Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Nat Neurosci. 2021 Jul;24(7):941-953. doi: 10.1038/s41593-021-00858-w. Epub 2021 May 20.
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.
常见的神经精神疾病遗传风险在皮质神经发生过程中活跃的调控元件中得到富集。然而，这些变异如何影响基因调控仍知之甚少。为了在人类皮质发育过程中模拟常见遗传变异对非编码基因组的功能影响，我们对 87 名供体的培养人神经祖细胞及其分化的神经元祖细胞进行了转座酶可及染色质测序（ATAC-seq）和分析染色质可及性数量性状基因座（QTL）。我们在 1839 个神经元/祖细胞调控元件中鉴定出了 988 个具有显著遗传效应的元件，这些效应具有高度的细胞类型和时间特异性。一小部分（约 30%）染色质可及性-QTL 与基因表达的变化有关。转录激活因子的 motif 破坏等位基因通常导致染色质可及性降低，而抑制因子的 motif 破坏等位基因则导致染色质可及性增加。通过整合细胞特异性染色质可及性-QTL 和与大脑相关的全基因组关联数据，我们能够精细定位和确定神经精神疾病风险位点的调控机制。
