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However, the role of specific lymphocyte subtypes and activation states remain unclear. CD4+ T cells\u2014a highly dynamic lymphocyte subtype\u2014undergo 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+ T cell activation states on CRC risk (78,473 cases; 107,143 controls). Analyses were stratified by CRC anatomical subsites and sex, with sensitivity analyses assessing whether the observed effect estimates were likely to be CD4+ T cell-specific. We identified 6 genes\u2014FADS2, FHL3, HLA-DRB1, HLA-DRB5, RPL28, and TMEM258\u2014with strong evidence for a causal role in CRC development (FDR-P &amp;lt; 0.05; colocalisation H4 &amp;gt; 0.8). Causal estimates varied by CD4+ T cell subtype, activation state, CRC subsite and sex. However, many of genetic proxies used to instrument gene expression in CD4+ T cells also act as eQTLs in other tissues, highlighting the challenges of using genetic proxies to instrument tissue-specific expression changes. We demonstrate the importance of capturing the dynamic nature of CD4+ T cells in understanding CRC risk, and prioritize genes for further investigation in cancer prevention.<\/jats:p>","DOI":"10.1093\/jleuko\/qiaf131","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T11:30:08Z","timestamp":1757935808000},"source":"Crossref","is-referenced-by-count":1,"title":["Transcriptome-wide Mendelian randomization exploring dynamic CD4+ T cell gene expression in colorectal cancer development"],"prefix":"10.1093","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-2738-4794","authenticated-orcid":false,"given":"Benedita","family":"Deslandes","sequence":"first","affiliation":[{"name":"MRC Integrative Epidemiology Unit, University of Bristol , Oakfield House, Oakfield Grove, Bristol BS8 2BN ,","place":["United Kingdom"]},{"name":"Population Health Sciences, Bristol Medical School, University of Bristol , First Floor, 5 Tyndall Avenue, Bristol BS8 1UD ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xueyan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine , 227 South Chongqing Road, Shanghai ,","place":["China"]},{"name":"Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiaotong University School of Medicine , 227 South Chongqing Road, Shanghai ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew A","family":"Lee","sequence":"additional","affiliation":[{"name":"Nutrition and Metabolism Branch, International Agency for Research on Cancer, WHO , 150 cours Alber Thomas, Lyon 69372 CEDEX 08 ,","place":["France"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucy J","family":"Goudswaard","sequence":"additional","affiliation":[{"name":"MRC Integrative Epidemiology Unit, University of Bristol , Oakfield House, Oakfield Grove, Bristol BS8 2BN ,","place":["United Kingdom"]},{"name":"Population Health Sciences, Bristol Medical School, University of Bristol , First Floor, 5 Tyndall Avenue, Bristol BS8 1UD ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gareth W","family":"Jones","sequence":"additional","affiliation":[{"name":"School of Cellular and Molecular Medicine, University of Bristol , Biomedical Sciences Building, University Walk, Bristol BS8 1TD ,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9795-1528","authenticated-orcid":false,"given":"Andrea","family":"Gsur","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Medical University of Vienna , Borschkegasse 8a, Vienna 1090 ,","place":["Austria"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annika","family":"Lindblom","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Karolinska University Hospital , Solna, Stockholm 171 64 ,","place":["Sweden"]},{"name":"Department of Molecular Medicine and Surgery, Karolinska Institutet , Karolinska University Hospital, Solna, Stockholm SE-171 76 ,","place":["Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3909-2323","authenticated-orcid":false,"given":"Shuji","family":"Ogino","sequence":"additional","affiliation":[{"name":"Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School , 221 Longwood Ave, Boston, MA 02115 ,","place":["United States"]},{"name":"Department of Oncologic Pathology, Dana-Farber Cancer Institute , 450 Brookline Avenue, Boston, MA 02215 ,","place":["United States"]},{"name":"Department of Epidemiology, Harvard T.H. Chan School of Public Health , 677 Huntington Avenue, Boston, MA 02115 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veronika","family":"Vymetalkova","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences , Videnska 1083, Prague 142 20 ,","place":["Czech Republic"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7387-6845","authenticated-orcid":false,"given":"Alicja","family":"Wolk","sequence":"additional","affiliation":[{"name":"Institute of Environmental Medicine, Karolinska Institutet , Nobels v\u00e4g 13, Solna, Stockholm ,","place":["Sweden"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0546-902X","authenticated-orcid":false,"given":"Anna H","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Population and Public Health Sciences, University of Southern California , 1845 N Soto St, Los Angeles, CA 90032 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeroen R","family":"Huyghe","sequence":"additional","affiliation":[{"name":"Public Health Sciences Division, Fred Hutchinson Cancer Center , 1100 Fairview Ave., Seattle, WA 98109-1024 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5666-9318","authenticated-orcid":false,"given":"Ulrike","family":"Peters","sequence":"additional","affiliation":[{"name":"Public Health Sciences Division, Fred Hutchinson Cancer Center , 1100 Fairview Ave., Seattle, WA 98109-1024 ,","place":["United States"]},{"name":"Department of Epidemiology, University of Washington , 1959 NE Pacific St #F262, Seattle, WA 98195 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda I","family":"Phipps","sequence":"additional","affiliation":[{"name":"Public Health Sciences Division, Fred Hutchinson Cancer Center , 1100 Fairview Ave., Seattle, WA 98109-1024 ,","place":["United States"]},{"name":"Department of Epidemiology, University of Washington , 1959 NE Pacific St #F262, Seattle, WA 98195 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claire E","family":"Thomas","sequence":"additional","affiliation":[{"name":"Public Health Sciences Division, Fred Hutchinson Cancer Center , 1100 Fairview Ave., Seattle, WA 98109-1024 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rish K","family":"Pai","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona , Pathology Research Core, Mayo Clinic, 13400 E. 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