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present in RA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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\u2010wide association study (PheWAS) was carried out to identify potential new associations. Second, inverse variance\u2013weighted regression (IVWR) meta\u2010analysis 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).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The wGRS for RA was significantly associated with type 1 diabetes mellitus (DM) (OR 1.10 [95% CI 1.04\u20131.16]; <jats:italic>P<\/jats:italic> = 9.82 \u00d7 10<jats:sup>\u22124<\/jats:sup>) and multiple sclerosis (OR 0.82 [95% CI 0.77\u20130.88]; <jats:italic>P<\/jats:italic> = 1.73 \u00d7 10<jats:sup>\u22128<\/jats:sup>), 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\u2010analyses, RA was significantly associated with an increased risk of type 1 DM (<jats:italic>P<\/jats:italic> = 1.15 \u00d7 10<jats:sup>\u221214<\/jats:sup>), with evidence of horizontal pleiotropy (Mendelian Randomization\u2013Egger intercept estimate <jats:italic>P<\/jats:italic> = 0.001) likely driven by rs2476601, a <jats:italic>PTPN22<\/jats:italic> variant. The association between type 1 DM and RA remained significant (<jats:italic>P<\/jats:italic> = 9.53 \u00d7 10<jats:sup>\u22129<\/jats:sup>) after excluding rs2476601, with no evidence of horizontal pleiotropy (intercept estimate <jats:italic>P<\/jats:italic> = 0.939). RA was also significantly associated with type 2 DM and C\u2010reactive protein levels. These associations were driven by variation in the major histocompatibility complex region.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41291","type":"journal-article","created":{"date-parts":[[2020,4,20]],"date-time":"2020-04-20T03:34:07Z","timestamp":1587353647000},"page":"1483-1492","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Pleiotropy in the Genetic Predisposition to Rheumatoid Arthritis: A Phenome\u2010Wide Association Study and Inverse Variance\u2013Weighted Meta\u2010Analysis"],"prefix":"10.1002","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5841-2575","authenticated-orcid":false,"given":"Vivian K.","family":"Kawai","sequence":"first","affiliation":[{"name":"Vanderbilt University Medical Center  Nashville Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjian","family":"Shi","sequence":"additional","affiliation":[{"name":"Vanderbilt University School of Medicine  Nashville Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiping","family":"Feng","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center  Nashville Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5908-9423","authenticated-orcid":false,"given":"Cecilia P.","family":"Chung","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center, Tennessee Valley Healthcare System Nashville Campus, and Vanderbilt University School of Medicine  Nashville Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge","family":"Liu","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center  Nashville Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy J.","family":"Cox","sequence":"additional","affiliation":[{"name":"Vanderbilt University Medical Center and Vanderbilt University School of Medicine  Nashville Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gail P.","family":"Jarvik","sequence":"additional","affiliation":[{"name":"University of Washington  Seattle"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming T. 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