Inflammatory bowel disease and risk of more than 1500 comorbidities: A disease-wide pre- and post-diagnostic phenomic association study

Background & Aims Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is associated with various extra-intestinal manifestations. Identifying comorbidities in IBD and the timing of their development provides valuable insight into mechanisms underlying IBD. Methods We conducted a population- and disease-wide phenomic association study in IBD, using >6 million ICD-10 coded healthcare contacts from 10 years before and up-to 17 years after IBD diagnosis to investigate associations with 1583 comorbidities. To explore diseases with potential aetiological significance, we compared strength of association with co-morbidities in the pre-diagnostic with the post-diagnostic period. To correct for multiple testing, we adjust the significance threshold with the Bonferroni correction (p-value < 7.90 × 10−6). Results We identified 312 statistically significant associations with 125 of these appearing before diagnosis. Risk of immune-mediated diseases and extra-intestinal manifestations is increased up to 10 years prior to IBD diagnosis (e.g., enteropathic arthropathies: RRCD: 3.57, 95% CI: 2.65-4.78; RRUC: 1.8, 95% CI: 1.38-2.32). As with hepatic and pancreatic disorders (e.g., acute pancreatitis: RRCD: 1.83, 95% CI: 1.30-2.53; RRUC: 2.27, 95% CI: 1.84-2.79). Risk of cardiometabolic diseases and neuropsychological disorders was increased both pre- and post-diagnostically. Potential sequelae of treatment, such as osteoporosis (HRCD: 2.56, 95% CI: 2.30-2.86; HRUC: 1.92, 95% CI: 1.79-2.07) were primarily seen post-diagnostically. Infectious mononucleosis (RR: 1.87, 95% CI: 1.37-2.52) was significantly associated with the pre-compared to the post-diagnostic period for CD. Conclusion Findings demonstrate that IBD is a multisystemic disease, particularly manifesting with metabolic, immune, and neuropsychological disorders, up-to 10 years prior to diagnosis. Diseases of aetiological interest identified warrant further investigation. ### Competing Interest Statement AE, GP, MB and RE report no competing interests. BV reports research support from AbbVie, Biora Therapeutics, Landos, Pfizer, Sossei Heptares and Takeda; speaker fees from Abbvie, Biogen, Bristol Myers Squibb, Celltrion, Chiesi, Falk, Ferring, Galapagos, Janssen, MSD, Pfizer, R-Biopharm, Takeda, Truvion and Viatris; consultancy fees from Abbvie, Alimentiv, Applied Strategic, Atheneum, Biora Therapeutics, Bristol Myers Squibb, Galapagos, Guidepont, Landos, Mylan, Inotrem, Ipsos, Janssen, Pfizer, Progenity, Sandoz, Sosei Heptares, Takeda, Tillots Pharma and Viatris. CWL has acted as a consultant to Abbvie, Janssen, Takeda, Pfizer, Galapagos, Bristol Myers Squibb, B.I., Sandoz, Novartis, GSK, Gilead, ViforPharma, Dr Falk, Trellus Health and Iterative Scopes; he has received speaking fees and travel support from Pfizer, Janssen, Abbvie, Galapagos, MSD, Takeda, Shire, Ferring, Hospira and Dr Falk. TJ reports consultancy fee from Ferring Pharmaceuticals. ### Funding Statement ACE, GP, MB, RE, and TJ are supported by the Danish National Research Foundation (DNRF148). BV is supported by the Clinical Research Fund (KOOR) at the University Hospitals Leuven and the Research Council at the KU Leuven. RE is supported by the Novo Nordisk Foundation (NNF21OC0068631). CWL is funded by a UKRI (UK research and Innovation) Future Leaders Fellowship "Predicting outcomes in IBD" (MR/S034919/1). ### 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: The study was register-based and followed the regulations set up by the Danish Data Protection Agency and the Danish Health Data Authority (FSEID-00006013). Ethical approval is not required for registry-based research in Denmark. 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 study was based on data from the Danish National Health registers (). The register data are protected by the Danish Act on Processing of Personal Data and are accessed through application to and approval from the Danish Data Protection Agency and the Danish Health Data Authority.