Colorectal cancer risk loci: GWAS, fine-mapping, and functional analysis

结直肠癌风险位点：GWAS、精细定位和功能分析

• 批准号: 9248726
• 负责人: Jirong Long
• 金额: $ 22.29万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9248726
• 关键词: Colorectal; cancer; risk; loci; GWAS

DESCRIPTION (provided by applicant): Since 2007, approximately 30 low-penetrance genetic susceptibility loci have been identified for colorectal cancer (CRC) in genome-wide association studies (GWAS). These genetic factors, along with rare, high-penetrance germline mutations in known CRC susceptibility genes, explain only a small fraction of CRC heritability. We propose to expand, in a very cost-efficient way, our ongoing GWAS of CRC conducted in East Asians to identify new genetic susceptibility loci for CRC. We propose further to fine-map and functionally characterize GWAS-identified risk loci for CRC to discover functional variants and genes that drive the associations. Specifically, we propose to accomplish the following aims: 1) Expand the GWAS to include approximately 10,100 cases and 22,700 controls in the discovery stage and 8,000 cases and 8,000 controls in replication stages. Genome-wide scan data will be imputed using the 1000 Genomes Project data as the reference. Promising SNPs will be selected, functionally annotated, and de novo genotyped for replication to identify new risk loci for CRC. 2) Use densely genotyped data from 5,000 cases and 5,000 controls, along with genome-wide scanned and imputed data from 30,400 cases and 44,700 controls of East Asian, African, and European-ancestry to fine-map 30 to 50 newly identified CRC loci to identify independent and potentially functional variants. 3) Perform in vitro experiments to identify functional variants inup to 15 newly identified CRC loci. 4) Utilize a novel stem-cell-driven mouse model of colonic neoplasia to further determine specific CRC genes and susceptibility alleles in selected loci identified in GWAS. This proposed GWAS expansion will be the first large study in East Asians to comprehensively search for genetic risk factors for CRC. This study, by capitalizing on GWAS data generated from existing studies and functional genomic data, will be extremely cost-efficient. Through functional characterization using experimental approaches, we anticipate identifying functional variants and novel genes/pathways for CRC to improve the understanding of biological mechanisms through which GWAS-identified loci contribute to CRC risk. This information will help accelerate the translation of GWAS findings into disease prevention and treatment.

描述（由申请人提供）：自2007年以来，在全基因组关联研究（GWAS）中已确定了约30个低突变率的结直肠癌（CRC）遗传易感性位点。这些遗传因素，沿着已知CRC易感基因中罕见的高突变率种系突变，只能解释CRC遗传性的一小部分。我们建议以一种非常具有成本效益的方式扩大我们正在进行的在东亚人中进行的CRC的GWAS，以确定CRC的新遗传易感性位点。我们建议进一步对GWAS确定的CRC风险位点进行精细定位和功能表征，以发现驱动相关性的功能变体和基因。具体而言，我们建议实现以下目标：1）扩大GWAS，在发现阶段包括约10，100例病例和22，700例对照，在复制阶段包括8，000例病例和8，000例对照。全基因组扫描数据将使用1000个基因组计划数据作为参考进行插补。将选择有前景的SNP，进行功能注释，并重新进行基因分型，以确定新的CRC风险基因座。2)使用来自5，000例病例和5，000例对照的密集基因型数据，沿着来自东亚，非洲和欧洲血统的30，400例病例和44，700例对照的全基因组扫描和插补数据，对30至50个新发现的CRC基因座进行精细定位，以识别独立的和潜在的功能性变体。3)进行体外实验以鉴定多达15个新鉴定的CRC基因座的功能变体。4)利用一种新的干细胞驱动的结肠肿瘤小鼠模型，进一步确定GWAS中确定的选定基因座中的特定CRC基因和易感等位基因。这项拟议的GWAS扩展将是第一项在东亚人中全面寻找CRC遗传风险因素的大型研究。这项研究通过利用现有研究产生的GWAS数据和功能基因组数据，将具有极高的成本效益。通过使用实验方法进行功能表征，我们预计将识别CRC的功能变体和新基因/途径，以提高对GWAS识别的基因座导致CRC风险的生物学机制的理解。这些信息将有助于加速将GWAS的发现转化为疾病预防和治疗。