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Hundreds of Genetic Loci Influence Shape of the Human Face

NEW YORK — Researchers have identified hundreds of genetic loci that appear to influence how the human face is shaped.

The human face is a complex morphological structure influenced by genetic, cellular, and environmental factors. Using a phenotyping approach they developed, researchers from the US and Belgium conducted a genome-wide association study meta-analysis of more than 8,000 European individuals to examine loci associated with normal-range facial morphology. As they reported on Monday in Nature Genetics, they uncovered more than 200 loci associated with facial morphology that hint at roles for enhancer activity and coordination between different loci in determining a face's shape.

"The face tells the outside world about your identity, who you are related to, where your ancestors come from, and even your health," co-lead author Julie White, a graduate student in anthropology at Pennsylvania State University, said in a statement. "But we only know a fraction of how faces are formed. The facial structure comes together in early development, and if it doesn't go right, you can get a cleft palate or other problem, but we don't fully know what controls those processes."

Based on three-dimensional facial surface scans, the researchers divided the face into 63 segments representing various facial features that they then grouped together using clustering and principal component analysis into 20 main components. They then tested for associations between these and more than 7.4 million SNPs in 8,246 individuals from the US and UK.

More than 17,600 SNPs met genome-wide significance, but the researchers refined their results to home in on 203 variants that were the lead SNPs across the facial segments and had consistent effects in both the US and UK cohorts. Eighty-nine of these SNPs overlapped with previous association studies of normal-range facial phenotypes, but 53 had no known role in facial development of disease.

The regions surrounding these SNPs were enriched for involvement in craniofacial shape and morphology as well as limb morphology. This finding, the researchers noted, suggests a shared genetic architecture between the face and limbs and is supported by findings that people with facial deformities sometimes have other physical problems.

In addition, these regions were enriched for chromatin signals indicative of enhancers, particularly enhancers that are active in cranial neural crest cells, fetal and adult osteoblasts, and mesenchymal stem cell-derived chondrocytes. This, the researchers noted, indicates that the genetic variations underpinning facial morphology influence enhancer activity during embryonic facial development.

A number of genomic regions harbored more than one lead SNP. For instance, variants at TBX15-WARS2 have previously been tied to forehead prominence and chin dimples, and the current research also tied a lead SNP in this region to forehead features. But the researchers noted another SNP in the region that was associated with the full face morphology, another with associations to the cheek-to-corner-of-the-mouth area, and yet another associated with the upper cheeks.

Overall, the researchers noted that their results reflect patterns from known biological processes. For instance, they found that correlations between various facial segments appear to reflect their shared embryological origins. 

"Our post-analyses provide us with additional evidence. For example, the epigenetic analyses showed that the genetic regions we found get expressed in cells relevant for craniofacial development," Karlijne Indencleef, a graduate student in biomedical sciences at KU Leuven and co-lead author on the paper, said in a statement. "We have tagged locations that can be interesting for wet labs to validate and further investigate their exact functions."