Genome scans of facial features in East Africans and cross-population comparisons reveal novel associations

Abstract

Facial morphology is highly variable, both within and among human populations, and a sizable portion of this variation is attributable to genetics. Previous genome scans have revealed more than 100 genetic loci associated with different aspects of normal-range facial variation. Most of these loci have been detected in Europeans, with few studies focusing on other ancestral groups. Consequently, the degree to which facial traits share a common genetic basis across diverse sets of humans remains largely unknown. We therefore investigated the genetic basis of facial morphology in an East African cohort. We applied an open-ended data-driven phenotyping approach to a sample of 2,595 3D facial images collected on Tanzanian children. This approach segments the face into hierarchically arranged, multivariate features that capture the shape variation after adjusting for age, sex, height, weight, facial size and population stratification. Genome scans of these multivariate shape phenotypes revealed significant (p < 2.5 × 10−8) signals at 20 loci, which were enriched for active chromatin elements in human cranial neural crest cells and embryonic craniofacial tissue, consistent with an early developmental origin of the facial variation. Two of these associations were in highly conserved regions showing craniofacial-specific enhancer activity during embryological development (5q31.1 and 12q21.31). Six of the 20 loci surpassed a stricter threshold accounting for multiple phenotypes with study-wide significance (p < 6.25 × 10−10). Cross-population comparisons indicated 10 association signals were shared with Europeans (seven sharing the same associated SNP), and facilitated fine-mapping of causal variants at previously reported loci. Taken together, these results may point to both shared and population-specific components to the genetic architecture of facial variation.

Combining genome-wide association studies highlight novel loci involved in human facial variation

“…Finally, we investigated the colocalization of genetic association at 56 C-GWAS-identified loci with eQTL signals by using expression data from 22 classified tissues potentially relevant to facial morphogenesis. Previously, a smaller scaled colocalization analysis had been conducted for 20 face-associated loci in 6 tissues 31 , which highlighted EEFSEC with evidence of colocalization. Our study confirmed this finding and additionally revealed many novel loci with evidence of colocalization in various tissues.…”

Super-enhancer associated core regulatory circuits mediate susceptibility to retinoic acid in neuroblastoma cells

“…This was reflected in the downregulation of their expression levels in responsive cell lines ( Figure 4D ). EEFSEC is a selenocysteine tRNA-specific eukaryotic elongation factor that has a critical role during embryonic development ( Zhang et al, 2017 ; Liu et al, 2021 ). Importantly, lower expression of EEFSEC in patient tumours correlates with improved survival outcomes suggesting the significance of this gene in neuroblastoma tumour biology ( Figure 4E ).…”

A common cis-regulatory variant impacts normal-range and disease-associated human facial shape through regulation of PKDCC during chondrogenesis

“…Morphometric differences in cranial bone surfaces of wild-type, Pkdcc +/- , and Pkdcc -/- E18.5 embryos were analyzed in Matlab 2021b. The MeshMonk toolbox ( White et al, 2019 ) was developed for spatially dense phenotyping of 3D surface meshes of anatomical structures and has been used extensively in studies of craniofacial variation in humans ( Claes et al, 2018 ; Liu et al, 2021 ; White et al, 2021 ). MeshMonk performs a non-rigid registration of a template mesh onto each target mesh.…”