biostudies-literatureDeslandes BCancer Research UK Population Research CommitteeNational Institute for Cancer ResearchCancer Research UK 25University of BristolMinistry of Health of the Czech RepublicNHLBI NIH HHSMedical Research CouncilCRUK Integrative Cancer Epidemiology ProgrammeNCI NIH HHSWellcome TrustNIH HHSqiaf131https://www.ebi.ac.uk/biostudies/studies/S-EPMC12571111biostudies-literatureUnknown117(10)Recent research suggests higher circulating lymphocyte counts may protect against colorectal cancer (CRC). However, the role of specific lymphocyte subtypes and activation states remain unclear. CD4+ T cells-a highly dynamic lymphocyte subtype-undergo gene expression changes upon activation that are critical to their effector function. Previous studies using bulk tissue have limited our understanding of their role in CRC risk to static associations. We applied Mendelian randomization (MR) and genetic colocalisation to evaluate causal relationships of gene expression on CRC risk across multiple CD4+ T cell subtypes and activation states. Genetic proxies were obtained from single-cell transcriptomic data, allowing us to investigate the causal effect of expression of 1,805 genes across CD4+ TJournal of leukocyte biologyTranscriptome-wide Mendelian randomization exploring dynamic CD4+ T cell gene expression in colorectal cancer development.PMC12571111U19 CA148107U01 CA122839LX22NPO5102U01 CA167551R01 CA143247R01 CA081488218495/Z/19/ZAZV NU22J-03-00033R01 CA81488MC_UU_00032/03HHSN268201200008IC18281/A29019C18281/A30905HHSN268201200008CHazelwood EGoudswaard LJLee MAYarmolinsky JPai RKLindblom AOgino SPhipps AIThomas CEZheng JDeslandes BHuyghe JRWu AHPeters UGrant RCGsur AVincent EEJones GWGunter MJWolk ABuchanan DDVymetalkova VWu XfalseTranscriptome-wide Mendelian randomization exploring dynamic CD4+ T cell gene expression in colorectal cancer development.Recent research suggests higher circulating lymphocyte counts may protect against colorectal cancer (CRC). However, the role of specific lymphocyte subtypes and activation states remain unclear. CD4+ T cells-a highly dynamic lymphocyte subtype-undergo gene expression changes upon activation that are critical to their effector function. Previous studies using bulk tissue have limited our understanding of their role in CRC risk to static associations. We applied Mendelian randomization (MR) and genetic colocalisation to evaluate causal relationships of gene expression on CRC risk across multiple CD4+ T cell subtypes and activation states. Genetic proxies were obtained from single-cell transcriptomic data, allowing us to investigate the causal effect of expression of 1,805 genes across CD4+ T2025-01-01T00:00:00Z2025 Oct2026-05-16T03:14:49.241Z2026-05-16T03:08:09.11ZS-EPMC125711114097409710.1093/jleuko/qiaf131