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

IntroductionInflammatory bowel disease (IBD) is associated with various extra-intestinal manifestations. We aim to identify comorbidities in IBD and the timing of their development to provide valuable insight into the mechanisms under-lying IBD. MethodsWe 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 association in the pre-diagnostic and the post-diagnostic periods. We corrected also for multiple-testing. These estimates were validated with publically available data from Finland. ResultsWe identified 312 significant associations with 125 appearing before diagnosis. Risk of immune-mediated diseases and extra-intestinal manifestations was increased up to 10 years prior to IBD diagnosis, such as psoriasis (ORCD: 2.58 95% CI: [2.00-3.31]; ORUC: 1.54 [1.26-1.88]) and reactive arthropathies (ORCD: 2.07 [1.42-2.96]; ORUC: 1.42 [1.08-1.84]). Risk of cardiometabolic and neuropsychological disorders was increased both pre- and post-diagnostically. Potential treatment sequelae, such as osteoporosis (HRCD: 2.56 [2.30-2.86]; HRUC: 1.92 [1.79-2.07]) were primarily seen post-diagnostically. In only 15.7% (44/281) and 11.4% (35/301) of comorbidities in CD and UC respectively did we observe heterogeneity between Denmark and Finland. ConclusionFindings demonstrate that IBD is a multisystemic disease, particularly manifesting with metabolic, im-mune, and neuropsychological disorders, up-to 10 years prior to diagnosis. We find evidence for the generality of these findings with an international comparison. Diseases of etiological interest warrant further investigation. STUDY HIGHLIGHTSO_ST_ABSWHAT IS KNOWNC_ST_ABSO_LIIBD is strongly associated with other diseases C_LIO_LIIBD has a complex etiology C_LI WHAT IS NEW HEREO_LIIBD appears to be a multiorgan systemic disease not confined to the gut C_LIO_LIAssociations between IBD and non-digestive disorders are present up to 10 years prior to diagnosis either reflecting a prolonged pre-diagnostic phase or common etiologies C_LIO_LIThese findings are validated in an international comparison C_LI