CD3 on CD39-Positive Resting CD4 Regulatory T Cells and ALS Risk: Genetic Localization to the CD247 Region

Abstract Previous studies implicated CD3-related T-cell traits in amyotrophic lateral sclerosis (ALS), but the regional genetic basis and cellular scope of these associations remain unclear. We examined the previously reported association involving CD3 on CD39-positive resting CD4 regulatory T cells (Tregs) within an exploratory 73-trait screen. Using an ALS genome-wide association study of 27,205 cases and 110,881 controls, we combined two-sample Mendelian randomization (MR), regional colocalization, locus-deletion analyses and comparisons across related Treg phenotypes. Higher genetically predicted CD3 on CD39-positive resting CD4 Tregs was inversely associated with ALS (odds ratio 0.923, 95% confidence interval 0.880–0.969; P = 0.00115). The 73-trait false discovery rate was 0.084 under uniform variance-floor inference and 0.042 under the original model, with unchanged phenotype-specific estimates. Colocalization supported a shared signal in the CD247 region (default posterior probability 0.983). Removing rs1723016 or the entire region attenuated the association, and related CD39-positive Treg gates showed similar regional dependence. Secondary multivariable, directionality, and expression analyses did not materially alter the regional interpretation. These findings localize a previously reported CD3–ALS association to the CD247 region and prioritize T-cell receptor–CD3 biology for cell-specific functional investigation. Screen-wide evidence remained sensitive to the variance specification, and the mediating cell type and mechanism require independent study.