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

描述（由申请人提供）：自2007年以来，在全基因组关联研究（GWAS）中，大约有30个低外显子遗传易感位点被确定为结直肠癌（CRC）。这些遗传因素，以及已知结直肠癌易感基因中罕见的高外显率种系突变，只能解释一小部分结直肠癌遗传性。我们建议以一种非常经济有效的方式，扩大我们正在东亚进行的结直肠癌GWAS，以确定结直肠癌的新的遗传易感性位点。我们建议进一步精细绘制和功能表征gwas识别的CRC风险位点，以发现驱动关联的功能变异和基因。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千人基因组计划数据作为参考。将选择有希望的snp，进行功能注释，并重新进行基因分型以进行复制，以确定结直肠癌的新风险位点。2)利用来自5000例病例和5000例对照的密集基因分型数据，以及来自东亚、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估算数据，精细绘制30至50个新发现的CRC位点，以识别独立的和潜在的功能变异。3)进行体外实验，鉴定多达15个新鉴定的CRC基因座的功能变异。4)利用一种新型的干细胞驱动小鼠结肠肿瘤模型，进一步确定GWAS中鉴定的特定CRC基因和易感等位基因。这项拟议的GWAS扩展将是东亚地区第一个全面寻找结直肠癌遗传风险因素的大型研究。通过利用现有研究和功能基因组数据产生的GWAS数据，这项研究将具有极高的成本效益。通过实验方法的功能表征，我们期望识别CRC的功能变异和新的基因/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。这一信息将有助于加速将GWAS发现转化为疾病预防和治疗。

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.