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首页> 外文期刊>The journals of gerontology.Series A. Biological sciences and medical sciences >Weighted Gene Coregulation Network Analysis of Promoter DNA Methylation on All-Cause Mortality in Old-Aged Birth Cohorts Finds Modules of High-Risk Associated Biomarkers
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Weighted Gene Coregulation Network Analysis of Promoter DNA Methylation on All-Cause Mortality in Old-Aged Birth Cohorts Finds Modules of High-Risk Associated Biomarkers

机译：旧式出生队列中的促进剂DNA甲基甲基甲基化的加权基因计重量网络分析发现高危相关生物标志物的模块

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摘要

Overall or all-cause mortality is a key measure of health in a population. Multiple epigenome-wide association studies have been conducted on all-cause mortality with limited significant findings and low replication. To elucidate the coregulated DNA methylation patterns associated with all-cause mortality, we conducted a weighted DNA methylation coregulation network analysis on whole-blood samples of 1,425 older individuals from the Lothian Birth Cohorts of 1921 and 1936. Our network-based analysis defined coregulated DNA methylation patterns in gene promoters into clusters or modules whose correlation with all-cause mortality was assessed by survival analysis. We found two significant modules or gene clusters associated with all-cause mortality in LBC1921 based on their eigengenes; one negatively correlated (p = 8.14E-03, 698 genes) and one positively correlated (p = 4.26E-02, 1,431 genes) with the risk of death. The two modules were replicated in LBC1936 with the same directions of correlation (p = 6.35E-02 and p = 3.64E-02, respectively). Furthermore, the modules revealed 32 genes associated with all-cause mortality (FDR < 0.05) linked to various diseases, including cancer and diabetes. Additionally, we performed pathway analysis and found 22 pathways (FDR < 0.05), including a pathway for taste transduction, which has been shown to be associated with poor prognosis in acutely hospitalized patients, and several pathways were linked to different types of cancer. The results from our network analysis show that DNA methylation of multiple genes could have been coregulated in an association with the overall risk of death. The identified epigenetic markers might help with our understanding of the molecular basis of all-cause mortality and general health.
机译：总体或全因死亡率是衡量人口健康状况的关键指标。已经对全因死亡率进行了多个表观基因组广泛关联研究，但显著发现有限，复制率低。为了阐明与全因死亡率相关的共调节DNA甲基化模式，我们对1921年和1936年洛锡安出生队列中1425名老年人的全血样本进行了加权DNA甲基化共调节网络分析。我们基于网络的分析将基因启动子中的共调控DNA甲基化模式定义为集群或模块，其与全因死亡率的相关性通过生存分析进行评估。根据特征基因，我们在LBC1921中发现了两个与全因死亡率相关的重要模块或基因簇；一个与死亡风险呈负相关（p=8.14E-03698个基因），另一个与死亡风险呈正相关（p=4.26E-021431个基因）。这两个模块在LBC1936中复制，相关方向相同（分别为p=6.35E-02和p=3.64E-02）。此外，这些模块还揭示了32个与包括癌症和糖尿病在内的各种疾病相关的全因死亡率（FDR<0.05）相关的基因。此外，我们进行了通路分析，发现22条通路（FDR<0.05），包括味觉传导通路，该通路已被证明与急性住院患者的不良预后相关，并且有几条通路与不同类型的癌症有关。我们网络分析的结果表明，多个基因的DNA甲基化可能与总体死亡风险相关。确定的表观遗传学标记可能有助于我们理解全因死亡率和总体健康的分子基础。

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