<b>Integrative proteogenomic analyses provide novel interpretations of type 1 diabetes risk loci through circulating proteins</b>

• DOI: 10.2337/figshare.28127258.v1
• Publication Date: 2025-01-06T19:34:54Z
• Authors: Tianyuan Lu; Despoina Manousaki; Lei Sun; Andrew D. Paterson
• Keywords: Mendelian Randomization; Genome-wide Association Study

&lt;p dir="ltr"&gt;Circulating proteins may be promising biomarkers or drug targets. Leveraging genome-wide association studies of type 1 diabetes (18,942 cases and 501,638 controls European ancestry) circulating protein abundances (10,708 ancestry individuals), Mendelian randomization analyses were conducted to assess the associations between 1,560 candidate risk diabetes, followed by multiple sensitivity colocalization analyses, horizontal pleiotropy examinations, replications. Bulk tissue single-cell gene expression enrichment performed explore tissues cell types for prioritized proteins. After validating assumptions evidence, we found that genetically predicted CTSH (OR=1.17 per one standard deviation increase; 95% CI:1.10-1.24), IL27RA (OR=1.13; CI:1.07-1.19), SIRPG (OR=1.37; CI:1.26-1.49), PGM1 (OR=1.66; CI:1.40-1.96) associated with diabetes. These findings consistently replicated in other cohorts. &lt;i&gt;CTSH&lt;/i&gt;, &lt;i&gt;IL27RA&lt;/i&gt;, &lt;i&gt;SIRPG&lt;/i&gt; strongly enriched immune system-related tissues, while &lt;i&gt;PGM1&lt;/i&gt; was muscle liver tissues. Amongst cells, &lt;i&gt;CTSH&lt;/i&gt; B cells myeloid T natural killer cells. explored as targets diabetes.&lt;/p&gt;