PMID- 37121095 OWN - NLM STAT- MEDLINE DCOM- 20230619 LR - 20240328 IS - 2352-3964 (Electronic) IS - 2352-3964 (Linking) VI - 92 DP - 2023 Jun TI - Identifying shared genetic architecture between rheumatoid arthritis and other conditions: a phenome-wide association study with genetic risk scores. PG - 104581 LID - S2352-3964(23)00146-9 [pii] LID - 10.1016/j.ebiom.2023.104581 [doi] LID - 104581 AB - BACKGROUND: Rheumatoid arthritis (RA) shares genetic variants with other autoimmune conditions, but existing studies test the association between RA variants with a pre-defined set of phenotypes. The objective of this study was to perform a large-scale, systemic screen to determine phenotypes that share genetic architecture with RA to inform our understanding of shared pathways. METHODS: In the UK Biobank (UKB), we constructed RA genetic risk scores (GRS) incorporating human leukocyte antigen (HLA) and non-HLA risk alleles. Phenotypes were defined using groupings of International Classification of Diseases (ICD) codes. Patients with an RA code were excluded to mitigate the possibility of associations being driven by the diagnosis or management of RA. We performed a phenome-wide association study, testing the association between the RA GRS with phenotypes using multivariate generalized estimating equations that adjusted for age, sex, and first five principal components. Statistical significance was defined using Bonferroni correction. Results were replicated in an independent cohort and replicated phenotypes were validated using medical record review of patients. FINDINGS: We studied n = 316,166 subjects from UKB without evidence of RA and screened for association between the RA GRS and n = 1317 phenotypes. In the UKB, 20 phenotypes were significantly associated with the RA GRS, of which 13 (65%) were immune mediated conditions including polymyalgia rheumatica, granulomatosis with polyangiitis (GPA), type 1 diabetes, and multiple sclerosis. We further identified a novel association in Celiac disease where the HLA and non-HLA alleles had strong associations in opposite directions. Strikingly, we observed that the non-HLA GRS was exclusively associated with greater risk of the validated conditions, suggesting shared underlying pathways outside the HLA region. INTERPRETATION: This study replicated and identified novel autoimmune phenotypes verified by medical record review that share immune pathways with RA and may inform opportunities for shared treatment targets, as well as risk assessment for conditions with a paucity of genomic data, such as GPA. FUNDING: This research was funded by the US National Institutes of Health (P30AR072577, R21AR078339, R35GM142879, T32AR007530) and the Harold and DuVal Bowen Fund. CI - Copyright (c) 2023 The Author(s). Published by Elsevier B.V. All rights reserved. FAU - Zhang, Harrison G AU - Zhang HG AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. FAU - McDermott, Greg AU - McDermott G AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. FAU - Seyok, Thany AU - Seyok T AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. FAU - Huang, Sicong AU - Huang S AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. FAU - Dahal, Kumar AU - Dahal K AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. FAU - L'Yi, Sehi AU - L'Yi S AD - Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. FAU - Lea-Bonzel, Clara AU - Lea-Bonzel C AD - Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. FAU - Stratton, Jacklyn AU - Stratton J AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. FAU - Weisenfeld, Dana AU - Weisenfeld D AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. FAU - Monach, Paul AU - Monach P AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; VA Boston Healthcare System, Boston, MA, USA. FAU - Raychaudhuri, Soumya AU - Raychaudhuri S AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; Center for Data Science, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA. FAU - Yu, Kun-Hsing AU - Yu KH AD - Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. FAU - Cai, Tianrun AU - Cai T AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. FAU - Cui, Jing AU - Cui J AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. FAU - Hong, Chuan AU - Hong C AD - Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA. FAU - Cai, Tianxi AU - Cai T AD - Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; VA Boston Healthcare System, Boston, MA, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. FAU - Liao, Katherine P AU - Liao KP AD - Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA; VA Boston Healthcare System, Boston, MA, USA. Electronic address: kliao@bwh.harvard.edu. LA - eng GR - R35 GM142879/GM/NIGMS NIH HHS/United States GR - T32 AR007530/AR/NIAMS NIH HHS/United States GR - UC2 AR081023/AR/NIAMS NIH HHS/United States GR - UH2 AR067677/AR/NIAMS NIH HHS/United States PT - Journal Article DEP - 20230428 PL - Netherlands TA - EBioMedicine JT - EBioMedicine JID - 101647039 RN - 0 (HLA Antigens) RN - 0 (Histocompatibility Antigens Class II) RN - 0 (HLA-DRB1 Chains) SB - IM MH - Humans MH - *Genetic Predisposition to Disease MH - Genotype MH - *Arthritis, Rheumatoid/diagnosis/genetics MH - Risk Factors MH - Phenotype MH - HLA Antigens/genetics MH - Histocompatibility Antigens Class II/genetics MH - HLA-DRB1 Chains/genetics MH - Alleles PMC - PMC10173154 OTO - NOTNLM OT - Genetic architecture OT - Genetic risk scores OT - Phenome-wide association study OT - Rheumatoid arthritis OT - Risk calibration OT - Vasculitis COIS- Declaration of interests SR is a founder of Mestag, a scientific advisor for Rheos Medicines, serves on the advisory boards for Janssen and Pfizer, and is a consultant for Sanofi. The remaining authors have no declarations of interests. EDAT- 2023/05/01 00:41 MHDA- 2023/06/19 13:09 PMCR- 2023/04/28 CRDT- 2023/04/30 18:08 PHST- 2022/10/08 00:00 [received] PHST- 2023/03/19 00:00 [revised] PHST- 2023/04/05 00:00 [accepted] PHST- 2023/06/19 13:09 [medline] PHST- 2023/05/01 00:41 [pubmed] PHST- 2023/04/30 18:08 [entrez] PHST- 2023/04/28 00:00 [pmc-release] AID - S2352-3964(23)00146-9 [pii] AID - 104581 [pii] AID - 10.1016/j.ebiom.2023.104581 [doi] PST - ppublish SO - EBioMedicine. 2023 Jun;92:104581. doi: 10.1016/j.ebiom.2023.104581. Epub 2023 Apr 28.