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

The "omnigenic" hypothesis postulates that polygenic effects of common variants on typical complex traits coalesce via trans 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 single nucleotide polymorphism associations with plasma levels of 5,130 proteins in three large cohorts, including the UK Biobank, to compute genome-wide aggregated trans effects (GATE) scores for protein levels in two type 1 diabetes case-control studies (6,828 case individuals, 416,000 control individuals). GATE scores for 27 proteins were associated with type 1 diabetes. Of these, 14 were replicated between data sets, 11 had support in Mendelian randomization analysis, and 9 had experimental support in mouse models of autoimmune diabetes. The strongest associations were for immune checkpoints (PDCD1, CD5, TIGIT, and LAG3), chemokines, and innate immune system proteins (NCR1 and KLRB1). While PDCD1 is a known cause of monogenic autoimmune diabetes, neither it nor most of the core proteins identified here were previously reported as genome-wide association study hits for type 1 diabetes. These results identify possible drug targets with genetic support for causality and suggest that programmed cell death protein 1 agonists under development for other indications should be trialed for type 1 diabetes prevention.

Demonstrating genetic evidence for a role of a protein in disease gives important support for its potential as a drug target. We aimed to identify proteins that have genetic evidence to support a causal role in the pathogenesis of type 1 diabetes. We found 27 core proteins had genetic evidence of causality for type 1 diabetes. Top hits included immune checkpoints (PDCD1, CD5, TIGIT, and LAG3) and innate immune system proteins (NCR1 and KLRB1). These results identify possible drug targets and suggest that programmed cell death protein 1 agonists should be trialed for type 1 diabetes prevention.