Impact of post-traumatic stress disorder on brain structural connectivity: A bidirectional Mendelian randomization study with meta-analysis

Post-traumatic stress disorder (PTSD) has a tremendous impact on health and well-being, yet the bidirectional effects between it and structural connectivity (SC) of brain networks remain unexplored. Using SC data of European populations in the UK Biobank and PTSD genome-wide association study (GWAS) datasets from FINNGEN, UK Biobank, PGC, and Neale lab, we performed bidirectional MR analysis using the inverse variance weighted (IVW) method as the primary approach, supplemented by other methods for validation. We used the MR Egger intercept and Cochrane's Q test for pleiotropy and heterogeneity analysis. We defined positive findings as phenotypes that satisfied all MR assumptions and demonstrated statistical significance (P < 0.05) in the meta-analysis. Of the 206 SC analyzed, five showed nominally significant forward associations with PTSD: left limbic network (L-LN) to right dorsal attention network (R-DAN), left visual network (L-VN) to the left control network (L-CN), L-VN to the L-DAN, L-VN to the left sensorimotor network (L-SMN), and R-DAN to the right salience/ventral attention network (R-SN/VAN). Additionally, no SC phenotype showed a nominally significant reverse association with PTSD in meta-analysis, and no reverse MR association survived correction for the effective number of independent tests. These findings provide preliminary evidence for bidirectional associations between PTSD and SC. However, no associations survived multiple testing correction using the effective number of independent tests (Meff) in either direction, suggesting these results are hypothesis-generating and require independent replication.