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Six NSCL/P loci show associations with normal-range craniofacial variation

Indencleef, Karlijne, Roosenboom, Jasmien, Hoskens, Hanne, White, Julie D., Shriver, Mark D., Richmond, Stephen ORCID:, Peeters, Hilde, Feingold, Eleanor, Marazita, Mary L., Shaffer, John R., Weinberg, Seth M., Hens, Greet and Claes, Peter 2018. Six NSCL/P loci show associations with normal-range craniofacial variation. Frontiers in Genetics 9 , 502. 10.3389/fgene.2018.00502

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Dentistry
Additional Information: This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY)
Publisher: Frontiers
ISSN: 1664-8021
Date of First Compliant Deposit: 29 October 2018
Date of Acceptance: 5 October 2018
Last Modified: 06 May 2023 03:51

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