moreno, George L. Wehby, Jeffrey C. Murray, Cecelia A. Laurie, Cathy C. Laurie, Joanne Cole, Tracey Ferrara, Stephanie Santorico, Ophir Klein, Washington Mio, Eleanor Feingold, Benedikt Hallgrimsson, Richard A. Spritz, Mary L. Marazita, Seth M. Weinberg

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.