Genome-Wide Aggregated Trans Effects Analysis for Circulating Proteins Indicates a Key Role of Immune Checkpoints in...

Area of Science:

• Genetics
• Immunology
• Pharmacology

Background:

• The omnigenic hypothesis suggests complex traits arise from polygenic effects on core effector genes.
• Identifying causal proteins is crucial for understanding type 1 diabetes pathogenesis and developing targeted therapies.

Purpose of the Study:

• To identify core proteins with genetic evidence supporting a causal role in type 1 diabetes.
• To explore potential new drug targets for type 1 diabetes.

Main Methods:

• Utilized summary statistics from large cohorts (UK Biobank) to compute genome-wide aggregated trans effects (GATE) scores for 5,130 proteins.
• Analyzed GATE scores in two type 1 diabetes case-control studies to identify associated proteins.
• Validated findings using replication across datasets, Mendelian randomization, and mouse models.

Main Results:

• Identified 27 proteins with genetic evidence for causality in type 1 diabetes.
• Strongest associations were observed for immune checkpoints (PDCD1, CD5, TIGIT, LAG3) and innate immune proteins (NCR1, KLRB1).
• Nine identified proteins had experimental support in mouse models of autoimmune diabetes.

Conclusions:

• The study identifies novel, genetically supported drug targets for type 1 diabetes.
• Suggests programmed cell death protein 1 (PDCD1) agonists as a potential therapeutic strategy for type 1 diabetes prevention.