Skip to main content
Grant Details

Grant Number: 5R01CA188214-06 Interpret this number
Primary Investigator: Zheng, Wei
Organization: Vanderbilt University Medical Center
Project Title: Colorectal Cancer Risk Loci: Gwas, Fine-Mapping, and Functional Analysis
Fiscal Year: 2018
Back to top


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.

Back to top


Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
Authors: Schmit S.L. , Edlund C.K. , Schumacher F.R. , Gong J. , Harrison T.A. , Huyghe J.R. , Qu C. , Melas M. , Van Den Berg D.J. , Wang H. , et al. .
Source: Journal Of The National Cancer Institute, 2018-06-16 00:00:00.0; , .
EPub date: 2018-06-16 00:00:00.0.
PMID: 29917119
Related Citations

Evaluation of genetic variants in association with colorectal cancer risk and survival in Asians.
Authors: Wang N. , Lu Y. , Khankari N.K. , Long J. , Li H.L. , Gao J. , Gao Y.T. , Xiang Y.B. , Shu X.O. , Zheng W. .
Source: International Journal Of Cancer, 2017-05-31 00:00:00.0; , .
EPub date: 2017-05-31 00:00:00.0.
PMID: 28567967
Related Citations

Estimation of heritability for nine common cancers using data from genome-wide association studies in Chinese population.
Authors: Dai J. , Shen W. , Wen W. , Chang J. , Wang T. , Chen H. , Jin G. , Ma H. , Wu C. , Li L. , et al. .
Source: International Journal Of Cancer, 2017-01-15 00:00:00.0; 140(2), p. 329-336.
EPub date: 2016-10-11 00:00:00.0.
PMID: 27668986
Related Citations

Common Risk Variants For Colorectal Cancer: An Evaluation Of Associations With Age At Cancer Onset
Authors: Song N. , Shin A. , Park J.W. , Kim J. , Oh J.H. .
Source: Scientific Reports, 2017-01-13 00:00:00.0; 7, p. 40644.
PMID: 28084440
Related Citations

Identification of Susceptibility Loci and Genes for Colorectal Cancer Risk.
Authors: Zeng C. , Matsuda K. , Jia W.H. , Chang J. , Kweon S.S. , Xiang Y.B. , Shin A. , Jee S.H. , Kim D.H. , Zhang B. , et al. .
Source: Gastroenterology, 2016 Jun; 150(7), p. 1633-45.
PMID: 26965516
Related Citations

Large-scale genetic study in East Asians identifies six new loci associated with colorectal cancer risk.
Authors: Zhang B. , Jia W.H. , Matsuda K. , Kweon S.S. , Matsuo K. , Xiang Y.B. , Shin A. , Jee S.H. , Kim D.H. , Cai Q. , et al. .
Source: Nature Genetics, 2014 Jun; 46(6), p. 533-42.
PMID: 24836286
Related Citations

Back to Top