研究人员测量了来自616个人类死后大脑的1932份分选神经元和非神经元等分样品的染色质可及性，并确定了34539个具有染色质可及性定量性状位点（caQTL）的开放染色质区域。只有10.4%的caQTL在神经元和非神经元之间共享，这支持了大脑调控组的细胞类型特异性遗传调控。纳入等位基因特异性染色质可及性可改善统计精细图谱并完善疾病风险的分子机制。
利用大规模并行的诱导兴奋神经元报告测定，研究人员筛选了19893个脑部QTL，并确定了476个调控变体的功能影响。综合来看，这一全面的资源捕捉到了人类大脑调节基因组的变异，并提供了对疾病病因的见解。
据悉，人脑中细胞类型特异性基因调控元件的核苷酸变异是导致人类疾病的风险因素。
附：英文原文
Title: Genetic regulation of cell type–specific chromatin accessibility shapes brain disease etiology
Author: Biao Zeng, Jaroslav Bendl, Chengyu Deng, Donghoon Lee, Ruth Misir, Sarah M. Reach, Steven P. Kleopoulos, Pavan Auluck, Stefano Marenco, David A. Lewis, Vahram Haroutunian, Nadav Ahituv, John F. Fullard, Gabriel E. Hoffman, Panos Roussos
Issue&Volume: 2024-05-24
Abstract: Nucleotide variants in cell type–specific gene regulatory elements in the human brain are risk factors for human disease. We measured chromatin accessibility in 1932 aliquots of sorted neurons and non-neurons from 616 human postmortem brains and identified 34,539 open chromatin regions with chromatin accessibility quantitative trait loci (caQTLs). Only 10.4% of caQTLs are shared between neurons and non-neurons, which supports cell type–specific genetic regulation of the brain regulome. Incorporating allele-specific chromatin accessibility improves statistical fine-mapping and refines molecular mechanisms that underlie disease risk. Using massively parallel reporter assays in induced excitatory neurons, we screened 19,893 brain QTLs and identified the functional impact of 476 regulatory variants. Combined, this comprehensive resource captures variation in the human brain regulome and provides insights into disease etiology.
DOI: adh4265
Source: https://www.science.org/doi/10.1126/science.adh4265