Shared Genetic Etiology of Autoimmune Diseases in Patients from a Biorepository Linked to De-identified Electronic Health Records.
Autoimmune diseases represent a significant medical burden affecting up to 5-8% of the U.S.


METHODS
While genetics is known to play a role, studies of common autoimmune diseases are complicated by phenotype heterogeneity, limited sample sizes, and a single disease approach. Here we performed a targeted genetic association study for cases of multiple sclerosis (MS), rheumatoid arthritis (RA), and Crohn's disease (CD) to assess which common genetic variants contribute individually and pleiotropically to disease risk. Joint modeling and pathway analysis combining the three phenotypes were performed to identify common underlying mechanisms of risk of autoimmune conditions. European American cases of MS, RA, and CD, (n= 119, 53, and 129, respectively) and 1924 controls were identified using de-identified electronic health records (EHRs) through a combination of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) billing codes, Current Procedural Terminology (CPT) codes, medication lists, and text matching. As expected, hallmark SNPs in MS, such asDQA1rs9271366 (OR = 1.91;p= 0.008), replicated in the present study. Both MS and CD were associated withTIMMDC1rs2293370 (OR = 0.27,p= 0.01; OR = 0.25,p= 0.02; respectively). Additionally,PDE2Ars3781913 was significantly associated with both CD and RA (OR = 0.46,p= 0.02; OR = 0.32,p= 0.02; respectively). Joint modeling and pathway analysis identified variants within the KEGG NOD-like receptor signaling pathway and Shigellosis pathway as being correlated with the combined autoimmune phenotype. Our study replicated previously-reported genetic associations for MS and CD in a population derived from de-identified EHRs. We found evidence to support a shared genetic etiology between CD/MS and CD/RA outside of the major histocompatibility complex region and identified KEGG pathways indicative of a bacterial pathogenesis risk for autoimmunity in a joint model. Future work to elucidate this shared etiology will be key in the development of risk models as envisioned in the era of precision medicine.
Department of Epidemiology and Biostatistics, Case Western Reserve University Cleveland, OH, USA.
Nicole A
NA
Restrepo
Department of Epidemiology and Biostatistics, Case Western Reserve University Cleveland, OH, USA.
Mariusz
M
Butkiewicz
Vanderbilt Eye Institute, Vanderbilt University Medical Center Nashville, TN, USA.
Josephine A
JA
McGrath
Department of Epidemiology and Biostatistics, Case Western Reserve UniversityCleveland, OH, USA; Institute for Computational Biology, Case Western Reserve UniversityCleveland, OH, USA.
Dana C
DC
Crawford
Crohn's disease; autoimmune disease; electronic health records; multiple sclerosis; rheumatoid arthritis