Genome-wide pathway analysis identifies oxidative stress related gene MSRA as rheumatoid arthritis susceptibility locus

Objective: Genome-wide association studies (GWASs) carried out in rheumatoid arthritis (RA) have led to the discovery of several genetic associations with this disease. Still, the current associated genetic variations can explain only part of the genetic risk involved in RA, and it is well recognised that these GWASs are likely underpowered to detect all common disease variants. Therefore, we explored the genomic regions showing low-significance associations in previous GWASs of RA. Methods: To reduce the false-positive signal fraction, we exploited pathway analysis to prioritise regions containing genes most likely to be implicated in RA. We hypothesised that true disease genes would be in a similar pathway. Therefore, genes from similar pathways but located in different regions were prioritised for replication using Prioritizer software. 384 genetic variants selected from previous RA GWASs were tested in a Spanish case/control discovery cohort comprising 376 RA patients and 478 healthy controls for replication. Statistically significant associations were further validated in replication cohorts from Spain and Netherlands, up to a total of 1,818 RA patients and 2,498 controls. Results: We detected a novel genetic association between RA and the MSRA gene (rs10903323, P = 2.91×10-5, OR = 1.51) in the Spanish combined population. This association was further tested in our independent Dutch replication cohort. Combined analysis showed an overall association of MSRA with RA (P = 2.19×10-4, OR = 1.28). Conclusion: Novel association in the MSRA gene related to oxidative stress is described herein and support a major role for this process in RA.