A Population-Based Multigenerational Family Coaggregation Study of Severe Infections and Obsessive-Compulsive Disorder

BACKGROUND: Postinfectious autoimmune processes have been proposed as potential causal risk factors for obsessive-compulsive disorder (OCD). In this large population-based study, we aimed to clarify the familial coaggregation pattern between severe infections and OCD across clusters of relatives with varying degrees of relatedness. METHODS: We identified 4,916,898 individuals born in Sweden between 1960 and 2008 and followed them until the end of 2020. Each individual was linked to their first-, second-, and third-degree relatives, including monozygotic and dizygotic twins, mothers, fathers, full siblings, maternal and paternal half siblings, aunts, uncles, and cousins. OCD and infection diagnoses from inpatient and specialized outpatient settings were retrieved from the Swedish National Patient Register. We compared the risk of OCD in relatives of probands with severe infections to those of probands without severe infections. Cox proportional hazard regression models, incorporating time-varying exposures, were used to estimate hazard ratios. Dose-response associations were examined using logistic regression models. RESULTS: Relatives of probands with severe infections had a higher risk of OCD, which increased with genetic relatedness, with hazard ratios (95% CI) ranging from 1.46 (1.07-1.98) in monozygotic twins to 1.10 (1.09-1.11) in cousins. The results remained robust after adjusting for severe infections among relatives, OCD in probands, and comorbid autoimmune disorders in both probands and relatives. A dose-response association was observed between the number of infections in the probands and their odds of OCD, as well as in their relatives. CONCLUSIONS: The results strongly suggest that the association between severe infections and OCD may be largely driven by shared genetic factors.