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Pleiotropy in the Genetic Predisposition to Rheumatoid Arthritis: A Phenome‐Wide Association Study and Inverse Variance–Weighted Meta‐Analysis
Author(s) -
Kawai Vivian K.,
Shi Mingjian,
Feng Qiping,
Chung Cecilia P.,
Liu Ge,
Cox Nancy J.,
Jarvik Gail P.,
Lee Ming T. M.,
Hebbring Scott J.,
Harley John B.,
Kaufman Kenneth M.,
Namjou Bahram,
Larson Eric,
Gordon Adam S.,
Roden Dan M.,
Stein C. Michael,
Mosley Jonathan D.
Publication year - 2020
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41291
Subject(s) - medicine , pleiotropy , mendelian randomization , rheumatoid arthritis , meta analysis , odds ratio , genetic predisposition , genetic association , genome wide association study , single nucleotide polymorphism , genetics , biology , phenotype , genotype , disease , genetic variants , gene
Objective This study was undertaken to investigate the hypothesis that a genetic predisposition toward rheumatoid arthritis (RA) increases the risk of 10 cardiometabolic and autoimmune disorders previously associated with RA in epidemiologic studies, and to define new genetic pleiotropy present in RA. Methods Two approaches were used to test our hypothesis. First, we constructed a weighted genetic risk score (wGRS) and then examined its association with 10 prespecified disorders. Additionally, a phenome‐wide association study (PheWAS) was carried out to identify potential new associations. Second, inverse variance–weighted regression (IVWR) meta‐analysis was used to characterize the association between genetic susceptibility to RA and the prespecified disorders, with the results expressed as odds ratios (ORs) and 95% confidence intervals (95% CIs). Results The wGRS for RA was significantly associated with type 1 diabetes mellitus (DM) (OR 1.10 [95% CI 1.04–1.16]; P = 9.82 × 10 −4 ) and multiple sclerosis (OR 0.82 [95% CI 0.77–0.88]; P = 1.73 × 10 −8 ), but not with other cardiometabolic phenotypes. In the PheWAS, wGRS was also associated with an increased risk of several autoimmune phenotypes including RA, thyroiditis, and systemic sclerosis, and with a decreased risk of demyelinating disorders. In the IVWR meta‐analyses, RA was significantly associated with an increased risk of type 1 DM ( P = 1.15 × 10 −14 ), with evidence of horizontal pleiotropy (Mendelian Randomization–Egger intercept estimate P = 0.001) likely driven by rs2476601, a PTPN22 variant. The association between type 1 DM and RA remained significant ( P = 9.53 × 10 −9 ) after excluding rs2476601, with no evidence of horizontal pleiotropy (intercept estimate P = 0.939). RA was also significantly associated with type 2 DM and C‐reactive protein levels. These associations were driven by variation in the major histocompatibility complex region. Conclusion This study presents evidence of pleiotropy between the genetic predisposition to RA and associated phenotypes found in other autoimmune and cardiometabolic disorders, including type 1 DM.