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Evidence for DNA methylation mediating genetic liability to non-syndromic cleft lip/palate.

Epigenomics

Authors: Laurence J Howe, Tom G Richardson, Ryan Arathimos, Lucas Alvizi, Maria R Passos-Bueno, Philip Stanier, Ellen Nohr, Kerstin U Ludwig, Elisabeth Mangold, Michael Knapp, Evie Stergiakouli, Beate St Pourcain, George Davey Smith, Jonathan Sandy, Caroline L Relton, Sarah J Lewis, Gibran Hemani, Gemma C Sharp

AIM: To determine if nonsyndromic cleft lip with or without cleft palate (nsCL/P) genetic risk variants influence liability to nsCL/P through gene regulation pathways, such as those involving DNA methylation.

MATERIALS & METHODS: nsCL/P genetic summary data and methylation data from four studies were used in conjunction with Mendelian randomization and joint likelihood mapping to investigate potential mediation of nsCL/P genetic variants.

RESULTS & CONCLUSION: Evidence was found at VAX1 (10q25.3), LOC146880 (17q23.3) and NTN1 (17p13.1), that liability to nsCL/P and variation in DNA methylation might be driven by the same genetic variant, suggesting that genetic variation at these loci may increase liability to nsCL/P by influencing DNA methylation. Follow-up analyses using different tissues and gene expression data provided further insight into possible biological mechanisms.

PMID: 30638414

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