Dissecting the shared genetic landscape of schizophrenia and hippocampal subfields: A genome-wide cross-trait analysis

Schizophrenia is associated with hippocampal volumetric changes, yet the genetic mechanisms linking schizophrenia to alterations in hippocampal volume and its subfields remain poorly understood. We analyzed the largest available GWAS summary statistics for schizophrenia (53,386 cases, 77,258 controls) and hippocampal volumetric traits (33,224 individuals). Linkage disequilibrium score regression (LDSC) was employed to estimate global genetic correlations, while conditional and conjunctional false discovery rate (cond/conjFDR) method was used to identify shared genetic variants across 44 hippocampal traits, including both whole hippocampal and subfield-specific volumes. Although weak global genetic correlations were observed between schizophrenia and hippocampal volumetric traits, variant-level analysis identified significant shared genetic variants. Specifically, the cond/conjFDR method revealed substantial overlap of genetic loci across 44 hippocampal traits, identifying 171 distinct shared loci, including 6 novel ones. Hemispheric differences were observed: we identified 106 left-hemispheric and 117 right-hemispheric loci; among the hemisphere-specific subset, 49 were left-specific (46.2%) and 61 right-specific (52.1%), with the remainder appearing in both hemispheres. Enrichment analysis of the mapped genes revealed involvement in processes such as nervous system development, neuron generation, and differentiation. Validation and replication analyses confirmed the robustness and reproducibility of our findings across different datasets and methods. Our findings reveal significant genetic overlap with mixed effects between schizophrenia and hippocampal volumetric traits, underscoring the complexity of their shared genetic architecture. These results also highlight hemispheric differences in genetic influence, providing new insights into the neurobiological mechanisms of schizophrenia.