ABSTRACT
Interpretation of the function of non-coding risk loci for neuropsychiatric disorders and brain-relevant traits via gene expression and alternative splicing quantitative trait locus (e/sQTL) analyses is generally performed in bulk post-mortem adult tissue. However, genetic risk loci are enriched in regulatory elements active during neocortical differentiation, and regulatory effects of risk variants may be masked by heterogeneity in bulk tissue. Here, we map e/sQTLs, and allele-specific expression in cultured cells representing two major developmental stages, primary human neural progenitors (n = 85) and their sorted neuronal progeny (n = 74), identifying numerous loci not detected in either bulk developing cortical wall or adult cortex. Using colocalization and genetic imputation via transcriptome-wide association, we uncover cell-type-specific regulatory mechanisms underlying risk for brain-relevant traits that are active during neocortical differentiation. Specifically, we identified a progenitor-specific eQTL for CENPW co-localized with common variant associations for cortical surface area and educational attainment.
Subject(s)
Chromosomal Proteins, Non-Histone/genetics , Gene Expression Regulation, Developmental , Neocortex/metabolism , Neurogenesis/genetics , Neurons/metabolism , Quantitative Trait Loci , Alleles , Alzheimer Disease/diagnosis , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Cell Differentiation , Chromatin/chemistry , Chromatin/metabolism , Chromosomal Proteins, Non-Histone/metabolism , Chromosome Mapping , Educational Status , Female , Fetus , Genetic Predisposition to Disease , Genome, Human , Genome-Wide Association Study , Humans , Male , Neocortex/cytology , Neocortex/growth & development , Neural Stem Cells/cytology , Neural Stem Cells/metabolism , Neurons/cytology , Neuroticism , Parkinson Disease/diagnosis , Parkinson Disease/genetics , Parkinson Disease/metabolism , Primary Cell Culture , Prognosis , Schizophrenia/diagnosis , Schizophrenia/genetics , Schizophrenia/metabolism , TranscriptomeABSTRACT
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.
