Pleiotropy in the Genetic Predisposition to Rheumatoid Arthritis ‐ a phenome‐wide association study and inverse‐variance weighted meta‐analysis

OBJECTIVE: To examine the hypothesis that a genetic predisposition toward rheumatoid arthritis (RA) increases the risk for 10 cardiometabolic and autoimmune disorders previously associated with RA in epidemiological studies and to define new genetic pleiotropy. METHODS: We tested the hypothesis using two approaches. First, we constructed a weighted genetic risk score (wGRS) and studied its association with the 10 prespecified disorders; additionally, we performed a phenome-wide study (PheWAS) to identify potential new associations. Second, we used inverse variance weighted regression (IVWR) meta-analysis to characterize the association between genetic susceptibility to RA and the prespecified disorders. RESULTS: The wGRS for RA was significantly associated with type I diabetes (T1D) (OR 1.10 [95% CI 1.04-1.16], P=9.82x10(-4) ) and multiple sclerosis (OR 0.82 [0.77-0.88], P=1.73x10(-8) ), but not with other cardiometabolic phenotypes. In the PheWAS, the wGRS was additionally associated with increased risk of several autoimmune phenotypes including RA, thyroiditis, and systemic sclerosis, and with decreased risk of demyelinating disorders. In the IVWR meta-analyses, RA was significantly associated with T1D (P=1.15x10(-14) ) with evidence of horizontal pleiotropy (MR-Egger intercept estimate P=0.001) likely driven by rs2476601, a PTPN22 variant. The association between T1D and RA remained significant (P=9.53x10(-9) ) after excluding rs2476601 with no evidence of horizontal pleiotropy (intercept estimate P=0.939). RA was also significantly associated with type 2 diabetes and C-reactive protein; these associations were driven by variation in the major histocompatibility complex (MHC). CONCLUSION: We found evidence suggesting pleiotropy between the genetic predisposition for RA and other autoimmune disorders including T1D.