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Abstract
Objectives: Orofacial clefting is one of the most prevalent craniofacial malformations. Previous research has demonstrated that unaffected relatives of patients with non-syndromic cleft lip with/without cleft palate (NSCL/P) show distinctive facial features, which can be an expression of underlying NSCL/P susceptibility genes. These results support the hypothesis that genes involved in the occurrence of a cleft also play a role in normal craniofacial development. In this study, we investigated the influence of genetic variants associated with NSCL/P on normal-range variation in facial shape.Methods: A literature review of genome wide association studies (GWAS) investigating the genetic etiology of NSCL/P was performed, resulting in a list of 75 single nucleotide polymorphisms (SNPs) located in 38 genetic loci. Genotype data were available for 65 of these selected SNPs in three datasets with a combined sample size of 7,418 participants of European ancestry, whose 3D facial images were also available. The effect of each SNP was tested using a multivariate canonical correlation analysis (CCA) against 63 hierarchically-constructed facial segments in each of the three datasets and meta-analyzed. This allowed for the investigation of associations between SNPs known to be involved in NSCL/P and normal-range facial shape variations in a global-to-local perspective, without preselecting specific facial shape features or characteristics.Results: Six NSCL/P SNPs showed significant associations with variation in normal-range facial morphology. rs6740960 showed significant effects in the chin area (p = 3.71 × 10−28). This SNP lies in a non-coding area. Another SNP, rs227731 near the NOG gene, showed a significant effect in the philtrum area (p = 1.96 × 10−16). Three SNPs showed significant effects on the shape of the nose. rs742071 (p = 8.71 × 10−14), rs34246903 (p = 6.87 × 10−12), and rs10512248 (p = 8.4 × 10−9). Respectively, these SNPs are annotated to PAX7, MSX1, and PTCH1. Finally, rs7590268, an intron variant of THADA, showed an effect in the shape of the supraorbital ridge (p = 3.84 × 10−7).Conclusions: This study provides additional evidence NSCL/P-associated genetic variants influence normal-range craniofacial morphology, with significant effects observed for the chin, the nose, the supraorbital ridges and the philtrum area.
Highlights
Human facial features are highly variable and mostly genetically determined
We investigated the involvement of NSCL/Passociated genetic variants in normal-range facial variation
We identified six genetic loci involved in the etiology of NSCL/P that had significant effects on craniofacial morphology, namely rs742071 in 1p36, rs6740960, and rs7590268 in 2p21, rs34246903 in 4p16.2, rs10512248 in 9q22.32 and rs227731 in 17q22 (Table 2)
Summary
Human facial features are highly variable and mostly genetically determined. craniofacial morphology is of interest to many scientists, its genetic architecture remains poorly understood (Roosenboom et al, 2016). Many loci found in genome wide association studies on human facial morphology were involved in syndromes affecting the face (Adhikari et al, 2016; Shaffer et al, 2016; Claes et al, 2018). Investigating genes involved in craniofacial disorders constitutes a suitable approach to help unravel the genetic architecture of facial morphology. With an incidence of 1.7 in 1,000 livebirths, non-syndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common craniofacial anomalies, causing significant functional and psychological burden to the patient (Mossey et al, 2009).
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