Abstract
The human face represents a combined set of highly heritable phenotypes, but knowledge on its genetic architecture remains limited, despite the relevance for various fields. A series of genome-wide association studies on 78 facial shape phenotypes quantified from 3-dimensional facial images of 10,115 Europeans identified 24 genetic loci reaching study-wide suggestive association (p < 5 × 10-8), among which 17 were previously unreported. A follow-up multi-ethnic study in additional 7917 individuals confirmed 10 loci including six unreported ones (padjusted < 2.1 × 10-3). A global map of derived polygenic face scores assembled facial features in major continental groups consistent with anthropological knowledge. Analyses of epigenomic datasets from cranial neural crest cells revealed abundant cis-regulatory activities at the face-associated genetic loci. Luciferase reporter assays in neural crest progenitor cells highlighted enhancer activities of several face-associated DNA variants. These results substantially advance our understanding of the genetic basis underlying human facial variation and provide candidates for future in-vivo functional studies.
Highlights
The human face represents a multi-dimensional set of correlated, mostly symmetric, complex phenotypes with high heritability
We investigated the potential links between facial phenotypes and 60 SNPs in 38 loci previously implicated in non-syndromic cleft lip and palate (NSCL/P) phenotype, which is linked with normal variation of facial morphology as suggested previously
We identified 24 genetic loci showing study-wide suggestive association with normal-range facial shape phenotypes in Europeans, including 17 novel ones, of which 10 were successfully replicated in additional multi-ethnic population cohorts including 6 novel loci
Summary
The human face represents a multi-dimensional set of correlated, mostly symmetric, complex phenotypes with high heritability. A most recent study (Claes et al, 2018) suggested that variants at genetic loci implicated in human facial shape are involved in the epigenetic regulation of human neural crest cells, suggesting that at least some of the functional variants may reside within regulatory elements such as enhancers This is in line with evidence for other appearance phenotypes such as human pigmentation traits, where experimental studies have proven enhancer effects of pigmentationassociated DNA variants (Visser et al, 2012; Visser et al, 2014, 2015), experimental evidence for understanding the functional basis of DNA variants for which facial phenotype associations have been previously established is missing as of yet. Led by the International Visible Trait Genetics (VisiGen) Consortium and together with its study partners, the current study represents a collaborative effort to identify novel genetic variants involved in human facial variation in the largest set of multi-ethnic samples available far It demonstrates the functional consequences of identified face-associated DNA variants based on in-silico work and in-vitro experimental evidence
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