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

ABSTRACT: 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.

SUBMITTER: Howe LJ

PROVIDER: S-EPMC6462847 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Howe Laurence J LJ Richardson Tom G TG Arathimos Ryan R Alvizi Lucas L Passos-Bueno Maria R MR Stanier Philip P Nohr Ellen E Ludwig Kerstin U KU Mangold Elisabeth E Knapp Michael M Stergiakouli Evie E Pourcain Beate St BS Smith George Davey GD Sandy Jonathan J Relton Caroline L CL Lewis Sarah J SJ Hemani Gibran G Sharp Gemma C GC

Epigenomics 20190114 2

<h4>Aim</h4>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.<h4>Materials & methods</h4>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.<h4>Results & conclusion</h4>Evidence was fou ...[more]

PMID: 30638414

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Project description:The etiology and pathogenesis of non-syndromic cleft lip and palate (NSCL/P) are largely unknown. Long non-coding RNAs (lncRNA) are thought to play important roles in NSCL/P, but reports on the underlying processes are currently unavailable. Our study focused on children diagnosed with NSCL/P alone. Based on the morphology, patients were categorized as either cleft lip with or without cleft palate (CL/P) or cleft palate-only (CPO). When patients received surgery for NSCL/P, tissue excised from the trimmed wound edge was reserved to serve as experimental samples; adjacent normal tissue was used as a positive control. Target lncRNAs in the collected tissues were identified using microarray and quantitative reverse transcription PCR (RT-qPCR). Immunohistochemical (IHC) staining and RT-qPCR were used to verify the target mRNAs. Pathway, gene ontology (GO) enrichment, and TargetScan prediction were employed to construct endogenous RNA networks (ceRNA networks) and explore their potential functions. RNA-Seq analysis revealed 24 upregulated and 43 downregulated lncRNAs in the CL/P and CPO groups compared with those in the control group; of these, MALAT1and NEAT1 were screened and validated using RT-qPCR. Common NSCL/P risk factors positively correlated with MALAT1 and NEAT1 expression (ORMALAT1 = 28.111, 95% CI: 4.054-194.923; ORNEAT1 = 30.556, 95% CI: 4.422-211.142; P < 0.05). Bioinformatics predicted four ceRNA networks: MALAT1-hsa-miR-1224-3p-SP1, MALAT1-hsa-miR-6734-5p/hsa-miR-1224-3p-WNT10A, NEAT1-hsa-miR-140-3p.1-CXCR4, and NEAT1-hsa-miR-3129-5p/hsa-miR-199a-3p/hsa-miR-199b-3p-ZEB1. GO enrichment focused on the potential functions of ceRNA networks, including biosynthesis of organic cyclic compounds, formation of membrane-enclosed and organelle lumens, and Wnt-protein binding. The results of RT-qPCR were consistent with those of IHC staining with regard to expression of related mRNAs. MALAT1 and NEAT1, which are upregulated in NSCL/P, are associated with the severity of NSCL/P. This study provides a new insight into NSCL/P pathogenesis and suggests that MALAT1 and NEAT1 act as potential therapeutic targets and prognostic biomarkers for NSCL/P.

Dataset Information

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

Publications

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

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