A genome-wide association scan implicates DCHS2, RUNX2, GLI3, PAX1 and EDAR in human facial variation

Abstract

We report a genome-wide association scan for facial features in ∼6,000 Latin Americans. We evaluated 14 traits on an ordinal scale and found significant association (P values<5 × 10−8) at single-nucleotide polymorphisms (SNPs) in four genomic regions for three nose-related traits: columella inclination (4q31), nose bridge breadth (6p21) and nose wing breadth (7p13 and 20p11). In a subsample of ∼3,000 individuals we obtained quantitative traits related to 9 of the ordinal phenotypes and, also, a measure of nasion position. Quantitative analyses confirmed the ordinal-based associations, identified SNPs in 2q12 associated to chin protrusion, and replicated the reported association of nasion position with SNPs in PAX3. Strongest association in 2q12, 4q31, 6p21 and 7p13 was observed for SNPs in the EDAR, DCHS2, RUNX2 and GLI3 genes, respectively. Associated SNPs in 20p11 extend to PAX1. Consistent with the effect of EDAR on chin protrusion, we documented alterations of mandible length in mice with modified Edar funtion.

The Genetic Diversity of the Americas

“…There is a strong and significant correlation between the average estimates of Native American, European, and African genetic ancestry and the frequency of the equivalent perceived ancestry categories reported in population survey data for these territories ( Figure 5): for native ancestry, R = 0.66 (p = 7  10 4 ); for European ancestry, R = 0.92 (p = 2  10 9 ); and for African ancestry, R = 0.96 (p = 4  10 12 ). The correlation between perceived and genetically estimated ancestry is consistent with the fact that physical appearance is partly genetic (1,2,4,82) and likely an important determinant of perception of ancestry. The review of genetic data underpins the interpretation of ancestry perception data in that, globally, variation in Native, European and African ancestry across the Western Hemisphere bears the imprint of the region's colonial history.…”

Latin Americans show wide-spread Converso ancestry and the imprint of local Native ancestry on physical appearance

“…This is consistent with physical anthropology analyses indicating that the Mapuche have a flatter, wider nose than Central Andean populations 21 . In a recent genome-wide association scan for facial features in the CANDELA sample most loci identified impacted on nose shape 22 and index SNPs at those loci show significantly differentiated allele frequencies between Central Andeans and the Mapuche, consistent with the phenotypic effects of the regional ancestry analyses (Supplementary Table 5). The nasal cavity is an important regulator of inhaled air temperature and humidity, and evolutionary studies suggest that nose shape has been influenced by adaptation to cold/dry versus hot/humid environments 23 .…”

“…PLINK v1.9 26,27 was used to exclude SNPs and individuals with more than 5% missing data, markers with minor allele frequency <1%, related individuals, and those who failed the Xchromosome sex concordance check. The same QC filters had been applied to the CANDELA dataset 22,24,25 . Individuals born outside the country were relocated when coming from one of the five countries included in this study or otherwise removed.…”

“…A structured interview recorded the birthplace of volunteers and their ancestors (up to grandparents), as well as information on the language(s) spoken by them. We have previously reported genome-wide association studies based on Illumina OmniExpress chip data obtained in these individuals 22,24,25 .…”

“…These traits have been described in detail previously 4,22,24,25 and brief definitions are provided in Supplementary text 5. To evaluate the phenotypic effect of sub-continental ancestry components defined by SOURCEFIND we used linear regression.…”