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

Author summary Genetic factors play an important role in shaping human facial features. Over the last decade, studies have identified numerous genes associated with various facial traits. The vast majority of these studies have focused on European or Asian populations, while African populations have been underrepresented. Increasing the diversity of these analyses can reveal novel associations and cross-population analyses can help deepen our understanding of known genetic associations. We therefore performed a genome scan of 3D facial features in African children from Tanzania and then compared our results to Europeans. We found 20 regions of the genome associated with facial shape in Tanzanian children, 10 of which were also present in Europeans, indicating evidence for a partly shared genetic basis for human facial shape across populations. In addition, about half of the genetic associations observed in Tanzanians were not present in Europeans, and some of the shared signals differed between populations in the specific genetic variants associated or specific facial traits affected. These results shed light on the shared and population-specific genetic contributors to normal-range facial variation. 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 x 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 x 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.

Automated summary

Genetic factors play a crucial role in shaping human facial features, with shared and population-specific genetic contributions to normal-range facial variation observed in Tanzanian children compared to Europeans. 20 genomic regions associated with facial shape were identified in Tanzanian children, 10 of which overlapped with Europeans, indicating some shared genetic basis for human facial shape across populations. Additionally, unique genetic associations and differing shared signals were found, suggesting both common and distinct genetic architecture of facial variation among populations.