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Cell-type-specific effects of genetic variation on chromatin accessibility during human neuronal differentiation

Cell-type-specific effects of genetic variation on chromatin accessibility during human neuronal differentiation
Common genetic risk for neuropsychiatric disorders is enriched in regulatory elements active during cortical neurogenesis. However, it remains poorly understood as to how these variants influence gene regulation. To model the functional impact of common genetic variation on the noncoding genome during human cortical development, we performed the assay for transposase accessible chromatin using sequencing (ATAC-seq) and analyzed chromatin accessibility quantitative trait loci (QTL) in cultured human neural progenitor cells and their differentiated neuronal progeny from 87 donors. We identified significant genetic effects on 988/1,839 neuron/progenitor regulatory elements, with highly cell-type and temporally specific effects. A subset (roughly 30%) of chromatin accessibility-QTL were also associated with changes in gene expression. Motif-disrupting alleles of transcriptional activators generally led to decreases in chromatin accessibility, whereas motif-disrupting alleles of repressors led to increases in chromatin accessibility. By integrating cell-type-specific chromatin accessibility-QTL and brain-relevant genome-wide association data, we were able to fine-map and identify regulatory mechanisms underlying noncoding neuropsychiatric disorder risk loci.
- David Geffen School of Medicine at UCLA United States
- UNC Lineberger Comprehensive Cancer Center United States
- Autism Treatment Center United States
- University of North Carolina at Chapel Hill United States
- University of California, Los Angeles United States
Neurons, Mental Disorders, Neurogenesis, Quantitative Trait Loci, Gene Expression Regulation, Developmental, Genetic Variation, Cell Differentiation, Article, Chromatin, Neural Stem Cells, Humans, Genetic Predisposition to Disease, Regulatory Elements, Transcriptional, Genome-Wide Association Study, Transcription Factors
Neurons, Mental Disorders, Neurogenesis, Quantitative Trait Loci, Gene Expression Regulation, Developmental, Genetic Variation, Cell Differentiation, Article, Chromatin, Neural Stem Cells, Humans, Genetic Predisposition to Disease, Regulatory Elements, Transcriptional, Genome-Wide Association Study, Transcription Factors
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