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

描述(申请人提供)：自2007年以来，在全基因组关联研究中，大约有30个低外显性遗传易感基因被确定为结直肠癌(CRC)。这些遗传因素，加上已知的CRC易感基因中罕见的高外显性胚系突变，只能解释一小部分CRC的遗传性。我们建议以非常具成本效益的方式，扩大我们在东亚人中进行的结直肠癌的GWA，以确定新的结直肠癌遗传易感基因座。我们建议进一步精细定位并从功能上表征GWAS确定的风险基因座，以便为结直肠癌发现功能变异和驱动关联的基因。具体地说，我们建议实现以下目标：1)扩大GWAS，将发现阶段的大约10,100个病例和22,700个对照以及复制阶段的8,000个病例和8,000个对照纳入其中。全基因组扫描数据将使用1000基因组计划数据作为参考。有希望的SNP将被选择、功能注释和重新进行基因分型以用于复制，以确定新的结直肠癌风险基因。2)使用来自5,000个病例和5,000个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个病例和44,700个对照的全基因组扫描和推算数据，精细定位30到50个新发现的CRC基因座，以识别独立的和潜在的功能变异。3)进行体外实验，以确定多达15个新发现的CRC基因座的功能变异。4)利用一种新的干细胞驱动的小鼠结肠肿瘤模型，进一步确定在Gwas中确定的特定基因座上的特定CRC基因和易感等位基因。这项拟议的Gwas扩展将是东亚人全面寻找结直肠癌遗传风险因素的第一项大型研究。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，我们期望识别结直肠癌的功能变异和新的基因/途径，以提高对GWAS识别的基因座导致结直肠癌风险的生物学机制的理解。这些信息将有助于加快将全球卫生组织的调查结果转化为疾病预防和治疗的工作。

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.