Introduction
Since the inception of coronavirus disease 2019 (COVID-19), many risk factors have been revealed, including obesity, hypertension, diabetes and smoking.1–6 Meanwhile, the neurological pathogenesis of COVID-19 remarkably threatens the mental health of affected individuals. Various COVID-19 outcomes cause an elevated risk for mental stress and mental disorders.7 8 After the acute phase of COVID-19, some patients develop lingering symptoms, such as pulmonary dysfunction, muscle exertion and mood changes that persist for months. These postrecovery symptoms are called ‘long COVID-19 syndrome’ and commonly include depression, anxiety and cognitive impairment.9–14 These psychopathological sequelae of COVID-19 are both from an improper immune response to the virus and neuroinflammation caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and augmented by disease-related psychological stressors.15 16
Major depressive disorder (MDD) is a common mood disorder that causes persistent sadness and loss of interest. Changes in various proinflammatory and anti-inflammatory cytokines are critical in the pathogenesis of MDD.17 Pre-existing depression symptoms may impact the outcomes of SARS-CoV-2 infection, which corresponds with higher rates of symptomatic disease, hospitalisation or death.18 The prolonged release of proinflammatory cytokines in COVID-19 may inhibit the activity of glucocorticoid receptors in the hippocampus and increase the levels of reactive oxygen species, resulting in the propagation of a vicious cycle between MDD and COVID-19.19
Until now, associations reported in observational studies have shown weak evidence for the causal associations between MDD and COVID-19, and the relationship between the two remains somewhat debatable. Therefore, in-depth studies are urgently needed to identify the relationship between MDD and COVID-19 and elucidate the mechanisms behind their interactions. The Mendelian randomisation (MR) method can be used to explore causal associations between traits.20–23 We tested genetic relationships between MDD and three COVID-19 outcomes (SARS-CoV-2 infection, COVID-19 hospitalisation and critical COVID-19) using genetic correlation analysis, the MR framework and literature-based network analysis.