Trans-ancestry analysis in over 799,000 individuals yields new insights into the genetic etiology of colorectal cancer

Background: Recent studies have demonstrated the relevance of circulating factors in the occurrence and development of colorectal cancer (CRC); however, the causal relationship remains unclear. Methods: Summary-level data for CRC were obtained from the UK Biobank (5,657 cases and 372,016 controls), FinnGen cohort (3,022 cases and 215,770 controls), and BioBank Japan Project (BBJ, 7,062 cases and 195,745 controls). Thirty-two peripheral markers with consistent definitions were collected from the three biobanks. Mendelian randomization (MR) was used to evaluate the causal effect of circulating factors on CRC. The effects from the three consortiums were combined using trans-ancestry meta-analysis methods. Results: Our analysis provided compelling evidence for the causal association of higher genetically predicted eosinophil cell count (EOS, odds ratio [OR], 0.8639; 95% confidence interval [CI] 0.7922–0.9421) and red cell distribution width (RDW, OR, 0.9981; 95% CI, 0.9972–0.9989) levels with a decreased risk of CRC. Additionally, we found suggestive evidence indicating that higher levels of total cholesterol (TC, OR, 1.0022; 95% CI, 1.0002–1.0042) may increase the risk of CRC. Conversely, higher levels of platelet count (PLT, OR, 0.9984; 95% CI, 0.9972–0.9996), total protein (TP, OR, 0.9445; 95% CI, 0.9037–0.9872), and C-reactive protein (CRP, OR, 0.9991; 95% CI, 0.9983–0.9999) may confer a protective effect against CRC. Moreover, we identified six ancestry-specific causal factors, indicating the necessity of considering patients’ ancestry backgrounds before formulating prevention strategies. Conclusions: MR findings support the independent causal roles of circulating factors in CRC, which might provide a deeper insight into early detection of CRC and supply potential preventative strategies.