Project Summary/Abstract Type 1 diabetes (T1D), which is characterized by T cell-mediated destruction of insulin-producing pancreatic beta cells, has a relatively well-defined genetic architecture that explains about 50% of inter-individual differences in disease risk. However, translating the genetic architecture into novel disease insights and therapies has lagged behind because its molecular and cellular mechanisms are incompletely understood. Studies have established a strong impact of T1D genetics on T cells, which supports the development of the only FDA-approved drug for delaying T1D-onset in high-risk individuals by targeting T cells. However, majority of individuals are non-responsive to this drug and/or develop disease regardless. The selective destruction of beta cells but no other endocrine cells that are embedded with beta cells in the islets implicates intrinsic beta- cell biology as a driver of T1D development. An emerging mechanism causing beta-cell destruction is noncanonical mRNA translation that generates neoantigens that act as autoantigens to invoke destruction by T cells. Accordingly, studies have elegantly demonstrated that insulin gene (INS) variation contributes to T1D risk by modulating the fidelity and efficiency of insulin mRNA translation in beta cells. In pursuit of our efforts to understand how genetics affect beta-cell biology and contribute to T1D, we overlayed T1D risk variants with variants that regulate gene expression and discovered genetic upregulation of RPS26 expression levels in human beta cells causally contributes to T1D risk. We further found that RPS26 expression is upregulated in beta cells from patients with T1D compared to control individuals. RPS26 is involved in mRNA translation and prior studies demonstrated that RPS26 protein can directly bind to certain mRNAs with features similar to that of insulin mRNA and orchestrate noncanonical translation. For instance, RPS26 has been shown to promote noncanonical translatio