Six NSCL/P Loci Show Associations With Normal-Range Craniofacial Variation

Abstract

<b>Objectives:</b> 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. <b>Methods:</b> 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. <b>Results:</b> Six NSCL/P SNPs showed significant associations with variation in normal-range facial morphology. rs6740960 showed significant effects in the chin area (<i>p</i> = 3.71 × 10^-28). This SNP lies in a non-coding area. Another SNP, rs227731 near the <i>NOG</i> gene, showed a significant effect in the philtrum area (<i>p</i> = 1.96 × 10^-16). Three SNPs showed significant effects on the shape of the nose. rs742071 (<i>p</i> = 8.71 × 10^-14), rs34246903 (<i>p</i> = 6.87 × 10^-12), and rs10512248 (<i>p</i> = 8.4 × 10^-9). Respectively, these SNPs are annotated to <i>PAX7, MSX1</i>, and <i>PTCH1</i>. Finally, rs7590268, an intron variant of <i>THADA</i>, showed an effect in the shape of the supraorbital ridge (<i>p</i> = 3.84 × 10^-7). <b>Conclusions:</b> 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.