To characterize the genetic basis of facial features in Latin Americans, we performed a genome-wide association study (GWAS) of more than 6000 individuals using 59 landmark-based measurements from two-dimensional profile photographs and ~9,000,000 genotyped or imputed single-nucleotide polymorphisms. We detected significant association of 32 traits with at least 1 (and up to 6) of 32 different genomic regions, more than doubling the number of robustly associated face morphology loci reported until now (from 11 to 23). These GWAS hits are strongly enriched in regulatory sequences active specifically during craniofacial development. The associated region in 1p12 includes a tract of archaic adaptive introgression, with a Denisovan haplotype common in Native Americans affecting particularly lip thickness. Among the nine previously unidentified face morphology loci we identified is the VPS13B gene region, and we show that variants in this region also affect midfacial morphology in mice.

Fluctuating asymmetry is a classic concept linked to organismal development. It has traditionally been used as a measure of developmental instability, which is the inability of an organism to buffer environmental fluctuations during development. Developmental stability has a genetic component that influences the final phenotype of the organism and can lead to congenital disorders. According to alternative hypotheses, this genetic component might be either the result of additive genetic effects or a by-product of developmental gene networks. Here we present a genome-wide association study of the genetic architecture of fluctuating asymmetry of the skull shape in mice. Geometric morphometric methods were applied to quantify fluctuating asymmetry: we estimated fluctuating asymmetry as Mahalanobis distances to the mean asymmetry, correcting first for genetic directional asymmetry. We applied the marginal epistasis test to study epistasis among genomic regions. Results showed no evidence of additive effects but several interacting regions significantly associated with fluctuating asymmetry. Among the candidate genes overlapping these interacting regions we found an over-representation of genes involved in craniofacial development. A gene network is likely to be associated with skull developmental stability, and genes originally described as buffering genes (e.g., Hspa2) might occupy central positions within these networks, where regulatory elements may also play an important role. Our results constitute an important step in the exploration of the molecular roots of developmental stability and the first empirical evidence about its genetic architecture.