The role of genetic liability for psychiatric disorders and personality traits in post covid syndrome: data from three Nordic population cohorts

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Background: Post-COVID syndrome (PCS) remains a substantial public health concern, yet its genetic determinants are poorly understood. Psychiatric disorders and related traits influence infection risk and acute COVID-19 outcomes, raising the possibility that shared genetic liability may also shape long-term symptom persistence. We examined whether polygenic scores (PGS) for schizophrenia (SCZ), bipolar disorder (BPD), major depressive disorder (MDD), attention-deficit/hyperactivity disorder (ADHD), and neuroticism are associated with PCS, and explored potential pathways underlying these associations. Methods: We analysed three population-based cohorts from Denmark, Norway and Iceland (total n = 80,726; PCS cases = 6103) between March 2020 and June 2022. PCS was defined as COVID-19-related symptoms lasting ≥3 months. Logistic regression models estimated associations between standardised PGS and PCS among COVID-19 positive individuals, adjusting for ancestry principal components. Additional analyses assessed associations with COVID-19 infection. In a subset with available personality data, models were additionally adjusted for measured Neuroticism (NEO-FFI). Supplementary analyses examined associations between PGS and COVID-19 infection risk, and we conducted LD score regression (LDSC) and proteomic analyses as contextual genetic and biological characterisations of the PGS traits. Findings: Higher PGS for neuroticism, MDD and ADHD were consistently associated with increased odds of PCS across all cohorts (ORs per SD: ∼1.07-1.16). Quintile analyses showed a graded pattern, with the highest PGS quintile displaying 30-45% higher odds of PCS than the lowest. PGS for SCZ and BPD showed no evidence of association with PCS. PGS associations with COVID-19 infection were weaker and inconsistent. In the subset with available personality data, these associations remained essentially unchanged after adjusting for measured Neuroticism, indicating that they are not solely attributable to observed personality differences. LDSC and proteomic analyses did not alter the primary interpretation of the PGS-PCS associations. Interpretation: Polygenic liability for neuroticism, MDD, and ADHD is associated with increased risk of PCS across three national cohorts. This pattern is consistent with shared symptom-related liability contributing to these associations, although the data do not allow differentiation between post-viral sequelae and pre-existing symptom liability. While PGS explain only a modest proportion of PCS variance, they provide useful insight into underlying psychiatric and personality-related factors associated with persistent symptom reporting following COVID-19 infection. Funding: The study was funded by EU Horizon REACT study (101057129), environMENTAL study (101057429), Nordforsk (project numbers 105668 and 138929), and the Independent Research Fund Denmark (0214-00127B).

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