Causal Impacts of Psychiatric Disorders on Cognition and the Mediating Effect of Oxidative Stress: A Mendelian Randomization Study

Many psychiatric disorders are associated with major cognitive deficits. However, it is uncertain whether these deficits develop as a result of psychiatric disorders and what shared risk factors might mediate this relationship. Here, we utilized the Mendelian randomization (MR) analysis to investigate the complex causal relationship between nine major psychiatric disorders and three cognitive phenotypes, while also examining the potential mediating role of oxidative stress as a shared biological underpinning. Schizophrenia (SZ), major depressive disorder (MDD), and attention deficit hyperactivity disorder (ADHD) showed a decreasing effect on cognitive performance, intelligence, and education, while bipolar disorder (BPD) increased educational attainment. MR-Clust results exhibit the shared genetic basis between SZ and other psychiatric disorders in relation to cognitive function. Furthermore, when oxidative stress was considered as a potential mediating factor, the associations between SZ and the three dimensions of cognition, as well as between MDD and intelligence and ADHD and intelligence, exhibited larger effect sizes than the overall. Mediation MR analysis also supported the causal effects between psychiatric disorders and cognition via oxidative stress traits, including carotene, vitamin E, bilirubin, and uric acid. Finally, summary-based MR identified 29 potential causal associations of oxidative stress genes with both cognitive performance and psychiatric disorders. Our findings highlight the importance of considering oxidative stress in understanding and potentially treating cognitive impairments associated with psychiatric conditions.