Neuronal and glial 3D chromatin architecture informs the cellular etiology of brain disorders

Cellular heterogeneity in the human brain obscures identification of robust regulatory networks needed to interpret non-coding elements and genetic variation. The authors integrate genome-wide chromosome conformation (Hi-C) from purified neurons (NeuN+) and glia (NeuN−) with transcriptomic and enhancer profiles to characterize regulatory landscapes of these cell classes and leverage them to study brain disorders. Alzheimer’s disease (AD)-associated epigenetic dysregulation links to neurons and oligodendrocytes, whereas genetic risk highlights microglia, suggesting distinct cell-type mechanisms. Integration of glutamatergic (Glu) and GABAergic (GABA) regulatory maps with schizophrenia (SCZ) and bipolar disorder (BD) genetics identifies shared (parvalbumin interneurons) and distinct etiologies (upper layer neurons for BD; deeper layer projection neurons for SCZ). These findings illuminate cell-type-specific gene regulatory networks in brain disorders.