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GWAS Finds Genes Associated with European Facial Features

NEW YORK (GenomeWeb News) – Members of the International Visible Trait Genetics, or VisiGen, Consortium have tracked down five loci influencing various facial features — ranging from nose width and height to the distance between a person's eyes — in individuals of European ancestry.

Through a genome-wide association study involving thousands of individuals whose facial landmarks had been measured using three-dimensional and/or two-dimensional methods, the group found five loci linked to facial features. Of these, three were genes identified in past studies of skull and face development or malformation conditions in vertebrates. The study appeared online last night in PLoS Genetics.

Additional research is needed to uncover the full suite of genes and regulatory regions associated with face shape in humans. Still, such findings are expected to enhance investigators' understanding of facial development, related diseases, and the evolution of human facial features.

If enough can be learned about this process, there is also the possibility that researchers will find ways to predict certain features of a person's face using genetic material, VisiGen members said.

"Perhaps some time it will be possible to draw a phantom portrait of a person solely from his or her DNA left behind, which provides interesting applications such as in forensics," Erasmus University Medical Center forensic molecular biology researcher Manfred Kayser, the study's corresponding author, said in a statement.

"We already can predict from DNA certain eye and hair colors with quite high accuracies," he added.

Face shape is known to be highly heritable and a few of the genes involved have been identified through studies of Mendelian conditions that affect the way the face and/or skull form, the researchers explained. Nevertheless, there's still a ways to go in order to flesh out the set of genes that contribute to the complicated process of facial development — and that spell out the specific features of each person's face.

If such genes can be discovered, though, they could eventually prove useful for everything from studies of disease and evolution to the advent of new forensics tools.

"An appreciation of the genetic basis of facial shape variation has far-reaching implications for understanding the etiology of facial pathologies, the origin of major sensory organ systems, and even the evolution of vertebrates," Kayser and his co-authors wrote.

"It is feasible to speculate that once the majority of genetic determinants of facial morphology are understood," they added, "predicting facial appearance from DNA found at a crime scene will become useful as [an] investigative tool in forensic case work."

In their search for genetic mediators of face shape variation, the team started by coming up with a list of measurable landmarks on the human face using three-dimensional magnetic resonance image information on thousands of subjects, as well as two-dimensional data from portrait photographs of these individuals.

Based on the facial patterns identified in this manner in almost 5,400 individuals of European descent from the Netherlands, Germany, and Australia, researchers defined four-dozen facial traits. After confirming that these facial landmarks were highly heritable using measurements from dozens of identical and non-identical twins, the investigators went on to look for genetic variants associated with these traits in the same 5,388 individuals assessed by MRI originally.

From genotype profiles generated using several Affymetrix and/or Illumina arrays, the team narrowed in on five loci with significant ties to face shape: sites in and around the PRDM16 gene on chromosome 1, the chromosome 2 gene PAX3, TP63 on chromosome 3, C5orf50 on chromosome 5, and the COL17A1 gene on chromosome 10.

Some, but not all, of the associations could be replicated in 568 French-Canadian adolescents, researchers reported. They suspect that this incomplete overlap could be a consequence of ongoing changes in facial features between adolescence and adulthood. Likewise, two of the five loci showed nominally significant associations in validation cohorts of 1,530 adults from the UK and 2,337 adults from Australia for whom only two-dimensional facial information from portrait photos was available.

When researchers focused on a handful of SNPs detected in a facial malformation condition known as non-syndromic cleft lip with or without cleft palate, meanwhile, they found that these variants also seemed to contribute to the natural spectrum of facial variation.

The VisiGen team noted that more work is needed to home in on functional variants and/or allele-specific expression patterns for the candidate genes identified.

But based on their findings so far, those involved in the study speculated that it should be possible to hunt down additional variants, including some with smaller effects, through studies that involve even larger sample sets and more detailed facial measurements.

"Future GWAS on the facial phenotype should … employ increased sample sizes as this has helped to identify more genes for many other complex human phenotypes such as height and various human diseases," the team concluded. "Combined with the emerging advances in 3D imaging techniques, this offers the potential to advance our understanding of the complex molecular interactions governing both normal and pathological variations in facial shape."