Causal relationships between white matter connectome and mental disorders: a large-scale genetic correlation study.

BACKGROUND

Abnormalities in white matter integrity in mental disorders have attracted widespread attention, yet the genetic correlations and causal effects between white matter structural connectome and various psychiatric conditions remain largely unexplored.

METHODS

In this study, we employed linkage disequilibrium score (LDSC) and high-definition likelihood (HDL) methods to analyze genetic correlations between white matter connectome and mental disorders, followed by bidirectional two-sample Mendelian randomization (MR) analysis to investigate causal relationships. We utilized 206 white matter connectome magnetic resonance imaging (MRI) phenotypes derived from the processed UK Biobank dataset (n = 26,333 individuals) and 12 mental disorders from the latest FinnGen database (n = 402,965 to 449,029 individuals).

RESULTS

Using both methods, we observed 26 pairs of brain white matter connectivity phenotypes and mental disorders showing significant correlations. Forward MR analysis identified two white matter structural connectome phenotypes causally associated with psychiatric disorder risk. Increased connectivity in left-hemisphere visual network (VIS) to right-hemisphere limbic network (LIM) white-matter structural connectivity was associated with increased risk of anxiety disorders. Additionally, decreased connectivity in left-hemisphere visual network to hippocampus white-matter structural connectivity was associated with reduced risk of post-traumatic stress disorder (PTSD). However, reverse MR analysis results did not survive multiple testing correction.

CONCLUSION

These findings provide crucial insights into the complex interplay between white matter structural connectivity and mental disorders, potentially offering new avenues for understanding the neurobiological underpinnings of psychiatric conditions and informing future diagnostic and therapeutic strategies.