Role of DNA methylation in the relationship between glioma risk factors and glioma incidence: a two-step Mendelian randomization study.
Role of DNA methylation in the relationship between glioma risk factors and glioma incidence: a two-step Mendelian randomization study.
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DOI：
10.1038/s41598-023-33621-1
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发表时间：
2023-04-21
影响因子：
4.6
通讯作者：
Kurian, Kathreena M. M.
中科院分区：
文献类型：
--
作者：
Howell, Amy E. E.;Relton, Caroline;Martin, Richard M. M.;Zheng, Jie;Kurian, Kathreena M. M.
遗传学证据表明，胶质瘤的风险是由白细胞端粒长度，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）和甘油三酯水平改变。DNA甲基化（DNAm）变异影响许多这些胶质瘤相关性状，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危险因素之间的因果关系尚不清楚。我们应用两步孟德尔随机化（MR）方法和几个敏感性分析（包括共定位和Steiger滤波）来评估DNAm与胶质瘤危险因素和胶质瘤发病率的相关性。我们使用了最近发表的与血液中DNAm变异密切相关的生殖系遗传变异目录（32，851名参与者）的数据和神经胶质瘤风险全基因组关联研究的数据（12，488例病例和18，169例对照，细分为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，在一个基因组区域（HEATR 3）中的3个CpG位点（cg01561092、cg05926943、cg01584448）处的DNAm与胶质瘤和胶质母细胞瘤风险具有推定的关联（假发现率[FDR] < 0.05）。Steiger过滤提供了反对反向因果关系的证据。共定位提供了反对遗传混杂的证据，并表明在3个CpG位点的差异DNAm和胶质瘤由相同的遗传变异驱动。MR几乎没有提供证据表明DNAm在先前检查的风险因素和胶质瘤发作之间的因果通路上起中介作用。据我们所知，这是第一个研究使用MR评估的因果关系与神经胶质瘤危险因素和神经胶质瘤发病的DNAm。随后的分析需要提高我们的结果的鲁棒性，并排除水平多效性。
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.
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影响因子：
3.7
作者：
Howell AE;Zheng J;Haycock PC;McAleenan A;Relton C;Martin RM;Kurian KM
通讯作者：
Kurian KM
影响因子：
4.6
作者：
Dong Y;Huang Y;Gutin B;Raed A;Dong Y;Zhu H
通讯作者：
Zhu H
影响因子：
30.8
作者：
Fortune MD;Guo H;Burren O;Schofield E;Walker NM;Ban M;Sawcer SJ;Bowes J;Worthington J;Barton A;Eyre S;Todd JA;Wallace C
通讯作者：
Wallace C
影响因子：
2.3
作者：
Little, Rebecca B.;Madden, Melissa H.;Thompson, Reid C.;Olson, Jeffrey J.;LaRocca, Renato V.;Pan, Edward;Browning, James E.;Egan, Kathleen M.;Nabors, L. Burton
通讯作者：
Nabors, L. Burton
影响因子：
4.6
作者：
He, Fan;Berg, Arthur;Liao, Duanping
通讯作者：
Liao, Duanping