31. MAPPING THE GENETIC ARCHITECTURE OF HUMAN CORTICAL EXPANSION AND ITS LINKS TO PSYCHIATRIC DISORDERS

Background The expansion of the cerebral cortex, one of the most distinctive aspects of human evolution and neurodevelopment, is characterized by the tangential growth and gyrification of the cerebral mantle. Large-scale neuroimaging studies underscore the necessity of this process to healthy brain function, as morphological features related to expansion (e.g., surface area, gyrification, folding) have been robustly associated with numerous psychiatric disorders. Although these findings suggest that delayed or atypical patterns of cortical expansion may represent a transdiagnostic liability, delineating the specific molecular pathways involved may provide new insight into the developmental neurobiology of cortical expansion and its relationship with human health. Methods We leveraged Genomic Structural Equation Modeling to establish a common cortical expansion factor underlying the genetics of five imaging-derived phenotypes (N=31,797-73,800): Surface Area, Folding Index, Intrinsic Curvature Index, Local Gyrification Index, and Intracranial Volume. We also modeled 180 regional cortical expansion factors based on the Glasser parcellation. Then, we evaluated enrichment of the genetic signal in developmentally expressed genes with Stratified Genomic Structural Equation Modeling. Finally, we estimated genetic correlations between cortical expansion and 20 neuropsychiatric disorders with LD-score regression and evaluated their polygenic overlap with MiXeR. Results The cortical expansion factor was most enriched in genes expressed early in prenatal development (Enrichment Ratio=2.37, P=2.85e-13), suggesting that the cortical expansion factor captures neurodevelopmental biology. In addition, cortical expansion was significantly correlated (Bonferroni-corrected P < 0.05) with six neuropsychiatric disorders and symptoms, including negative correlations with ADHD, (rg=-0.19), Tobacco Use Disorder (rg=-0.17), PTSD (rg=-0.13), Cannabis Use Disorder (rg=-0.13), and Neuroticism (rg=-0.10) and a positive correlation with Parkinson's (rg=0.20). Across brain regions, genetic correlations between cortical expansion and psychiatric disorders tended to operate along the principal axis of organization of the brain, linking decreased expansion of transmodal, higher-order regions to increased psychiatric liability. Beyond genetic correlations, cortical expansion demonstrated substantial polygenic overlap with all tested disorders via MiXeR (50.01-97.03% overlap of causal variants). Discussion Despite convergent evidence linking variation in cortical morphology and neurodevelopment to human health and disease, the shared genetic architecture underlying the tangential growth and gyrification of the cortex has remained poorly characterized. Here, we address this gap by characterizing common variant influences on cortical expansion, charting the developmental biology of this process through a genomic lens and mapping its genetic relationships with a diverse set of neuropsychiatric disorders. Specifically, we found that the common variant architecture of cortical expansion exhibited substantial polygenic overlap with diverse neuropsychiatric disorders. Viewed in the context of recent psychiatric genetics studies, these findings suggest that cortical expansion represents a common neural mechanism through which pleiotropic liability for psychopathology manifests.