Genetic regulation of cell type-specific chromatin accessibility shapes brain disease etiology
成果类型：
Article
署名作者：
Zeng, Biao; Bendl, Jaroslav; Deng, Chengyu; Lee, Donghoon; Misir, Ruth; Reach, Sarah M.; Kleopoulos, Steven P.; Auluck, Pavan; Marenco, Stefano; Lewis, David A.; Haroutunian, Vahram; Ahituv, Nadav; Fullard, John F.; Hoffman, Gabriel E.; Roussos, Panos
署名单位：
Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; Icahn School of Medicine at Mount Sinai; University of California System; University of California San Francisco; University of California System; University of California San Francisco; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; Icahn School of Medicine at Mount Sinai; US Department of Veterans Affairs; Veterans Health Administration (VHA); James J. Peters VA Medical Center
刊物名称：
SCIENCE
ISSN/ISSBN：
0036-8155
DOI：
10.1126/science.adh4265
发表日期：
2024-05-24
关键词：
alzheimers-disease
causal variants
RISK
identify
neurons
signals
predict
IMPACT
eqtls
gwas
摘要：
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.