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Facial Architecture GWAS Finds Novel Loci Associated With East African Facial Features

NEW YORK – In conducting a genome-wide association study of the genomic loci responsible for facial morphology in an East African cohort, an international team of researchers has found 20 regions of the genome associated with facial shape in Tanzanian children, 10 of which were also present in Europeans. 

In a study published on Thursday in PLOS Genetics, the researchers noted that previous GWAS of facial morphology have found more than 100 genetic loci associated with different aspects of normal-range facial variation, but that most of these loci have been detected in Europeans, with few studies focusing on other ancestral groups. Therefore, the researchers focused on East African individuals for their paper, applying an open-ended data-driven phenotyping approach to a sample of 2,595 3D facial images collected on Tanzanian children.

In using this approach, they were able to segment the faces of their study subjects into hierarchically arranged, multivariate features that captured the variation of facial shapes, after adjusting for age, sex, height, weight, facial size, and population stratification. The researchers found that their genome scans of these multivariate shape phenotypes revealed significant 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, and six of the 20 loci surpassed a stricter threshold accounting for multiple phenotypes with study-wide significance. Further, they said, cross-population comparisons indicated that 10 association signals were shared with Europeans, with seven of the 10 sharing the same associated SNP.

"Our findings confirm that the genes connected to human facial features are basically the same across populations," University of Pittsburgh researcher and co-corresponding author John Shaffer said in a statement. "Observed differences were mostly explained by how frequently an allele occurs in a given population. By comparing populations, we were able to uncover genetic signals that would otherwise remain obscured and narrow the field of genetic variants that are functionally impacting facial traits." 

The phenotyping approach the researchers used broke up each subject's face into 63 segments. They then identified 189 SNPs across 20 genetic loci in those 63 segments, including seven loci associated with nose-related traits, four loci associated with eye-related traits, and three loci associated with segments in more than one quadrant of the face. Of these 20 GWAS signals in Tanzanians, 10 loci represented novel associations with facial variation.

Further, the researchers identified co-localization with expression quantitative trait loci in fibroblast, skeletal muscle, skin, and adipose tissues and cells for the gene EEFSEC. When comparing the data from the Tanzanian cohort to data from a European cohort, the researchers found a variant in common that co-localized with the eQTL signal for EEFSEC, suggesting a possible role for that gene in craniofacial morphology. 

They also used the Roadmap Epigenomics Project data of human embryonic craniofacial samples to identify specific genetic elements that might play a regulatory role during embryonic development near the 20 GWAS signals, and found that 11 were located in the vicinity of active enhancers marked by H3K27ac, H3K4me1, or H3K4me2 epigenomic modifications. This suggested that these loci were involved in enhancer activity in craniofacial development, the researchers said.

"These findings improve our understanding of genetic and biological basis underpinning the diversity of human facial structure and may offer valuable insights into biological mechanisms responsible for craniofacial morphogenesis and dysmorphology," the authors concluded. "Additional genetic replication and experimental validation will be required to verify the handful of newly identified genes/loci with unclear roles in craniofacial development."