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

Laurence Howe, Thomas Richardson, Ryan Arathimos, Lucas Alvizi, Maria Rita Passos-Bueno, Philip Stanier, Ellen A Nohr, Kerstin Ludwig, Elisabeth Mangold, Michael Knapp, Evie Stergiakouli, Beate St Pourcain, George Davey Smith, Jonathan Sandy, Caroline Relton, Sarah Lewis, Gibran Hemani, Gemma Sharp*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

25 Citations (Scopus)
240 Downloads (Pure)


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.

Original languageEnglish
Pages (from-to)133-145
Number of pages13
Issue number2
Early online date14 Jan 2019
Publication statusPublished - 1 Feb 2019


  • epigenetics
  • mendelian randomization
  • nsCL/P


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