Leveraging genomic data to dissect the association of internalizing disorders with the risk, onset, and vulnerability of COVID-19

Abstract. Although our understanding of the COVID-19 and its infectious agent, SARS-Cov-2, is greatly improved and effective vaccines have been developed, there are many uncertainties regarding how and when the pandemic is going to end. Additionally, there are many consequences due to the pervasive impact of COVID-19 on individuals and societies that we will continue to face in the post-pandemic world. An aspect that is strongly contributing to the ongoing crisis is the systematic lack of reliable information to guide healthcare professionals and policymakers. To apply a network approach to COVID-19 research, we should prioritize the "hubs" connecting the different domains of COVID-19 consequences. Mental health is surely one of the health domains that are being more strongly affected by COVID-19 outcomes. Isolation, psychological stress, and "free-time" boredom induced by COVID-19 restrictions have been consistently associated with increased internalizing symptoms, including anxiety and depression. Additionally, traumatic experiences related to COVID-19 (e.g., severe symptoms, hospitalization, and death of a loved one) have been also linked to posttraumatic stress disorder. In a vicious circle, internalizing disorders have been associated with an increased risk of SARS-Cov-2 infection and COVID-19 severe symptoms, hospitalization, and mortality. For instance, SARS-Cov-2 infection and COVID-19 severity can be due to the effect of a weakened immune system associated with internalizing disorders. In recent years, genetic research has demonstrated to be an invaluable tool to dissect the underlying dynamics related to internalizing disorders and traits. Indeed, genetic information can be used as an anchor for causal inference to test the relationships linking human traits and diseases and to investigate the effect of genomic regulatory mechanisms on disease risk. Based on our expertise and the supporting findings generated by our studies, we propose a multivariate investigation to identify the latent factors linking the internalizing spectrum (anxiety, major depressive disorder, and posttraumatic stress disorder) and COVID-19 outcomes (infection, hospitalization, and critical illness). Then, we will investigate the regulatory mechanisms of these latent factors across multiple omics domains, tissues, and cell types. In parallel, we will also test the interaction of the internalizing spectrum with blood-based transcriptomic and epigenomic changes associated with COVID-19 morbidity and psychological stress. Our findings will provide a multi-dimensional perspective on the processes underlying the associations between COVID-19 outcomes and internalizing disorders.