Transcriptome-wide association study to identify susceptibility genes for colorectal cancer

全转录组关联研究以确定结直肠癌的易感基因

基本信息

批准号：
10232085
负责人：
Xingyi Guo
金额：
$ 56万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-04 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10232085
关键词：
Asia Asians Bioinformatics Biological Assay Biological Process Breast Cancer Risk Factor CRISPR interference Cancer Biology Cancer Patient Cancer-Predisposing Gene Carcinoma Cell physiology Cessation of life Code Collaborations Colon Colorectal Colorectal Cancer Complex Data Data Pooling Data Set Disease Distant Etiology European Gene Expression Genes Genetic Genetic Predisposition to Disease Genotype Genotype-Tissue Expression Project Heritability Heterogeneity In Vitro Individual Malignant Neoplasms Malignant neoplasm of prostate Modeling Newly Diagnosed Pathway interactions Patient Care Phenotype Play Psyche structure Regulation Research Design Role Scanning Small RNA Study models Susceptibility Gene Testing Time Tissues Translations United States Untranslated RNA Variant base cancer chemoprevention cancer genetics cancer prevention cancer therapy causal variant colon cancer cell line colon cancer patients colorectal cancer risk cost efficient density design disorder prevention disorder risk experimental study genetic epidemiology genetic variant genome wide association study genomic locus improved in vitro Assay innovation interest novel novel strategies predictive modeling risk variant trait transcriptome transcriptome sequencing tumor

项目摘要

PROJECT SUMMARY Genetic factors play an important role in the etiology of colorectal cancer (CRC). To date, approximately 50 genetic loci have been identified for CRC through genome-wide association studies (GWAS). However, these loci explain only a small fraction of heritability. Moreover, target genes and underlying mechanisms for most of these risk loci remain unclear. The large majority are noncoding variants, many of which have been shown to regulate gene expression. Recent studies suggest that ~80% of disease heritability can be explained by regulatory variants. However, these variants are each associated with only a small alteration in disease risk; thus they are difficult to identify using GWAS. Recently, a novel approach, the transcriptome-wide association study (TWAS), was developed to systematically investigate the transcriptome's association with disease risk. In TWAS, models are built to predict gene expression with cis-SNPs using a reference transcriptome, and then applied to GWAS data to evaluate their associations with disease risk. Here, we propose to use this innovative approach to scan the whole transcriptome to discover novel CRC susceptibility genes and uncover likely causal genes in loci revealed in previous GWAS. In Aim 1, we will conduct a TWAS in European descendants. We will build expression prediction models for coding genes and non-coding RNAs in hundreds of colorectal tissues, other multiple tissues, and cross tissues using transcriptome and high-density genotyping data from individuals of European ancestry in the Genotype-Tissue Expression (GTEx) project. The models will be used to predict gene expression levels using GWAS data from approximately 27,911 CRC cases and 23,059 controls included in the ColoRectal Transdisciplinary Study (CORECT) and the Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia, and then to evaluate their associations with CRC risk. In Aim 2, we will conduct a TWAS in East-Asian descendants. We will generate transcriptome data and high-density genotyping data from 400 CRC patients of Asian ancestry from the Asia Colorectal Cancer Consortium (ACCC). We will use these data to build expression prediction models for coding genes and non-coding RNAs and perform a TWAS in approximately 18,999 CRC cases and 31,269 controls from the ACCC. In Aim 3, we will experi- mentally evaluate biological function of the top 30 genes identified in Aims 1 and 2. Based on the association direction between their expression levels and CRC risk, we will either suppress expression using CRISPRi or promote it using CRISPRa in multiple normal colon epithelial and CRC cell lines. We will then perform in vitro assays and analyze bioinformatics evidence to examine the biological functions of these selected genes and to assess their potential roles in regulating known cancer-related pathways. Our proposed study is extremely cost-efficient, as both the transcriptome dataset (GTEx) for European descendants and the GWAS data are already available to us. This proposed study will provide strong evidence for pinpointing CRC susceptibility genes, thereby facilitating the translation of our findings to cancer prevention and patient care.

项目概要遗传因素在结直肠癌（CRC）的病因学中发挥着重要作用。迄今为止，大约有 50 通过全基因组关联研究 (GWAS) 已确定了 CRC 的遗传位点。然而，这些位点只能解释遗传力的一小部分。此外，大多数的靶基因和潜在机制这些风险位点仍不清楚。绝大多数是非编码变体，其中许多已被证明调节基因表达。最近的研究表明，约 80% 的疾病遗传力可以解释为监管变体。然而，这些变异仅与疾病风险的微小变化相关。因此，使用 GWAS 很难识别它们。最近，一种新方法，全转录组关联研究（TWAS）旨在系统地研究转录组与疾病风险的关联。在 TWAS 中，使用参考转录组构建模型来预测顺式 SNP 的基因表达，然后应用于 GWAS 数据以评估其与疾病风险的关联。在这里，我们建议使用这种创新扫描整个转录组以发现新的 CRC 易感基因并发现可能的方法之前的 GWAS 揭示了基因座中的因果基因。在目标 1 中，我们将在欧洲后裔中开展 TWAS。我们将建立数百个结直肠中编码基因和非编码RNA的表达预测模型使用转录组和高密度基因分型数据对组织、其他多种组织和跨组织进行分析基因型组织表达 (GTEx) 项目中的欧洲血统个体。将使用模型使用来自约 27,911 例 CRC 病例和 23,059 例的 GWAS 数据预测基因表达水平结肠直肠跨学科研究 (CORECT) 以及遗传学和流行病学中包含的控制措施结直肠癌 (GECCO) 联盟，然后评估其与结直肠癌风险的关联。在目标 2 中，我们将对东亚后裔进行 TWAS。我们将生成转录组数据和高密度基因分型来自亚洲结直肠癌联盟 (ACCC) 的 400 名亚洲血统 CRC 患者的数据。我们将使用这些数据构建编码基因和非编码 RNA 的表达预测模型，并执行 TWAS 处理了来自 ACCC 的约 18,999 个 CRC 病例和 31,269 个对照病例。在目标 3 中，我们将体验对目标 1 和 2 中确定的前 30 个基因的生物学功能进行心理评估。基于关联它们的表达水平和 CRC 风险之间的方向，我们将使用 CRISPRi 抑制表达或使用 CRISPRa 在多种正常结肠上皮和结直肠癌细胞系中促进它。然后我们将在体外进行测定和分析生物信息学证据，以检查这些选定基因的生物学功能并评估它们在调节已知癌症相关途径中的潜在作用。我们提出的研究非常具有成本效益，因为欧洲后裔的转录组数据集 (GTEx) 和 GWAS 数据都是已经可供我们使用。这项拟议的研究将为查明 CRC 易感性提供有力的证据基因，从而促进我们的发现转化为癌症预防和患者护理。