Genome-wide aggregated <i>trans</i>-effects analysis for circulating proteins indicates a key role of immune checkpoints in type 1 diabetes

作者：Xuan Zhou, Andrii Iakovliev, Stuart J. McGurnaghan, Buddhiprabha Erabadda, Caroline Hayward, Paul McKeigue, Athina Spiliopoulou, Helen M Colhoun · 年份：2025 · DOI：10.2337/figshare.29561384.v1 · 研究领域：Diabetes and associated disorders、Pancreatic function and diabetes、Diet, Metabolism, and Disease

<p dir="ltr">The “omnigenic” hypothesis postulates that polygenic effects of common variants on typical complex traits coalesce via <i>trans</i>-effects on the expression of a relatively sparse set of “core” effector genes and their encoded proteins in relevant tissues. The objective of this study was to identify core proteins for type 1 diabetes. We used summary statistics for SNP associations with plasma levels of 5130 proteins in three large cohorts to compute genome-wide aggregated <i>trans</i>-effects (GATE) scores for protein levels in two type 1 diabetes case-control studies (6828 cases, 416,000 controls). GATE scores for 27 proteins were associated with type 1 diabetes. Fourteen were replicated between datasets, 11 had support in Mendelian randomisation analysis and 9 had experimental support in mouse models of autoimmune diabetes. The strongest associations were for immune checkpoints (<i>PDCD1</i>, <i>CD5</i>, <i>TIGIT</i>, <i>LAG3</i>), chemokines and innate immune system proteins (<i>NCR1</i>, <i>KLRB1</i>). Whilst <i>PDCD1</i> is a known cause of monogenic autoimmune diabetes, neither it nor most of the core proteins identified here were previously reported as GWAS hits for type 1 diabetes. These results identify possible drug targets with genetic support for causality and suggest that PD-1 agonists under development for other indications should be tr...