Polygenic hierarchies of macroscale brain structural organisation

A comprehensive genome-wide association study of 2,326 magnetic resonance imaging-derived cortical, subcortical, and white matter measures in the UK Biobank and ABCD studies has revealed a hierarchical organisation of the genetic architecture of macroscale human brain structure. The research identified 14,176 experiment-wide significant loci and prioritized 848 genes associated with these measures.

The genetic variations primarily clustered into six families based on the type of measure: brain size, cortical thickness, cortical curvature, microstructural coherence, microstructural diffusivity, and orientation dispersion. These clusters were consistent across prioritized genes, cell types, and developmental timing.

The study found that brain size is influenced by first-trimester radial glia programs, while white matter coherence is affected by adolescent astrocyte and oligodendrocyte lineages. Within individual measures, genetic effects were further organized along broad spatial gradients. A principal gradient reflected allometric scaling for most measures, while secondary gradients showed correspondence with the sensory-association topographic axis across several measures.

The research also identified 79 genes with spatially restricted effects along the cortex. Many of these genes aligned with the dominant gradients, while a substantial subset exhibited additional spatial patterns. These findings suggest a complex hierarchical organisation of the genetic architecture of macroscale human brain structure, encompassing phenotype families, broad spatial gradients, and regionally restricted developmental programmes.