| Application: | 8614, Evaluating genome-wide association and gene-environment interaction in colorectal cancer |
| Title: | Discovery of common and rare genetic risk variants for colorectal cancer |
| Size: | 13583 B |
| Archived: | 26 Feb 2021 |
| Stability: | Complete |
| Personal: | No individual-level data |
Return 3140
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Notes
To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P?<?5? ?10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Kr ppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.Application 8614
Evaluating genome-wide association and gene-environment interaction in colorectal cancer
1)Combine data from existing and ongoing genomewide association studies (GWAS) of colorectal cancer (CRC). We will combine data from UK Biobank with existing GWAS to identify rare and common genetic variation associated with risk and survival. 2)Investigate whether associations with genetic variants are modified by environmental predictors of CRC. These include demographic factors, obesity, exercise, non-steroidal anti-inflammatory drugs, postmenopausal hormones, alcohol, smoking, dietary factors, and exposures as measured by circulating biomarkers of nutrients, metabolism, inflammation, and sex hormones. Secondarily, we?ll conduct gene-gene, functional annotation, candidate gene, pathway, Mendelian randomization, mediation, and risk modeling analyses. Genetic and environmental factors contribute to the etiology of colorectal cancer (CRC). Genomewide association studies (GWAS) have identified novel loci contributing to CRC susceptibility and survival outcomes, and we expect that additional loci can be identified by combining data across large sample sets, as proposed here. To evaluate the impact of genetic variants on CRC risk and survival, it is important to explore the interplay between genetic and environmental factors in disease, and to translate these findings into public health applications, it is critical to understand the penetrance of new loci and develop risk models that include these risk factors. To comprehensively explore genetic and environmental contributions to CRC risk and survival, we propose to combine UK Biobank data with existing and ongoing CRC studies that are part of the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). These combined studies will allow for considerable statistical power to identify and characterize genetic variants associated with CRC and enable analyses of gene-environment interaction. In addition, this large sample size will facilitate exploratory analyses of gene-gene interaction, candidate genes, pathways, Mendelian randomization, mediation, as well as risk modeling of genetic variants identified by genome-wide association studies. To maximize statistical power to detect associations and interactions, data from the entire UK Biobank cohort, including approximately 1,163 incident and 2,271 prevalent cases of CRC (these are the current number of cases in the UK Biobank and we will include any newly diagnosed CRC cases as they occur), will be combined with that from GECCO, which includes over 35,000 CRC cases and 37,000 controls with directly sequenced/genotyped and imputed genome-wide genetic data.
| Lead investigator: | Dr Ulrike Peters |
| Lead institution: | Fred Hutchinson Cancer Center |
1 Publication
| Pub ID | Title | Author(s) | Year | Journal |
|---|---|---|---|---|
| 3141 | Discovery of common and rare genetic risk variants for colorectal cancer | Huyghe JR et al. | 2019 | Nat Genet |
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