The genetic architecture of cortical similarity networks

The genetic architecture of human brain networks is central to understanding the organization and evolution of the cortex, the causal relationships between brain structure and function, and the pathogenesis of heritable neuropsychiatric disorders. However, the current understanding of the genetics of brain networks remains fragmented. Here, we investigated common genetic effects on Morphometric INverse Divergence (MIND), a biologically-validated, heritable, and multimodal MRI metric of inter-areal similarity and connectivity. Using a discovery dataset (N>30,000 adults), we estimated subject-specific MIND networks from the multivariate distributions of four MRI features at each of 23 cortical areas and performed genome-wide association studies (GWAS) at each of the 276 inter-areal edges. These edge-level genetic effects were highly replicated by parallel GWAS of an independent validation dataset (N>18,000 adults). We found that strong genetic correlations between multiple edges were largely reducible to two gradients of genetically-determined cortical similarity, each of which was aligned with geodesic distance from one of the two phylogenetically primitive areas (paleocortex and archicortex) predicted by the dual origin theory of cortical evolution. Genetic MIND gradients were more heritable than comparable gradients derived from GWAS of functional MRI connectivity networks; and the paleocortical trend was genetically correlated with, and causally predictive of, functional connectivity. Finally, we identified multiple global and local genetic correlations between both MIND gradients and nine clinical diagnoses or biomedical traits, indicating that the normative genetic architecture of human brain networks is pleiotropically associated with inherited risk of neuropsychiatric disorders and systemic metabolic and immune traits. These results provide fresh insight into the dual origins of the human cortex and their implications for brain function and health.