Abstract
BACKGROUND: Cerebral resting-state networks were suggested to be strongly associated with depressive disorders. However, the causal relationship between cerebral networks and depressive disorders remains controversial. In this study, we aimed to investigate the effect of resting-state networks on depressive disorders using a bidirectional Mendelian randomization (MR) design. METHODS: Updated summary-level genome-wide association study (GWAS) data correlated with resting-state networks were obtained from a meta-analysis of European-descent GWAS from the Complex Trait Genetics Lab. Depression-related GWAS data were obtained from the FinnGen study involving participants with European ancestry. Resting-state functional magnetic resonance imaging and multiband diffusion imaging of the brain were performed to measure functional and structural connectivity in seven well-known networks. Inverse-variance weighting was used as the primary estimate, whereas the MR-Pleiotropy RESidual Sum and Outliers (PRESSO), MR-Egger, and weighted median were used to detect heterogeneity, sensitivity, and pleiotropy. RESULTS: In total, 20,928 functional and 20,573 structural connectivity data as well as depression-related GWAS data from 48,847 patients and 225,483 controls were analyzed. Evidence for a causal effect of the structural limbic network on depressive disorders was found in the inverse variance-weighted limbic network (odds ratio, [Formula: see text]; 95% confidence interval, [Formula: see text]; [Formula: see text]), whereas the causal effect of depressive disorders on SC LN was not found(OR=1.0025; CI,1.0005-1.0046; P=0.012). No significant associations between functional connectivity of the resting-state networks and depressive disorders were found in this MR study. CONCLUSIONS: These results suggest that genetically determined structural connectivity of the limbic network has a causal effect on depressive disorders and may play a critical role in its neuropathology.