Integrative Proteogenomic Analyses Provide Novel Interpretations of Type 1 Diabetes Risk Loci Through Circulating Proteins

This is the authors' abstract. We don't add key points for this paper.

Circulating proteins may be promising biomarkers or drug targets. Leveraging genome-wide association studies of type 1 diabetes (18,942 case and 501,638 control individuals of European ancestry) and circulating protein abundances (10,708 European ancestry individuals), Mendelian randomization analyses were conducted to assess the associations between circulating abundances of 1,560 candidate proteins and the risk of type 1 diabetes, followed by multiple sensitivity and colocalization analyses, horizontal pleiotropy examinations, and replications. Bulk tissue and single-cell gene expression enrichment analyses were performed to explore candidate tissues and cell types for prioritized proteins. After validating Mendelian randomization assumptions and colocalization evidence, we found that genetically predicted circulating abundances of CTSH (odds ratio [OR] 1.17 per 1 SD increase; 95% CI 1.10–1.24), IL27RA (OR 1.13; 95% CI 1.07–1.19), SIRPG (OR 1.37; 95% CI 1.26–1.49), and PGM1 (OR 1.66; 95% CI 1.40–1.96) were associated with the risk of type 1 diabetes. These findings were consistently replicated in other cohorts. CTSH, IL27RA, and SIRPG were strongly enriched in immune system-related tissues, while PGM1 was enriched 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 may be explored as biomarkers or drug targets for type 1 diabetes. Article Highlights Identification of circulating proteins that may play a role in the pathogenesis of type 1 diabetes can provide promising targets for biomarker and drug target identification. Supported by multiple lines of evidence, circulating abundances of CTSH, IL27RA, SIRPG, and PGM1 were associated with the risk of type 1 diabetes. Tissues and cell types with enrichment of target protein-coding gene expression were identified. CTSH, IL27RA, SIRPG, and PGM1 may be explored as biomarkers or drug targets for type 1 diabetes.