Mendelian Randomization Analyses Accounting for Causal Effect of COVID-19 on Brain Imaging-Derived Phenotypes

The coronavirus disease 2019 (COVID-19) has been a major challenge to global health and a financial burden. Little is known regarding the possible causal effects of COVID-19 on the macro- and micro-structures of the human brain. To determine the causal links between susceptibility, hospitalization, and the severity of COVID-19 and brain imaging-derived phenotypes (IDPs). Mendelian randomization (MR) analyses were performed to investigate the causal effect of three COVID-19 exposures (SARS-CoV-2 infection, hospitalized COVID-19, and critical COVID-19) on brain structure employing summary datasets of genome-wide association studies. In terms of cortical phenotypes, hospitalization due to COVID-19 was associated with a global decrease in the surface area (SA) of the cortex structure (β= -624.77, 95% CI: -1227.88 to -21.66, p = 0.042). At the regional level, SARS-CoV-2 infection was found to have a nominally causal effect on the thickness (TH) of the postcentral region (β= -0.004, 95% CI: -0.007 to -0.001, p = 0.01), as well as eight other IDPs. Hospitalized COVID-19 has a nominally causal relationship with TH of postcentral (β= -0.004, 95% CI: -0.007 to -0.001, p = 0.01) and other 6 IDPs. The nominally causal effects of critical COVID-19 on TH of medial orbitofrontal (β=0.004, 95% CI: 0.001to 0.007, p = 0.004) and other 7 IDPs were revealed. Our study provides compelling genetic evidence supporting causal relationships between three COVID-19 traits and brain IDPs. This discovery holds promise for enhancing predictions and interventions in brain imaging.