Mendelian randomization analyses reveal causal relationships between brain functional networks and risk of psychiatric disorders

Dysfunction of brain resting-state functional networks has been widely reported in psychiatric disorders. However, the causal relationships between brain resting-state functional networks and psychiatric disorders remain largely unclear. Here we perform bidirectional two-sample Mendelian randomization (MR) analyses to investigate the causalities between 191 resting-state functional magnetic resonance imaging (rsfMRI) phenotypes (n = 34,691 individuals) and 12 psychiatric disorders (n = 14,307 to 698,672 individuals). Forward MR identified 8 rsfMRI phenotypes causally associated with the risk of psychiatric disorders. For example, the increase in the connectivity of motor, subcortical-cerebellum and limbic network was associated with lower risk of autism spectrum disorder. In adddition, increased connectivity in the default mode and central executive network was associated with lower risk of post-traumatic stress disorder and depression. Reverse MR analysis revealed significant associations between 4 psychiatric disorders and 6 rsfMRI phenotypes. For instance, the risk of attention-deficit/hyperactivity disorder increases the connectivity of the attention, salience, motor and subcortical-cerebellum network. The risk of schizophrenia mainly increases the connectivity of the default mode and central executive network and decreases the connectivity of the attention network. In summary, our findings reveal causal relationships between brain functional networks and psychiatric disorders, providing important interventional and therapeutic targets for psychiatric disorders at the brain functional network level. Mu et al. use two-sample Mendelian randomization analyses to examine the causal impact of resting-state fMRI phenotypes on 12 psychiatric disorders.