Sarah Lewis

Title of presentation: Using genetics to identify causal risk factors and biological mechanisms for cleft lip and palate

Presenter: Sarah Lewis

Affiliation: Population Health Sciences, University of Bristol, UK

Abstract

Around 70% of clefts display a complex mode of inheritance in which risk is determined by both genetic and environmental risk factors. More than 40 common genetic variants have been identified via genome wide association studies (GWAS) which contribute to this risk. In addition, observational studies suggest that maternal lifestyle factors such as smoking, drinking alcohol, BMI and diet may be risk factors for cleft lip and palate, however the evidence for these risk factors remains inconclusive. The reason for this is because of inaccurate and biased reporting of exposures, and confounding by other lifestyle factors.

At the University of Bristol, UK we have pioneered a method for using common genetic variants to determine whether modifiable risk factors cause disease. This method is called Mendelian randomization and uses genetic variants which are not susceptible to confounding as proxies for the exposure of interest to obtain an unconfounded estimate of the relationship between an exposure and an outcome. I will demonstrate examples of where this method has been used to show that maternal smoking has a casual influence on birth weight and outline how we will use this method to identify cause risk factors for cleft.

I will discuss how further GWAS, including GWAS of the mothers of children with a cleft, may be used to identify further modifiable risk factors for cleft and to elucidate biological pathways to specific cleft subtypes. I will present results which show that common genetic variants for cleft lip and/or palate are associated with philtrum width among the general population and discuss how such analyses can shed light on the biological pathways involved in cleft formation.