10-years disease trajectories and genetic insights into long COVID susceptibility

Background Long COVID refers to the persistence of symptoms after SARS-CoV-2 infection. While individual comorbidities have been studied, the role of coexisting chronic conditions remains underexplored. This study investigates whether pre-pandemic disease trajectories—sequential patterns of chronic conditions—affect long COVID risk and symptom profiles, and explores shared genetic susceptibility. Methods We analysed 8,322 participants (58.6% women) from the COVICAT, followed between 2021 and 2023. Disease trajectories were reconstructed from electronic health records (2010–2019), focusing on sequences of two chronic conditions found in ≥ 1% of the cohort. We evaluated shared genetic architecture and polygenic risk scores (PRS) for predictive capacity. Results Thirty-eight disease trajectories were associated with increased long COVID risk. These trajectories primarily involved mental and neurological disorders (e.g., depression, anxiety, migraine), respiratory diseases (e.g., asthma, allergic rhinitis), and cardiometabolic or digestive conditions (e.g., hypertension, lipidaemia, obesity, gastroesophageal reflux). No significant genetic correlations with long COVID were detected, but polygenic risk scores for two nervous system and musculoskeletal conditions showed modest associations with increased risk. Conclusions Disease trajectories were significantly associated with long COVID, highlighting the importance of multimorbidity and the temporal sequence of conditions. While no strong overall genetic correlations were found, modest polygenic associations suggest a role for shared susceptibility in nervous system and musculoskeletal disorders. From a public health perspective, identifying high-risk multimorbid individuals may inform targeted prevention and care strategies.