Genetic Variants in METTL16 Affect the Risk of Non-Syndromic Orofacial Clefts

Objective: N6-methyladenosine (m(6)A) is the most prevalent modification of RNA in eukaryotes which is associated with many cellular processes and diseases. Here, our objective is to explore whether genetic variants in m(6)A modification genes are associated with the risk of non-syndrome orofacial clefts (NSOCs). Methods: The transmission disequilibrium test (TDT) was performed to calculate the association between single nucleotide polymorphisms (SNPs) in m(6)A modification genes and NSOCs risk in 944 case-parent trios. The function of SNP was predicted by HaploReg, RegulomeDB and histone enrichment data. The expression quantitative trait locus (eQTL) analysis was examined using Genotype-Tissue Expression (GTEx) and eQTLGen. The role of gene in the development of NSOCs was assessed with correlation and enrichment analysis based on gene expression data in mice craniofacial tissue and zebrafish embryo. Results: We identified that rs8078195 (A > C) in METTL16 was suggestively associated with the increased risk of NSOCs (OR = 1.32, p = 1.80E - 03). The region surrounding rs8078195 was subjected to deoxyribonuclease hypersensitivity and enriched with multiple histone modifications. In addition, it had a significant eQTL effect with METTL16 in skin tissue and human peripheral blood, which played an important role in NSOCs development. Bioinformatic analysis indicated that METTL16 contributed to the development of NSOCs probably by regulating cell cycle process. Conclusions: Rs8078195 in METTL16 was associated with the occurrence of NSOCs.