Distinct DNA methylation profiles in subtypes of orofacial cleft

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-017-0362-2) contains supplementary material, which is available to authorized users.

LINE‐1 methylation in cleft lip tissues: Influence of infant MTHFR c.677C>T genotype

“…Studies investigating the role of epigenetic variation in the etiology of non‐syndromic orofacial clefts have recently begun to emerge in humans (Alvizi et al, ; Khan et al, ; Sharp et al, ). There are, however, no reports of the effect of the MTHFR c.677C>T variant on LINE‐1 methylation and nsCL/P etiology.…”

“…Studies investigating the role of epigenetic variation in the etiology of non-syndromic orofacial clefts have recently begun to emerge in humans (Alvizi et al, 2017;Khan et al, 2018;Sharp et al, 2017).…”

Gene-methylation interactions: Discovering region-wise DNA methylation levels that modify SNP-associated disease risk

“…It might be that this interaction is not specific to cleft lip since the methylation data we have is measured in cord blood, not in the tissue of interest. Nevertheless, the overall correlation between DNA methylation levels in blood and the lip/palate tissues were found to be high 68 .…”

Whole‐genome sequencing in a pair of monozygotic twins with discordant cleft lip and palate subtypes

“…Altered DNA methylation at specific genomic locations may affect both nonfamilial and familial NSCLP and could serve as a “second‐hit” in terms of penetrance (Alvizi et al., ). A previous study identified differential methylation patterns in several genomic regions in blood and lip samples from nonsyndromic children with CL only, CLP, and CP only (Sharp et al., ). It is interesting that although each subtype had a distinct DNA methylation profile, those of CL only and CLP cases were more similar to each other than to the DNA methylation profile of CP only.…”