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

IF 1.6 4区医学 Q4 DEVELOPMENTAL BIOLOGY Birth Defects Research Pub Date : 2024-10-15 DOI:10.1002/bdr2.2403

Xinze Xu, Xiaofeng Li, Minxuan Han, Changyue Xing, Guirong Zhu, Xing Cui, Lin Wang, Shu Lou, Yongchu Pan

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Abstract

Objective

N6-methyladenosine (m⁶A) 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 m⁶A 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 m⁶A 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.

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METTL16 基因变异影响非综合征性口腔颚裂的风险

目的 N6-甲基腺苷（m6A）是真核生物中最常见的 RNA 修饰，与许多细胞过程和疾病有关。在此，我们的目的是探讨 m6A 修饰基因的遗传变异是否与非综合征口面裂（NSOCs）的风险有关。方法采用传递不平衡检验（TDT）计算 944 例父母三人中 m6A 修饰基因中单核苷酸多态性（SNPs）与非综合征口面裂（NSOCs）风险之间的关联。通过HaploReg、RegulomeDB和组蛋白富集数据预测了SNP的功能。利用基因型-组织表达（GTEx）和 eQTLGen 对表达定量性状位点（eQTL）进行了分析，并根据小鼠颅面部组织和斑马鱼胚胎中的基因表达数据，通过相关性和富集分析评估了该基因在 NSOCs 发病中的作用。结果我们发现，METTL16 中的 rs8078195 (A > C) 与 NSOC 风险的增加有提示性关联（OR = 1.32，p = 1.80E-03）。围绕 rs8078195 的区域受到脱氧核糖核酸酶超敏反应的影响，富含多种组蛋白修饰。此外，它与皮肤组织和人体外周血中的 METTL16 具有显著的 eQTL 效应，在 NSOCs 的发生发展中起着重要作用。生物信息学分析表明，METTL16 可能通过调控细胞周期过程促进了 NSOCs 的发展。结论 METTL16 中的 Rs8078195 与 NSOCs 的发生有关。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Birth Defects Research Medicine-Embryology

CiteScore

3.60

自引率

9.50%

发文量

153

期刊介绍： The journal Birth Defects Research publishes original research and reviews in areas related to the etiology of adverse developmental and reproductive outcome. In particular the journal is devoted to the publication of original scientific research that contributes to the understanding of the biology of embryonic development and the prenatal causative factors and mechanisms leading to adverse pregnancy outcomes, namely structural and functional birth defects, pregnancy loss, postnatal functional defects in the human population, and to the identification of prenatal factors and biological mechanisms that reduce these risks. Adverse reproductive and developmental outcomes may have genetic, environmental, nutritional or epigenetic causes. Accordingly, the journal Birth Defects Research takes an integrated, multidisciplinary approach in its organization and publication strategy. The journal Birth Defects Research contains separate sections for clinical and molecular teratology, developmental and reproductive toxicology, and reviews in developmental biology to acknowledge and accommodate the integrative nature of research in this field. Each section has a dedicated editor who is a leader in his/her field and who has full editorial authority in his/her area.