Integrative proteogenomic analyses provide novel interpretations of type 1 diabetes risk loci through circulating proteins

Type 1 diabetes (T1D) requires new preventive measures and interventions. Circulating proteins are promising biomarkers and drug targets. Leveraging genome-wide association studies (GWASs) of T1D (18,942 cases and 501,638 controls) and circulating protein abundances (10,708 individuals), the associations between 1,565 circulating proteins and T1D risk were assessed through Mendelian randomization, followed by multiple sensitivity and colocalization analyses, examinations of horizontal pleiotropy, and replications. Genetically increased circulating abundances of CTSH, IL27RA, SIRPG, and PGM1 were associated with an increased risk of T1D, consistently replicated in other cohorts. Bulk tissue and single-cell gene expression profiles revealed strong enrichment of CTSH, IL27RA, and SIRPG in immune system-related tissues, and PGM1 in muscle and liver tissues. Among immune cells, CTSH was enriched in B cells and myeloid cells, while SIRPG was enriched in T cells and natural killer cells. These proteins warrant exploration as T1D biomarkers or drug targets in relevant tissues.