Brain Tumour Research Centre, Institute of Clinical Neurosciences, University of Bristol, Bristol, UK.
MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, UK.
Sci Rep. 2023 Apr 21;13(1):6590. doi: 10.1038/s41598-023-33621-1.
Genetic evidence suggests glioma risk is altered by leukocyte telomere length, allergic disease (asthma, hay fever or eczema), alcohol consumption, childhood obesity, low-density lipoprotein cholesterol (LDLc) and triglyceride levels. DNA methylation (DNAm) variation influences many of these glioma-related traits and is an established feature of glioma. Yet the causal relationship between DNAm variation with both glioma incidence and glioma risk factors is unknown. We applied a two-step Mendelian randomization (MR) approach and several sensitivity analyses (including colocalization and Steiger filtering) to assess the association of DNAm with glioma risk factors and glioma incidence. We used data from a recently published catalogue of germline genetic variants robustly associated with DNAm variation in blood (32,851 participants) and data from a genome-wide association study of glioma risk (12,488 cases and 18,169 controls, sub-divided into 6191 glioblastoma cases and 6305 non-glioblastoma cases). MR evidence indicated that DNAm at 3 CpG sites (cg01561092, cg05926943, cg01584448) in one genomic region (HEATR3) had a putative association with glioma and glioblastoma risk (False discovery rate [FDR] < 0.05). Steiger filtering provided evidence against reverse causation. Colocalization presented evidence against genetic confounding and suggested that differential DNAm at the 3 CpG sites and glioma were driven by the same genetic variant. MR provided little evidence to suggest that DNAm acts as a mediator on the causal pathway between risk factors previously examined and glioma onset. To our knowledge, this is the first study to use MR to appraise the causal link of DNAm with glioma risk factors and glioma onset. Subsequent analyses are required to improve the robustness of our results and rule out horizontal pleiotropy.
遗传证据表明，白细胞端粒长度、过敏性疾病（哮喘、花粉热或湿疹）、饮酒、儿童肥胖、低密度脂蛋白胆固醇（LDLc）和甘油三酯水平会改变胶质瘤风险。DNA 甲基化（DNAm）变异会影响许多与胶质瘤相关的特征，并且是胶质瘤的一个既定特征。然而，DNAm 变异与胶质瘤发病率和胶质瘤风险因素之间的因果关系尚不清楚。我们应用了两步孟德尔随机化（MR）方法和几种敏感性分析（包括共定位和 Steiger 过滤）来评估 DNAm 与胶质瘤风险因素和胶质瘤发病率的关联。我们使用了最近发表的血液中与 DNAm 变异密切相关的种系遗传变异目录中的数据（32851 名参与者）和胶质瘤风险的全基因组关联研究中的数据（12488 例病例和 18169 名对照，分为 6191 例胶质母细胞瘤病例和 6305 例非胶质母细胞瘤病例）。MR 证据表明，一个基因组区域（HEATR3）中的 3 个 CpG 位点（cg01561092、cg05926943、cg01584448）的 DNAm 与胶质瘤和胶质母细胞瘤风险存在潜在关联（错误发现率 [FDR]<0.05）。Steiger 过滤提供了反向因果关系的证据。共定位提供了遗传混杂的证据，并表明 3 个 CpG 位点的差异 DNAm 和胶质瘤是由相同的遗传变异驱动的。MR 几乎没有证据表明 DNAm 在先前研究的风险因素与胶质瘤发病之间的因果途径中起中介作用。据我们所知，这是第一项使用 MR 评估 DNAm 与胶质瘤风险因素和胶质瘤发病之间因果关系的研究。需要进一步的分析来提高我们结果的稳健性，并排除水平多效性。
