Background: Craniofacial morphology has been reported to be highly heritable, but prior to this research, little was known as to which genetic variants influence normal lip phenotypes. Much of the previous genetic research involved assigning rare genetic mutations to craniofacial abnormalities, giving little insight as to what causes normal variation. More recent studies have attempted to assign genetic variants to facial genotypes using landmarking methods, however, these markers are sparse in the lip region. Considerable variation of lip morphology exists, which is not amenable to landmarking methods. The aim of this study was to investigate the biological basis of lip phenotypes. Objectives: • Develop a robust, reproducible classification system of lip phenotypes; • Measure the prevalence of lip phenotypes within a population sample of 4,747; • Assess for associations of lip phenotypes with other lip phenotypes; • Assess if there were any sex variations of lip phenotypes; •Assess the reproducibility of the classification system with other acquisition methods; •Perform a nome-wide association study (GWAS) of lip phenotypes; • Assess for associations of non-syndromic cleft lip/palate (NSCL/P) SNPs to lip phenotypes; • Perform a case-control study to assess the prevalence of lip phenotypes amongst unaffected biological parents of cleft and non-cleft children; • Assess the predictive capability of lip phenotypes as a precursor of cleft risk. Methods: Three-dimensional laser scanned facial images were obtained of 4,747 subjects recruited from the Avon Longitudinal Study of Parents and Children (ALSPAC). A total of 102 individuals were recruited from the University Dental Hospital, Cardiff to assess the reproducibility of the classification system with other acquisition methods. Genetic data was available for 3,687 ALSPAC subjects for the discovery phase of GWAS, and 3,215 digital photographs of Australian twins for the replication phase. Images of 597 3dMD case-parent trios and controls were obtained through FaceBase, to assess the prevalence of lip phenotypes amongst unaffected biological parents of cleft and non-cleft children. Results: Twenty-five reproducible lip phenotypes have been described. Most phenotypes occur in combinations, except mentolabial fold and chin dimple, which are distinct. Prevalence of features and sex dimorphism are also explained. A modification of the lip scale is required for facial shells with reduced surface resolution taken with 3dMD or digital photographs. A discovery GWAS of 3,687 ALSPAC subjects revealed two new GWAS significant hits: chin dimple and DOCK1 (P=2x10⁻⁸) and mentolabial fold and CDH4 (P=1x10⁻⁸). Both genes have been reported to play a role in tumour pathways (Du, C. et al, 2011, Laurin, M. et al, 2013), and CDH4 may have a role to play in muscle development (Nogueira, J.M. et al, 2015). In addition, 29 near-hit associations were found with 18 lip phenotypes (P < 10⁻⁷). Replication was attempted for 2 lip phenotypes (chin dimple and mentolabial fold). However, it was not possible to replicate these findings. Genotype analysis discovered associations with 14 out of 17 candidate NSCL/P SNPs with 21 out of 25 lip phenotypes. The main findings were the association of NOG and skeletal II pattern (P=1.58x10⁻⁶) and V-shaped Cupid's bow (P=2.48x10⁻³) with 8q24. A generated NSCL/P genetic allele score demonstrated association with V-shaped Cupid's bow (P=2x10⁻⁴), narrow philtrum (P=3x10⁻⁴), upturned commissures (P=0.03) and deep philtrum (P=0.045). The prevalence of 12 out of 23 lip phenotypes was found to be higher amongst case-parent trios compared with control parents. Case mothers had increased prevalence of convex upper lip contours, upper lip groove, absent lower lip groove, flat lower lip contour and angular lower lip tone with bumping. Case fathers had absent lower lip vermilion borders and double borders. Conclusions: A robust and reliable scale has been presented, which allows categorisation of lip phenotypes. Considerable variation exists within the ALSPAC population of 15 year olds, including some rare phenotypes and evidence of sex dimorphism. Lip phenotypes tend to appear in combinations with other lip phenotypes, whilst chin dimple and mentolabial fold are generally distinct. Discovery GWAS indicated genotype/phenotype associations with chin dimple and DOCK1* (P=2x10⁻⁸) and mentolabial fold and CDH4 (P=1x10⁻⁸). However, this was not replicated in an independent sample. NSCL/P SNPs and combined high-MNSCL/P genetic alleles affect lip phenotypes, and appear to induce a narrow philtrum, V-shaped Cupid's bow and a skeletal II pattern. Parents of cleft children had higher prevalence of some lip phenotypes compared with control parents. As such, this study proposes that certain lip phenotypes may be utilised as subphenotypic markers of cleft risk.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:704939 |
| Date | January 2016 |
| Creators | Wilson-Nagrani, Caryl |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/98591/ |
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