Distinct DNA methylation profiles in subtypes of orofacial cleft

Gemma C Sharp,George Davey Smith,Jonathan Sandy,Sarah J Lewis,Karen Ho,Amy Davies,Caroline L Relton,Kerry Humphries,Wendy Mcardle,Evie Stergiakouli

doi:10.1186/s13148-017-0362-2

Gemma C Sharp, George Davey Smith + Show 8 more

Open Access

https://doi.org/10.1186/s13148-017-0362-2

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Abstract

BackgroundEpigenetic data could help identify risk factors for orofacial clefts, either by revealing a causal role for epigenetic mechanisms in causing clefts or by capturing information about causal genetic or environmental factors. Given the evidence that different subtypes of orofacial cleft have distinct aetiologies, we explored whether children with different cleft subtypes showed distinct epigenetic profiles.MethodsIn whole-blood samples from 150 children from the Cleft Collective cohort study, we measured DNA methylation at over 450,000 sites on the genome. We then carried out epigenome-wide association studies (EWAS) to test the association between methylation at each site and cleft subtype (cleft lip only (CLO) n = 50; cleft palate only (CPO) n = 50; cleft lip and palate (CLP) n = 50). We also compared methylation in the blood to methylation in the lip or palate tissue using genome-wide data from the same 150 children and conducted an EWAS of CLO compared to CLP in lip tissue.ResultsWe found four genomic regions in blood differentially methylated in CLO compared to CLP, 17 in CPO compared to CLP and 294 in CPO compared to CLO. Several regions mapped to genes that have previously been implicated in the development of orofacial clefts (for example, TBX1, COL11A2, HOXA2, PDGFRA), and over 250 associations were novel. Methylation in blood correlated with that in lip/palate at some regions. There were 14 regions differentially methylated in the lip tissue from children with CLO and CLP, with one region (near KIAA0415) showing up in both the blood and lip EWAS.ConclusionsOur finding of distinct methylation profiles in different orofacial cleft (OFC) subtypes represents a promising first step in exploring the potential role of epigenetic modifications in the aetiology of OFCs and/or as clinically useful biomarkers of OFC subtypes.

Highlights

Epigenetic data could help identify risk factors for orofacial clefts, either by revealing a causal role for epigenetic mechanisms in causing clefts or by capturing information about causal genetic or environmental factors
Methylated region analysis of blood Epigenome-wide association studies (EWAS) results When we interrogated differential methylation over larger regions of the genome, we found four Differentially methylated regions (DMRs) in cleft lip only (CLO) compared to cleft palate (CLP), 17 in cleft palate only (CPO) compared to CLP and 294 in CPO compared to CLO (Sidak-corrected P value
Eight mapped to regions that were differentially methylated in CPO compared to CLO, and two mapped to regions that were differentially methylated in CPO compared to CLP in our study

Summary

Introduction

Epigenetic data could help identify risk factors for orofacial clefts, either by revealing a causal role for epigenetic mechanisms in causing clefts or by capturing information about causal genetic or environmental factors. Given the evidence that different subtypes of orofacial cleft have distinct aetiologies, we explored whether children with different cleft subtypes showed distinct epigenetic profiles. Non-syndromic cases, which comprise around 70% of cases of cleft lip with or without cleft palate, have a complex aetiology involving both genetic and environmental factors [2]. Emotional and financial costs, they undergo surgery in the first year of life and many need additional surgical procedures later in life They may experience low self-esteem, psychosocial problems and poor educational attainment, and the condition can harm the emotional wellbeing of the whole family [2,3,4]

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