This study integrates genome-wide chromosome conformation data from purified neurons and glia with transcriptomic and enhancer profiles to characterize the gene regulatory landscape of these cell types in the human brain. The researchers then leverage these cell-type-specific regulatory landscapes to investigate the cellular etiology of Alzheimer's disease (AD), schizophrenia (SCZ), and bipolar disorder (BD). They find that AD-associated epigenetic dysregulation is linked to neurons and oligodendrocytes, while genetic risk factors for AD highlight microglia. Similarly, analysis of SCZ and BD risk factors reveals shared (parvalbumin-expressing interneurons) and distinct cellular etiologies (upper layer neurons for BD, and deeper layer projection neurons for SCZ).

Benxia Hu, Hyejung Won, Won Mah, Royce B. Park, Bibi Kassim, Keeley Spiess, Alexey Kozlenkov, Cheynna A. Crowley, Sirisha Pochareddy, The PsychENCODE Consortium, Yun Li, Stella Dracheva, Nenad Sestan, Schahram Akbarian, Daniel H. Geschwind