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An international research team at the Fred Hutchinson Cancer Research Center identified a combination of rare and common genetic variants that coincide with susceptibility to colorectal cancer (CRC). Starting with complete genome sequencing on more than 2,100 CRC cases and controls, the researchers used variants imputed from these and other data in a two-stage genome-wide association study that included nearly 125,500 individuals with or without CRC. The findings were published in Nature Genetics, revealing in previous studies 40 CRC-associated variants previously undocumented and 55 variants involved in CRC risk.
Using paired-end sequencing of Illumina HiSeq 2500, the researchers performed complete genome sequencing on 1,439 individuals with CRC and 720 controls that were not affected. Using sequence data from the Haplotype Reference Consortium covering each genome to 3.8-to 8.6-fold coverage, on average, and population sequence data, they obtained phasing information for 31.8 million variants, including rare variants.
With variants imputed from these data, the team conducted a meta-analysis of GWAS and GWAS based on array-based genotyping profiles for 34,869 CRC cases and 29,051 controls from the study's discovery phase and a validation group comprising 23,262 more CRC and 38,296 non-CRC individuals. A subset of participants was genotyped using a custom Illumina array that included both known cancer-related loci and suspicious variants found in the association's first phase study.
The researchers uncovered known CRC contributors along with new associations involving common, low-frequency, and rare variants from the GWAS meta-analysis and their subsequent conditional analysis. They explored 40 new variants involved in CRC with functional annotation, open chromatin maps, and ATAC-sequence profiling of chromatin accessibility. The team also found a polygenic score based on 95 new and previously known risk variants, although it warned that the polygenic risk score in non-European populations is expected to be less accurate due to the over-representation of European participants in the current study.
The next step for this research is to expand the population of the study to make it more diverse. Investigators acknowledged that their study consisted mostly of European descent individuals, which could result in the results being biased.