Identification of Genes and DNA Methylation Markers for Lung Cancer Risk by Integrating Multi-omics Data

项目摘要 肺癌是美国和许多其他国家癌症死亡的主要原因。 全基因组关联研究（GWAS）已经确定了约55个与肺癌风险相关的基因位点。 然而，大多数这些基因座的致病基因（及其潜在的生物学机制）仍然未知。 基因表达是遗传变异和疾病之间的中间表型。DNA甲基化是 在调节基因表达中起着关键作用。直接整合基因组、转录组和甲基组数据 与疾病风险的关系可以揭示新的疾病易感基因和潜在机制。但据 如果可能的话，直接分析肺中的转录组和甲基化组是非常困难和昂贵的。 来自大量病例和对照的组织用于评估这些关联。在此，我们提出一个 新方法：转录组关联研究（TWAS）和甲基化关联研究 （MeWAS）使用遗传仪器鉴定与肺癌风险相关的新基因和甲基化位点。 这些新的方法已被证明是非常强大的，在确定新的基因和甲基化位点 在最近的多项研究中，包括我们的试点研究， 肺癌的研究。我们建议进行一个强大的TWAS和MeWAS来发现新的基因， 甲基化基因座（GWAS鉴定的基因座中的潜在靶向基因/甲基化位点和GWAS鉴定的基因座中的基因/甲基化位点两者）。 GWAS尚未发现的位点）的肺癌风险（目标1）。我们将评估 肺间质中TWAS鉴定基因的表达水平和MeWAS鉴定基因座的甲基化水平 癌组织和正常组织，以优先考虑可能导致肺癌的基因和甲基化位点 风险（目标2）。我们将研究甲基化位点对有希望的 目的3：通过功能基因组学分析，对基因和甲基化位点的功能进行评价。 最后，我们将进行一系列的功能分析，以评估所确定的基因的潜在功能， 甲基化位点（Aim 4）。我们预计，这项拟议的研究将确定大量的新基因， 甲基化基因座的肺癌风险，并提供功能数据，以提高对生物学的理解。 机制等拟议的研究是高度创新和成本效益。我们的成果将帮助我们更好地 了解遗传和表观遗传变异之间的机械关系，以及这些变异如何 与肺癌风险有关，并可能导致发现有助于早期检测肺癌的生物标志物。 肺癌和个性化治疗的靶向基因疗法的发展。

Project Summary Lung cancer is the leading cause of cancer death in the United States and many other countries. Genome-wide association studies (GWAS) have identified ~55 genetic loci associated with lung cancer risk. However, causal genes (and their underlying biological mechanisms) for most of these loci remain unknown. Gene expression is an intermediate phenotype between genetic variants and disease. DNA methylation plays a critical role in regulating gene expression. Directly integrating genomic, transcriptomic, and methylomic data with disease risk can uncover novel disease susceptibility genes and potential mechanisms. However, it is extremely difficult, if at all possible, and costly to directly profile the transcriptome and methylome in lung tissues from a large number of cases and controls for evaluating these associations. Herein, we propose a novel approach: transcriptome-wide association study (TWAS) and methylation-wide association study (MeWAS) to identify novel genes and methylation loci related to lung cancer risk using genetic instruments. These novel approaches have been shown to be very powerful in identifying novel genes and methylation sites in both GWAS-reported loci and regions not yet revealed in GWAS in multiple recent studies, including our pilot study in lung cancer. We propose to conduct a well-powered TWAS and MeWAS to discover novel genes and methylation loci (both potential targeted genes/methylation sites in GWAS-identified loci and genes/methylation sites in loci not yet uncovered by GWAS) for lung cancer risk (Aim 1). We will evaluate the differences in the expression levels of TWAS-identified genes and the methylation levels of MeWAS-identified loci between lung cancer tissues and normal tissues to prioritize genes and methylation loci that may contribute to lung cancer risk (Aim 2). We will investigate the regulating effects of methylation sites on the expression of promising genes and evaluate the functions of genes and methylation loci by functional genomics analyses (Aim 3). Finally, we will perform a serial of functional analyses to evaluate the potential functions of identified genes and methylation loci (Aim 4). We anticipate that this proposed study will identify a large number of novel genes and methylation loci for lung cancer risk and provide functional data to improve understanding of biological mechanisms. The proposed study is highly innovative and cost efficient. Our results will help us to better understand the mechanistic relationship between genetic and epigenetic variations and how those variations relate to lung cancer risk, and may lead to the discovery of biomarkers that would facilitate early detection of lung cancer and the development of targeted gene therapies for personalized treatment.