Strategies to avert type 1 diabetes (T1D), a condition driven by autoimmune processes and necessitating continuous lifelong therapy, are still constrained. This investigation aimed to uncover new candidate therapeutic targets for T1D by employing Mendelian randomization together with colocalization analyses that relied on genetic instruments originating from immune cells. We identified cis-acting genetic variants across 14 transcriptomic datasets to instrument the expression of 8998 genes profiled in various immune cell populations. Association data for the outcome were derived from a large T1D genome-wide association study encompassing 18,942 cases and 501,638 controls. Secondary evaluations examined potential horizontal pleiotropy, assessed novelty of signals, and conducted phenome-wide scans combined with colocalization (PheWAS-coloc) using the instrumental variants. We highlighted 21 genes (CLNK, EED, LZTFL1, MGAT4A, NAA38, NFKB1, PHACTR4, PHLPP2, PLEKHA1, P2RY12, REST, RGS14, SERPINB6, SESN3, SLC25A29, SPAG1, STIM2, THEMIS, TMEM80, VSIR, ZNF217) that had not previously emerged in T1D genome-wide association studies. Of particular interest, increased genetically determined expression of VSIR (which codes for the immune checkpoint molecule VISTA) correlated with lower T1D susceptibility. This genetic evidence from humans reinforces and extends animal model data indicating a protective function of VISTA against autoimmune pathology. Another prioritized gene, P2RY12, is already the target of multiple approved pharmaceuticals, suggesting a feasible drug repurposing strategy. Complementary PheWAS-coloc results associated P2RY12 expression with antibody responses to Epstein-Barr virus EBNA-1, thereby implicating an autoimmune-relevant biological pathway. The present results open fresh opportunities for developing and repositioning therapeutic agents intended to prevent or postpone the emergence of T1D.
