Project description:Abstract: Noncoding variants of presumed regulatory function contribute to neuropsychiatric disease heritability. 4442 noncoding variants connected to risk for 10 neuropsychiatric disorders, including autism spectrum disorder, attention deficit hyperactivity disorder, bipolar disorder, borderline personality disorder, major depression, generalized anxiety disorder, panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder, and schizophrenia, were studied within developing human neural cells. Integrating epigenomic and transcriptomic data with massively parallel reporter assays identified 637 disease-associated single-nucleotide variants (daSNVs) with altered transcription-regulating activity. Expression-gene mapping, network analyses, and chromatin looping identified 619 candidate disease-relevant target genes modulated by these daSNVs. Specific daSNV-associated molecular pathways mapped to prevalent mental health symptoms. These data provide a framework resource to study inherited pathogenic risk for human neuropsychiatric disorders. Purpose: To place disease-associated single nucleotide variants (daSNVs) in genomic context within human neural cells, matched RNA-seq, chromatin accessibility profiling via ATAC-seq, and enhancer-promoter looping via H3K27ac HiChIP was performed in ES cells and at day 2 (N-D2), 10 (N-D10), and 28 (N-D28) of neuronal differentiation. Additionally, anterior (A-NPC) and posterior (P-NPC) neuronal stem cells were generated and studied. Matched sequencing was also performed on primary human astrocytes from adult brains. Processed data for all cell types can be found in this repository. Raw data D10 and D28 RNA seq samples can be found here. Raw data for D0, D2, A-NSC, A-D2, P-NSC, and P-D2 data can be found here: https://www.biorxiv.org/content/10.1101/2020.12.02.398677v1.abstract. Raw data for Astrocytes can be found with the Donohue, et al. "The combinatorial cis-regulatory vocabulary of cell type-specific gene regulation in homeostasis and disease".

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

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