Phenome-wide examination of comorbidity burden and multiple sclerosis disease severity

OBJECTIVE: We assessed the comorbidity burden associated with multiple sclerosis (MS) severity by performing a phenome-wide association study (PheWAS). METHODS: We conducted a PheWAS in 2 independent cohorts: a discovery (Boston, United States; 1993–2014) and extension cohort (British Columbia, Canada; 1991–2008). We included adults with MS, ≥1 Expanded Disability Status Scale (EDSS) score, and ≥1 International Classification of Diseases (ICD) code other than MS. We calculated the Multiple Sclerosis Severity Score (MSSS) using the EDSS. We mapped ICD codes into PheCodes (phenotypes), using a published system with each PheCode representing a unique medical condition. Association between the MSSS and the presence of each condition was assessed using logistic regression adjusted for covariates. RESULTS: The discovery and extension cohorts included 3,439 and 4,876 participants, respectively. After Bonferroni correction and covariate adjustments, a higher MSSS was associated with 37 coexisting conditions in the discovery cohort. Subsequently, 16 conditions, including genitourinary, infectious, metabolic, epilepsy, and movement disorders, met the reporting criteria, reaching the Bonferroni threshold of significance with the same direction of effect in the discovery and extension cohort. Notably, benign neoplasm of the skin was inversely associated with the MSSS. CONCLUSION: The phenome-wide approach enabled a systematic interrogation of the comorbidity burden and highlighted clinically relevant medical conditions associated with MS severity (beyond MS-specific consequences) and defines a roadmap for comprehensive investigation of comorbidities in chronic neurologic diseases. Further prospective investigation of the bidirectional relationship between disability and comorbidities could inform the individualized patient management.