Deciphering the genetic architecture of low-penetrance susceptibility to colorectal cancer

Abstract

Recent genome-wide association studies (GWASs) have identified common variants at 16 autosomal regions influencing the risk of developing colorectal cancer (CRC). To decipher the genetic basis of the association signals at these loci, we performed a meta-analysis of data from five GWASs, totalling 5626 cases and 7817 controls, using imputation to recover un-typed genotypes. To enhance our ability to discover low-frequency risk variants, in addition to using 1000 Genomes Project data as a reference panel, we made use of high-coverage sequencing data on 253 individuals, 199 with early-onset familial CRC. For 13 of the regions, it was possible to refine the association signal identifying a smaller region of interest likely to harbour the functional variant. Our analysis did not provide evidence that any of the associations at the 16 loci being a consequence of synthetic associations rather than linkage disequilibrium with a common risk variant.

Figure 1.

Coverage distribution within each target region. The depth of coverage is calculated based on the number of reads that mapped to that position and is averaged over 100 kb windows. The x-axis denotes the relative position from the start of the target region.

Figure 2.

The number of variants specific to 1000 genomes and to the CG-panel reference panels as well as those that are in common between the two panels according to MAF.