Cross-cancer pleiotropic analysis identifies three novel genetic risk variants for colorectal cancer.

BACKGROUND: To understand the shared genetic basis between colorectal cancer (CRC) and other cancers and identify potential pleiotropic loci for compensating the missing genetic heritability of CRC.

METHODS: We conducted a systematic genome-wide pleiotropy scan to appraise associations between cancer-related genetic variants and CRC risk among European populations. SNP-set analysis was performed using data from the UK Biobank and the Study of Colorectal Cancer in Scotland (10 039 CRC cases and 30 277 controls) to evaluate the overlapped genetic regions for susceptibility of CRC and other cancers. The variant-level pleiotropic associations between CRC and other cancers were examined by CRC GWAS meta-analysis and the PLACO pleiotropy test. Gene-based, co-expression, and pathway enrichment analyses were performed to explore potential shared biological pathways. Interaction between novel genetic variants and common environmental factors was further examined for their effects on CRC.

RESULTS: Genome-wide pleiotropic analysis identified three novel SNPs (rs2230469, rs9277378, rs143190905) and three mapped genes (PIP4K2A, HLA-DPB1, RTEL1) to be associated with CRC. These genetic variants were significant eQTL in colon tissue, influencing the expression of their mapped genes. Significant interactions of PIP4K2A and HLA-DPB1 with environmental factors, including smoking and alcohol drinking, were observed. All mapped genes and their co-expressed genes were significantly enriched in pathways involved in carcinogenesis.

CONCLUSION: Our findings provide an important insight into the shared genetic basis between CRC and other cancers. We revealed several novel CRC susceptibility loci to help understand the genetic architecture of CRC.