Integrative Analysis of Genome-Wide Association Studies and DNA Methylation Profile Identified Genetic Control Genes of DNA Methylation for Kashin-Beck Disease
Integrative Analysis of Genome-Wide Association Studies and DNA Methylation Profile Identified Genetic Control Genes of DNA Methylation for Kashin-Beck Disease
复制标题
全基因组关联研究和 DNA 甲基化谱的综合分析确定了大骨节病 DNA 甲基化的遗传控制基因
DOI：
10.1177/1947603519858748
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发表时间：
2021-12-01
期刊：
影响因子：
2.8
通讯作者：
Zhang, Feng
中科院分区：
文献类型：
--
作者：
Li, Ping;Wu, Cuiyan;Zhang, Feng
目的DNA的表观遗传修饰被认为是理解复杂表型的分子基础的关键因素。本研究旨在通过整合全基因组关联研究（GWAS）、甲基化数量性状基因座（meQTL）和DNA甲基化谱数据，揭示大骨节病（KBD）的表观遗传修饰。设计采用Illumina Infinium HumanMethylation 450 BeadChip对5例大骨节病患者和5例健康对照者的膝关节软骨进行DNA甲基化分析。使用4名大骨节病患者和3名健康对照的独立样本，以及先前用于大骨节病GWAS研究的2743名汉族个体和用于meQTLs注释数据集的697名正常受试者的研究，对鉴定的不同甲基化基因进行质谱验证。将大骨节病GWAS单核苷酸多态性（SNPs）和正常meQTLs SNPs与大骨节病关节软骨DNA甲基化图谱整合，以确定大骨节病DNA甲基化的遗传控制基因（GC）。进行定量聚合酶链反应（qPCR）以验证几个鉴定的候选基因的mRNA表达。结果共检测到162个CpG位点、253个SNPs和123个GC基因。富集分析共检测到642个标记GO术语和19条KEGG通路（P < 0.05）。对6个潜在关键GC基因（ERG、MN1、MITF、WISP1、TRIO和NOSTRIN）进行qPCR实验。结论GC基因甲基化可能是导致大骨节病软骨破坏的原因之一，为进一步了解大骨节病的表观遗传学改变提供了依据。
Objective Epigenetic modifications of DNA are regarded as a crucial factor for understanding the molecular basis of complex phenotypes. This study aims to uncover insight into the epigenetic modifications for Kashin-Beck disease (KBD) by integrating genome-wide association studies (GWAS), methylation quantitative trait loci (meQTLs), and DNA methylation profiles data. Design The knee articular cartilages of 5 KBD patients and 5 healthy controls were collected for DNA methylation profiling, using Illumina Infinium HumanMethylation450 BeadChip. Mass spectrograph validation of identified differently methylated genes was conducted using independent samples of 4 KBD patients and 3 healthy controls, together with a previous sample of 2743 Han Chinese individuals of GWAS study for KBD and a study of 697 normal subjects for meQTLs annotation datasets. KBD GWAS single nucleotide polymorphisms (SNPs) and normal meQTLs SNPs were integrated with DNA methylation profiles of KBD articular cartilage to identify genetic control (GC) genes of DNA methylation for KBD. Quantitative polymerase chain reaction (qPCR) was performed to validate the mRNA expression of several identified candidate genes. Results A total of 162 CpG sites, 253 SNPs, and 123 GC genes for KBD were identified. Enrichment analysis detected 642 marked GO terms and 19 KEGG pathways (P < 0.05). Six potential key GC genes were conducted for qPCR experiment (ERG, MN1, MITF, WISP1, TRIO, and NOSTRIN). Conclusions The results suggest that GC genes of DNA methylation may lead to the erosion of cartilage in KBD, which may help us in understanding the epigenetic alteration of KBD.