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

Abstract

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.

Genome-wide mapping of global-to-local genetic effects on human facial shape

“…Note that some prior studies 2,3,5 , also analyzed facial shape data using PCs, but they did so by analyzing them separately. Basically, in these studies full facial multivariate sparse landmark configurations were projected onto each PC, and thus the phenotypic data was preselected along the PCs individually and one-by-one.…”

Exploring the Underlying Genetics of Craniofacial Morphology through Various Sources of Knowledge

“…Furthermore, they were able to replicate the correlation between nasal ala length and SNPs in CACNA2D3 and PRDM16 and between intercanthal width and SNP rs7559271 in PAX3 . A third recently published GWAS looked at 3D images of African children and found an association of SCHIP1 and PDE8A with facial shape and size [57]. They were also able to show clear expression of these genes in the developing mouse face, indicating a role for these genes in normal craniofacial development.…”

“…However, this conventional morphometric approach oversimplifies the 3D craniofacial complex such that facial characteristics of interest may be discounted [67]. The previously described GWAS on typical-range facial variation [29, 54–57] and all of the familial studies on facial heritability thus far started from sparse landmark representation of facial shape. Subsequently, interlandmark distances and/or angles are extracted in combination with a set of principal coordinates using principal component analysis on the landmark coordinates.…”

Facial shape manifestations of growth faltering in Tanzanian children

“…This population does not exhibit significant genetic structure by school with a median fixation index ( F ST ) across pair‐wise samples of 0.0005 (Cole et al. ). However, there is potential for environmental variation among schools.…”

“…Landmarks were obtained via automated landmarking as described previously (Cole et al. , ; Li et al. ).…”