Hemispheric Asymmetry in the Genetic Overlap between Schizophrenia and White Matter Microstructure

White matter microstructure, essential for neural communication, is genetically influenced and often disrupted in schizophrenia. Large-scale genome-wide association studies have identified over 200 genome-wide significant loci for schizophrenia, yet the extent to which schizophrenia shares genetic architecture with white matter microstructure-particularly across multidimensional diffusion tensor imaging (DTI) metrics and hemispheric distinctions-remains incompletely understood. Here, we employed the conditional/conjunctional false discovery rate (cond/conjFDR) approach to investigate the genetic overlap between schizophrenia and white matter microstructure. These analyses utilized large-scale genome-wide association datasets for schizophrenia (<i>N</i> _case = 53,386, <i>N</i> _control = 77,258) and the microstructure of 48 white matter tracts (<i>N</i> = 33,224), derived from individuals of European ancestry. White matter integrity was assessed using fractional anisotropy (FA), mean diffusivity (MD), and 3 eigenvalues. Additionally, we performed comprehensive functional and validation analyses for the shared loci. We identified 435 shared loci, including 154 loci exclusive to 3 eigenvalues. Hemisphere-specific analysis of white matter tracts revealed lateralized patterns, with 25.5% to 34.4% of loci being left-specific and 23.9% to 33.7% right-specific. Enrichment analysis highlighted the shared loci related to nervous system and central nervous system development, supporting their role in neurodevelopmental mechanisms. Validation analyses across diverse methods and datasets further confirmed the reliability of the shared loci. This study demonstrates a complex, shared genetic architecture between schizophrenia and white matter microstructure, highlighting hemispheric genetic asymmetry and the value of multidimensional DTI metrics in uncovering the genetic basis of structural brain abnormalities.