This review explores how chromatin accessibility profiling, particularly ATAC-seq, combined with single-cell technologies, GWAS, and transcriptomics, has advanced our understanding of the noncoding genome’s role in neuropsychiatric and neurodegenerative diseases

We present a comprehensive catalog that captures variation in the human brain regulome, which illuminates the cell type–specific molecular mechanisms that underlie neuropsychiatric and neurodegenerative disorders. Our work highlights an approach to move from statistical associations from large-scale GWASs to functionally validated variants and molecular mechanisms of disease.

Our results describe the complex regulation of cell composition at critical stages in lineage determination and shed light on the impact of spatiotemporal alterations in gene expression on neuropsychiatric disease.

The authors generated the largest epigenome atlas of postmortem brains with Alzheimer’s disease. They reported regulatory genomic signatures associated with AD, including variability in open chromatin regions, transcription factor networks and cis-regulatory domains.

Transcriptomic and epigenomic profiling of human microglia identifies putative gene regulatory mechanisms for 21 Alzheimer’s disease (AD) risk loci. SPI1/PU.1 is nominated as a key regulator of microglia gene expression and AD risk.

Here, the authors perform ATAC-seq on four distinct cell populations from three different regions of the human brain, finding that chromatin accessibility varies greatly by cell type and less by brain region. This study reveals differences in biological function and gene regulation, as well as overlap of genetic variants associated with schizophrenia and other neuropsychiatric traits.

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