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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


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.




Sarah Lewis is a Senior Lecturer in Genetic Epidemiology at the University of Bristol where she has worked since January 2004. Prior to this S.Lewis obtained a BSc in Genetics at the University of Sheffield, UK in 1995 and then went on to complete a PhD in Genetic Epidemiology at the University of Manchester, UK in 1999. She then had a series of short postdoctoral positions including a post at the International Agency for Research on Cancer. She joined the University of Bristol as a lecturer in Genetic Epidemiology and was promoted to Senior Lecturer in 2009.  Her research interests are in using Mendelian Randomization to understand risk factors for cancer and to identify modifiable factors which influence in utero development. S.Lewis became involved in cleft research in 2014, when she joined the Cleft team as head of the genetics strand on the Cleft Collective cohort studies.  She is also joint work package lead in a large Cancer Research UK programme grant and also a co-investigator on a large NIHR Biomedical research centre award. She has over 90 peer reviewed publications.