Systematic functional interrogation of genome-wide association studies locus 17p13.3 deciphered role and genetic control of FAM57A in colorectal cancer development.

Objective: Genome-wide association studies (GWAS) have identified over 150 risk loci linked to colorectal cancer (CRC), including the 17p13.3 locus with the tag single nucleotide polymorphism (SNP) rs12603526 in the Asian population. However, the specific causal gene and the functional regulatory mechanisms in this region remain unresolved, necessitating further investigation to elucidate the underlying mechanisms of CRC. Methods: We employed an RNA interference-based functional approach to identify genes critical for CRC cell proliferation at the GWAS locus 17p13.3. Bioinformatic fine-mapping analysis was conducted to prioritize causal variants. A large-scale study involving 7,013 cases and 7,329 controls from a Chinese population, along with another cohort of 5,158 cases and 20,632 controls from the UK Biobank, was performed to validate the association between the candidate variant and the gene. A series of biological experiments was conducted to explore the function of the candidate gene and its regulatory mechanisms. Results: We identified Conclusions: We reveal the underlying mechanisms of CRC predisposition at the GWAS locus 17p13.3. Additionally, our findings highlight the critical role of