Causal association of COVID-19 with brain structure changes: Findings from a non-overlapping 2-sample Mendelian randomization study

Recent cohort studies suggested that SARS-CoV-2 infection is associated with changes in brain structure. However, the potential causal relationship remains unclear. We performed a two-sample Mendelian randomization analysis to determine whether genetic susceptibility of COVID-19 is causally associated with changes in cortical and subcortical areas of the brain. This 2-sample MR (Mendelian Randomization) study is an instrumental variable analysis of data from the COVID-19 Host Genetics Initiative (HGI) meta-analyses round 5 excluding UK Biobank participants (COVID-19 infection, N = 1,348,701; COVID-19 severity, N = 1,557,411), the Enhancing NeuroImaging Genetics through Meta Analysis (ENIGMA) Global and regional cortical measures, N = 33,709; combined hemispheric subcortical volumes, N = 38,851), and UK Biobank (left/right subcortical volumes, N = 19,629). A replication analysis was performed on summary statistics from different COVID-19 GWAS study (COVID-19 infection, N = 80,932; COVID-19 severity, N = 72,733). We found that the genetic susceptibility of COVID-19 was not significantly associated with changes in brain structures, including cortical and subcortical brain structure. Similar results were observed for different (1) MR estimates, (2) COVID-19 GWAS summary statistics, and (3) definitions of COVID-19 infection and severity. This study suggests that the genetic susceptibility of COVID-19 is not causally associated with changes in cortical and subcortical brain structure.