Mendelian randomization analyses uncover causal relationships between brain structural connectome and risk of...

Growing evidence suggests abnormalities of brain structural connectome in psychiatric disorders, but the causal relationships remain underexplored. We conducted bidirectional two-sample Mendelian randomization (MR) analyses to investigate the causal links between 206 white-matter connectivity phenotypes (n = 26,333, UK Biobank) and 13 major psychiatric disorders (n = 14,307 to 1,222,882). Forward MR analyses identified causal effects of genetically predicted five white-matter structural connectivity phenotypes on six psychiatric disorders, with associations being significant or suggestive. For instance, structural connectivity between the left-hemisphere frontoparietal control network and right-hemisphere default mode network was significantly negatively associated with autism spectrum disorder risk, while increased structural connectivity between the right-hemisphere frontoparietal control network and hippocampus was significantly linked to decreased anorexia nervosa and cannabis use disorder risk. Reverse MR analyses revealed significantly or suggestively causal relationships between the risk of two psychiatric disorders and four different white-matter structural connectivity phenotypes. For example, the susceptibility of anorexia nervosa was found to be significantly negatively associated with structural connectivity between the left-hemisphere visual network and pallidum. These findings offer new insights into the etiology of psychiatric disorders and highlight potential biomarkers for early detection and prevention at the brain structural connectome level.