Genome-wide association study of facial morphology reveals novel associations with FREM1 and PARK2

Abstract

Several studies have now shown evidence of association between common genetic variants and quantitative facial traits in humans. The reported associations generally involve simple univariate measures and likely represent only a small fraction of the genetic loci influencing facial morphology. In this study, we applied factor analysis to a set of 276 facial linear distances derived from 3D facial surface images of 2187 unrelated individuals of European ancestry. We retained 23 facial factors, which we then tested for genetic associations using a genome-wide panel of 10,677,593 single nucleotide polymorphisms (SNPs). In total, we identified genome-wide significant (p < 5 × 10−8) associations in three regions, including two that are novel: one involving measures of midface height at 6q26 within an intron of PARK2 (lead SNP rs9456748; p = 4.99 × 10−8) and another involving measures of central upper lip height at 9p22 within FREM1 (lead SNP rs72713618; p = 2.02 × 10−8). In both cases, the genetic association was stronger with the composite facial factor phenotype than with any of the individual linear distances that comprise those factors. While the biological role of PARK2 in the craniofacial complex is currently unclear, there is evidence from both mouse models and Mendelian syndromes that FREM1 may influence facial variation. These results highlight the potential value of data-driven multivariate phenotyping for genetic studies of human facial morphology.

Genome-wide Association study of facial morphology identifies novel genetic loci in Han Chinese

“…Interestingly, this study observed the same association between soft-tissue nasal width and PAX1 identified in Latin Americans (Adhikari et al, 2016). Lee et al identified two genetic variants of FREM1 and PARK2 associated with face shape in individuals of European ancestry (Lee et al, 2017). In 2018, two studies (Claes et al, 2018;Crouch et al, 2018) found a number of newly associated genetic loci by applying novel approaches to a European-derived cohort and replicated many loci in previous studies Paternoster et al, 2012;Adhikari et al, 2016;Shaffer et al, 2016).…”

Genome-wide mapping of global-to-local genetic effects on human facial shape

“…Additionally, in supplementary Note 2, Tables S3–S6 and Figures S4–S5, we first report statistical replication for 10 out of 16 SNPs from six previous facial GWAS based on 2D or 3D images 2–7 (Table S3). Second, we consulted GWAS central and Phenoscanner 29 and report additional evidence for nine SNPs in Table 1 (Table S4).…”

“…In mice, whole-genome QTL studies have identified numerous genetic regions associated with craniofacial traits 31–33 . In humans, both candidate gene 10,34,35 and GWAS 2–7 have implicated specific variants. While the highly complex nature of craniofacial morphogenesis suggests that many genes are likely to influence facial morphology, the number of associated loci uncovered so far using GWAS has been limited with few independent replications.…”

“…However, our knowledge of which genetic variants are responsible for human facial variation is still lacking 1 . Several genome-wide association studies (GWAS) have each identified a handful of loci associated with a small number of facial traits, few of which have been replicated 2–7 . While a GWAS benefits from being an unbiased approach to gene mapping, the phenotypic descriptions used in such studies are typically preselected and used to classify individuals in a “phenotype-first” way of thinking.…”

Hunting for genes that shape human faces: Initial successes and challenges for the future

“…To date, there have been nine GWAS focused on quantifiable aspects of human craniofacial morphology. [15][16][17][18][19][20][21][22][23] The main characteristics and results of these studies are summarized in Table 1.…”