Mapping Chromatin Accessibility In Human Adult Brain Infers Functional Roles For Neuropsychiatric Risk Variants

Abstract

BackgroundOpen chromatin regions (OCRs) provide access to DNA binding proteins for the correct spatiotemporal regulation of gene expression. Mapping chromatin accessibility has been widely used to identify the location of cis regulatory elements (CREs) including promoters and enhancers. CREs show tissue- and cell-type specificity and disease-associated variants are often enriched for CREs in the tissues and cells that pertain to a given disease. MethodsTo better understand the role of CREs in neuropsychiatric disorders we have applied the Assay for Transposase Accessible Chromatin followed by sequencing (ATAC-seq) to generate OCR maps of multiple brain regions and cell types isolated from frozen postmortem human brain by fluorescence-activated nuclear sorting. The enrichment of risk loci with OCRs was examined using LD score regression. Transcription factor (TF) footprinting analysis was used to generate TF-gene regulome networks in each region and cell type. ResultsChromatin accessibility varied markedly by cell type brain region and largely overlapped corresponding differences in gene expression. Amongst brain regions, the most extensive differences were seen between neurons of the cortical regions, primary visual cortex, hippocampus, thalamus, and the striatum. Risk schizophrenia variants were enriched for neuronal OCRs in cortical regions, hippocampus and striatum. Enrichment analysis of TF-gene networks with common and rare schizophrenia variants identified significant subnetworks related to synaptic transmission and neuronal function. DiscussionThese results represent the first analysis of multiregional OCRs and TF binding sites in distinct populations of postmortem human brain cells and further our understanding of the regulome and the impact of neuropsychiatric disease-associated genetic risk variants.