Transcriptome and chromatin accessibility landscapes across 25 human brain regions expand the susceptibility gene set for neuropsychiatric disorders [ATAC-Seq]

Brain region- and cell-specific transcriptome and epigenome molecular features are associated with heritability for neuropsychiatric traits. Here, we provide an atlas of chromatin accessibility and gene expression in neuronal and non-neuronal cells across 25 distinct regions across cortical and subcortical areas of the human brain from 6 neurotypical controls. We identified extensive gene expression and chromatin accessibility differences across brain regions. We further identified variation in alternative promoter-isoform usage and enhancer-promoter interactions across brain regions and found genes with distinct promoter-isoform usage are strongly enriched for neuropsychiatric risk variants. We identified brain region-specific chromatin co-accessibility and gene-coexpression modules that are robustly associated with genetic risk variants for neuropsychiatric disorders. Using an integrative approach, we identify a novel set of genes that is enriched for neuropsychiatric disorders risk variants but is independent of cell-type specific gene expression and annotated pathways. Our results provide a valuable multi-brain region molecular regulation resource and suggest a unique contribution of epigenetic modifications from the subcortical areas to neuropsychiatric disorders. RNA-seq profiles in neuronal and non-neuronal nuclei isolated from 25 brain regions covering the forebrain, basal ganglia , midbrain/thalamus, and hindbrain of six control subjects