Genome-Wide Aggregated Trans Effects Analysis Identifies Genes Encoding Immune Checkpoints as Core Genes for...

Area of Science:

• Genetics
• Immunology
• Rheumatology

Background:

• The sparse effector "omnigenic" hypothesis suggests complex traits are influenced by a few core genes.
• Identifying these core genes is crucial for understanding disease mechanisms.

Purpose of the Study:

• To identify core genes for rheumatoid arthritis (RA).
• To test the association of RA with genome-wide aggregated trans effects (GATE) scores for gene expression and protein levels.

Main Methods:

• Calculated GATE scores for 5,400 RA cases and 453,705 controls from UK Biobank.
• Utilized Mendelian randomization and validation through SNP association, protein levels, mouse models, and drug response.

Main Results:

• Identified 16 putative core genes for RA outside the HLA region.
• Six genes were supported by Mendelian randomization; multiple genes showed validation through various methods.
• Fourteen genes are involved in immune/inflammatory pathways; six encode immune checkpoint receptors.

Conclusions:

• The study highlights the critical role of immune checkpoints in rheumatoid arthritis.
• Identified potential therapeutic targets for RA treatment.