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

ABSTRACT Introduction Inflammatory 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. 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 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. Results We 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 (OR CD 2.58 95% CI: [2.00-3.31]; OR UC 1.54 [1.26-1.88]) and reactive arthropathies (OR CD 2.07 [1.42-2.96]; OR UC 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 (HR CD 2.56 [2.30-2.86]; HR UC 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. Conclusion Findings: 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 HIGHLIGHTS WHAT IS KNOWN IBD is strongly associated with other diseases IBD has a complex etiology WHAT IS NEW HERE IBD appears to be a multiorgan systemic disease not confined to the gut Associations 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 These findings are validated in an international comparison