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 twodimensional
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.