Genomewide Association Study of African Children Identifies Association of SCHIP1 and PDE8A with Facial Size and Shape

The human face is a complex assemblage of highly variable yet clearly heritable anatomic structures that together make each of us unique, distinguishable, and recognizable. Relatively little is known about the genetic underpinnings of normal human facial variation. To address this, we carried out a large genomewide association study and two independent replication studies of Bantu African children and adolescents from Mwanza, Tanzania, a region that is both genetically and environmentally relatively homogeneous. We tested for genetic association of facial shape and size phenotypes derived from 3D imaging and automated landmarking of standard facial morphometric points. SNPs within genes SCHIP1 and PDE8A were associated with measures of facial size in both the GWAS and replication cohorts and passed a stringent genomewide significance threshold adjusted for multiple testing of 34 correlated traits. For both SCHIP1 and PDE8A, we demonstrated clear expression in the developing mouse face by both whole-mount in situ hybridization and RNA-seq, supporting their involvement in facial morphogenesis. Ten additional loci demonstrated suggestive association with various measures of facial shape. Our findings, which differ from those in previous studies of European-derived whites, augment understanding of the genetic basis of normal facial development, and provide insights relevant to both human disease and forensics.Author Summary: The human face is made up of distinct yet related anatomic structures that together make both individuals and families recognizable. It is clear there is a strong genetic component to the human face, and though the genetics of the face have been studied for several years, there are relatively few genes known to impact normal human facial development and facial shape. We report here a large-scale human genetic study in which we successfully identify and replicate genetic markers associated with normal facial variation using advanced 3D facial imaging in African children. We identified two significant replicated genes associated with measures of human facial size, SCHIP1 and PDE8A, demonstrated their clear expression in the developing face in the mouse, and identified 10 additional candidate genetic loci for human facial shape. Gene discovery for human facial development is an important first step for both diagnosing and treating craniofacial syndromes and for developing forensic modeling of the human face.