Genome‐wide aggregated trans‐ effects analysis identifies genes encoding immune checkpoints as core genes for rheumatoid arthritis

Objectives The sparse effector “omnigenic” hypothesis postulates that the polygenic effects of common SNPs on a typical complex trait are mediated by trans ‐ effects that coalesce on expression of a relatively sparse set of core genes. The objective of this study was to identify core genes for rheumatoid arthritis by testing for association of rheumatoid arthritis with genome‐wide aggregated trans ‐ effects (GATE) scores for expression of each gene as transcript in whole blood or as circulating protein levels. Methods GATE scores were calculated for 5400 cases and 453705 non‐cases of primary rheumatoid arthritis in UK Biobank participants of European ancestry. Results Testing for association with GATE scores identified 16 putative core genes for rheumatoid arthritis outside the HLA region, of which six – TP53BP1 , PDCD1 , TNFRSF14 , LAIR1 , LILRA4 , and IDO1 – were supported by Mendelian randomization analysis based on the marginal likelihood of the causal effect parameter. Five of these 16 genes were validated by a reported association of rheumatoid arthritis with SNPs within 200 kb of the transcription site, 8 by association of the measured protein level with rheumatoid arthritis in UK Biobank, 10 by experimental perturbation in mouse models of inflammatory arthritis, and two – CTLA4 and PDCD1 – by evidence that drugs targeting the gene cause or ameliorate inflammatory arthritis in humans. 14 of these 16 genes are in pathways affecting immunity or inflammation and six – CD5 , CTLA4 , TIGIT , LAIR1 , TNFRSF14 , PDCD1 – encode receptors that have been characterized as immune checkpoints exploited by cancer cells to escape the immune response. Conclusion These results highlight the key role of immune checkpoints in rheumatoid arthritis and identify possible therapeutic targets.