Dissecting cell-type-specific genetic associations between colorectal cancer liability and thrombotic risk in peripheral blood immune cells

Venous thromboembolism (VTE) is a major complication of colorectal cancer (CRC), but whether CRC-associated thrombotic susceptibility includes cell-specific inherited regulatory components in peripheral blood remains unclear. To investigate associations between CRC genetic liability and VTE-related outcomes within peripheral blood mononuclear cell (PBMC) regulatory contexts. We integrated CRC GWAS, FinnGen VTE-related outcomes, and TenK10K PBMC single-cell eQTL data across 28 immune cell types using cell-stratified Mendelian randomization (csMR). Prioritized signals were further examined in single-cell RNA-seq datasets and bulk transcriptomes. Conventional MR showed no clear evidence that CRC liability increased VTE, DVT, or PE risk, and LD Score regression detected no significant genome-wide genetic correlation. In contrast, csMR identified nominal, cell-context-dependent associations. B intermediate cells were prioritized across VTE (OR, 1.16; 95% CI, 1.03-1.32), DVT (OR, 1.30; 95% CI, 1.08-1.57), and PE (OR, 1.26; 95% CI, 1.07-1.49), while CD14 + monocytes and CD4 + central memory T cells received additional support from downstream single-cell analyses. Gene-level analyses prioritized LAMA5, LIMA1, and TRIM28 in these respective cell contexts. In bulk blood, RPS21 showed consistent disease-associated expression patterns and discriminated VTE patients from healthy controls in an external dataset (AUC, 0.865; 95% CI, 0.800-0.923). These findings suggest that genetic overlap between CRC liability and thrombotic phenotypes may be localized to selected PBMC regulatory contexts rather than broadly detectable genome-wide. Among the prioritized signals, B intermediate cells showed the most consistent csMR associations across VTE, DVT, and PE. The cell-gene pairs, together with RPS21, warrant independent genetic, functional, and prospective validation as candidates for studying peripheral immune regulation and blood-based markers of CRC-associated thrombosis.