Psychiatric genetic liability is associated with the severity of COVID-19 and other acute respiratory infections: an observational study across five Northern European countries

Abstract Background Pre-existing psychiatric disorders have been associated with the severity of acute respiratory infections, including COVID-19, particularly in hospitalized populations. However, the underlying mechanisms, especially in community-based populations, remain unknown, limiting preparedness for future pandemics. We investigated the role of genetic liability for psychiatric disorders and related traits in COVID-19 and other respiratory infection severity among individuals reporting SARS-CoV-2 testing and available respiratory symptom data. Methods We included population-based cohort data from Denmark, Estonia, Iceland, Norway, and the United Kingdom (N = 78,507; 62% female; 41% SARS-CoV-2-positive; May 2020—March 2023). Respiratory infection severity was defined by self-reported days bedridden and an eleven-symptom composite score during the acute illness phase. Polygenic scores (PGSs) for eight psychiatric disorders and the personality trait neuroticism indexed genetic liability. Meta-analysed estimates from stepwise-adjusted regression analyses controlling for education, lifestyle, and psychiatric and somatic diagnosis history were used to assess associations between PGSs and acute respiratory infection severity, stratified by COVID-19 status. Results Higher genetic liability to insomnia, major depression (MD), and neuroticism was consistently associated with longer time bedridden (relative risk ratios per 1 SD change in PGS: 1.07–1.14, 95% confidence intervals [CIs]: 1.03–1.21) and more symptoms (incident rate ratios [IRRs]: 1.02–1.04, 95% CIs: 1.01–1.05) due to COVID-19. PGSs for insomnia, MD, neuroticism, anxiety disorder, bipolar disorder, and schizophrenia were also linked to higher non-COVID-19 symptom count (IRRs: 1.01–1.05, 95% CIs: 1.00–1.07). These associations remained robust after adjustment for lifestyle, education and medical comorbidities. Individuals in the highest MD PGS decile reported 20% more symptoms in non-COVID-19 illness and 10% more in COVID-19 compared with the bottom decile. No consistent associations were detected with attention-deficit/hyperactivity disorder, alcohol dependence and post-traumatic stress disorder. No genetic link was observed with ischaemic heart disease or type 2 diabetes. Conclusions Shared genetics may contribute to the link between psychiatric conditions and respiratory infection severity in community settings. Our results underscore the role of psychiatric genetic liability, beyond diagnosed psychiatric disorders, in contributing to both COVID-19 and other respiratory infection severity. These findings provide insights that may improve future risk stratification and public health strategies targeting respiratory viruses.