Dr. Jason Stein (Assistant Professor, Department of Genetics) and colleagues have published a manuscript in Nature Neuroscience (20 May 2021) titled “Cell-type specific effects of genetic variation on chromatin accessibility during human neuronal differentiation”.
This study, led by Dr. Dan Liang as part of her dissertation research, was focused on modeling the functional impact of common genetic variation on the noncoding genome during human cortical development. To accomplish this, the investigators 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. The team 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, the investigators were able to fine-map and identify regulatory mechanisms underlying noncoding neuropsychiatric disorder risk loci.