Zeng Biao, Yang Hui, N M Prashant, Venkatesh Sanan, Mathur Deepika, Auluck Pavan, Bennett David A, Marenco Stefano, Haroutunian Vahram, Voloudakis Georgios, Lee Donghoon, Fullard John F, Bendl Jaroslav, Girdhar Kiran, Hoffman Gabriel E, Roussos Panos
Center for Disease Neurogenomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Res Sq. 2024 Dec 11:rs.3.rs-5368620. doi: 10.21203/rs.3.rs-5368620/v1.
Genetic risk variants for common diseases are predominantly located in non-coding regulatory regions and modulate gene expression. Although bulk tissue studies have elucidated shared mechanisms of regulatory and disease-associated genetics, the cellular specificity of these mechanisms remains largely unexplored. This study presents a comprehensive single-nucleus multi-ancestry atlas of genetic regulation of gene expression in the human prefrontal cortex, comprising 5.6 million nuclei from 1,384 donors of diverse ancestries. Through multi-resolution analyses spanning eight major cell classes and 27 subclasses, we identify genetic regulation for 14,258 genes, with 857 showing cell type-specific regulatory effects at the class level and 981 at the subclass level. Colocalization of genetic variants associated with gene regulation and disease traits uncovers novel cell type-specific genes implicated in Alzheimer's disease, schizophrenia, and other disorders, which were not detectable in bulk tissue analyses. Analysis of dynamic genetic regulation at the single nucleus level identifies 2,073 genes with regulatory effects that vary across developmental trajectories, inferred from a broad age range of donors. We also uncover 1,655 genes with -regulatory effects, revealing distal regulation of gene expression. This high-resolution atlas provides unprecedented insight into the cell type-specific regulatory architecture of the human brain, and offers novel mechanistic targets for understanding the genetic basis of neuropsychiatric and neurodegenerative diseases.
常见疾病的遗传风险变异主要位于非编码调控区域，并调节基因表达。尽管大量组织研究已经阐明了调控遗传学和疾病相关遗传学的共同机制，但这些机制的细胞特异性在很大程度上仍未得到探索。本研究展示了人类前额叶皮质基因表达遗传调控的全面单核多祖先图谱，该图谱包含来自1384名不同祖先供体的560万个细胞核。通过跨越八个主要细胞类别和27个子类别的多分辨率分析，我们确定了14258个基因的遗传调控，其中857个在类别水平上表现出细胞类型特异性调控效应，981个在子类水平上表现出细胞类型特异性调控效应。与基因调控和疾病性状相关的遗传变异的共定位揭示了与阿尔茨海默病、精神分裂症和其他疾病相关的新型细胞类型特异性基因，这些基因在大量组织分析中无法检测到。对单核水平动态遗传调控的分析确定了2073个基因，其调控效应在不同发育轨迹上有所不同，这些发育轨迹是从广泛年龄范围的供体中推断出来的。我们还发现了1655个具有调控效应的基因，揭示了基因表达的远端调控。这一高分辨率图谱为人类大脑细胞类型特异性调控结构提供了前所未有的见解，并为理解神经精神疾病和神经退行性疾病的遗传基础提供了新的机制靶点。
