Exploring the aetiology and phenotypic consequences of non-syndromic cleft lip/palate using polygenic risk scoring and Mendelian randomization

  • Laurence Howe

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)


Non-syndromic cleft lip/palate (nsCL/P) is a congenital birth defect characterised by cleft(s) of the upper lip with or without a cleft of the palate. The aetiology of nsCL/P is complex with both genetic and environmental risk factors. In this thesis, I applied Mendelian randomization (MR) and polygenic risk scoring (PRS) to explore the aetiology of nsCL/P and possible consequences of the phenotype.
In Chapter 3, strong evidence was found for nsCL/P having a highly polygenic architecture with a substantial SNP heritability suggesting that PRS are likely to be effective genetic proxies for nsCL/P.
In Chapter 4, three putative loci were identified where the effect of nsCL/P genetic risk variants on disease liability may be mediated by DNA methylation, although conclusions are limited by possible tissue specific effects.
In Chapter 5, nsCL/P genetic risk variants were shown to have a consistent additive effect on philtrum width in the general population suggesting that liability to nsCL/P causes decreased philtrum width which supports a polygenic threshold model of inheritance for nsCL/P.
In Chapter 6, nsCL/P genetic variants were shown to not be strongly associated with adverse developmental outcomes that are common in nsCL/P cases. These findings suggest that the adverse outcomes tested are unlikely to be related to underlying liability to nsCL/P.
In Chapter 7, nsCL/P PRS were found to predict increased risk of oral cavity/oropharyngeal cancer (OC/OPC). Follow-up analyses suggested the relationship was non-causal and that nsCL/P and OC/OPC likely share risk factors, possibly environmental risk factors or biological processes.
Date of Award25 Sept 2018
Original languageEnglish
Awarding Institution
  • The University of Bristol
SupervisorGeorge Davey Smith (Supervisor), Sarah J Lewis (Supervisor) & M U B St Pourcain (Supervisor)

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