Massively parallel reporter assay investigates shared genetic variants of eight psychiatric disorders
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE276947 | GEO | 2025/01/16
REPOSITORIES: GEO
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Project description:A meta-genome-wide association study across eight psychiatric disorders has highlighted the genetic architecture of pleiotropy in major psychiatric disorders. However, mechanisms underlying pleiotropic effects of the associated variants remain to be explored. We conducted a massively parallel reporter assay to decode the regulatory logic of variants with pleiotropic and disorder-specific effects. Pleiotropic variants differ from disorder-specific variants by exhibiting chromatin accessibility that extends across diverse cell types in the neuronal lineage and by altering motifs for transcription factors with higher connectivity in protein-protein interaction networks. We mapped pleiotropic and disorder-specific variants to putative target genes using functional genomics approaches. In vitro CRISPR perturbation of selected variants confirmed the variant-gene relationships, and in vivo CRISPR perturbation of a pleiotropic and a disorder-specific gene suggests that pleiotropy may involve regulation of genes expressed broadly across neuronal cell types and with higher network connectivity.
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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 and raw data for all cell types can be found in this repository. All biological replicates (n=2) are merged using the ENCODE pipeline.
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