The Association between Endometriosis and Immunological diseases

The evidence for a greater prevalence of immunological diseases among endometriosis patients has varied in robustness and been subject to selection bias. We investigated the phenotypic and genetic association between endometriosis and 31 immunological diseases in the UK Biobank (8,223 endometriosis, 64,620 immunological disease cases). In cross-sectional and retrospective cohort analyses, endometriosis patients were at significantly increased (30-80%) risk of classical-autoimmune (rheumatoid arthritis, multiple sclerosis, coeliac disease), autoinflammatory (osteoarthritis) and mixed-pattern (psoriasis) diseases. Osteoarthritis (genetic-correlation (rg)=0.28, P=3.25x10-15), rheumatoid arthritis (rg=0.27, P=1.54x10-5) and multiple sclerosis (rg=0.09, P=4.00x10-3) were significantly genetically correlated with endometriosis. Mendelian randomisation analysis suggested a causal association between endometriosis and rheumatoid arthritis (OR=1.16, 95%CI=1.02-1.33). Expression QTL analyses highlighted effector genes enriched for seven pathways across all four conditions, with three genetic loci shared between endometriosis and osteoarthritis and one with rheumatoid arthritis. Although the increased risk of immunological diseases among endometriosis patients is modest, their shared genetic basis opens-up opportunities for new treatments. ### Competing Interest Statement K.T.Z. and C.M.B. reported grants in three years prior, outside the submitted work, from Bayer AG, AbbVie Inc, Volition Rx, MDNA Life Sciences, PrecisionLife Ltd, Roche Diagnostics Inc. S.A.M. reports grants in the three years prior, outside this submitted work, from AbbVie Inc. N.R. is a consultant for Endogene.bio. ### Funding Statement We thank all the UK Biobank and 23andMe participants. Part of this research was conducted using the UK Biobank Resource under Application Number 9637. N.R. was supported by a grant from Wellbeing of Women UK (RG2031) and the EU Horizon 2020 funded project FEMaLe (101017562). A.P.M. was supported in part by Versus Arthritis (grant 21754). H.F. was supported by National Natural Science Foundation of China (grant 32170663). N.R., S.A.M and K.T.Z. were supported in part by a grant from CDMRP DoD PRMRP (W81XWH-20-PRMRP-IIRA). S.A.M. and K.T.Z. gratefully acknowledge funding provided by the Nezhat Family Foundation on behalf of Worldwide EndoMarch to their research programmes. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Data from UK biobank was utilised (Application Number 9637) and publicly available GWAS summary statistics for immunological conditions. The UK Biobank was approved by the North West Multi-Centre Research Ethics Committee (MREC). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The GWAS meta-analyses for immunological conditions made use of data from the UK Biobank (Application Number 9637) and publicly available GWAS summary statistics for immunological conditions. GWAS data for endometriosis was based on the latest analyses of International Endogene Consortium: summary statistics excluding 23andMe data is available from EBI GWAS Catalog Study Accession GCST90205183; endometriosis GWAS summary statistics from 23andMe, Inc. were made available under a data use agreement that protects participant privacy. Please contact dataset-request@23andme. com or visit research.23andMe.com/collaborate for more information and to apply to access the data.