Reid Madigan M, Menon Shreya, Liu Hao, Zhou Haoyue, Hu Zhirui, Frerich Simon, Ding Bella, Oveisgharan Shahram, Zhang Zimo, Nelson Sophia, Apolonio Amanda, Bennett David A, Dichgans Martin, Pollard Katherine S, Corces M Ryan, Yang Andrew C
Gladstone Institute of Neurological Disease, San Francisco, CA, USA.
Gladstone Institute of Neurological Disease, San Francisco, CA, USA; Gladstone Institute of Data Science & Biotechnology, San Francisco, CA, USA; Medical Scientist Training Program and Biological and Medical Informatics Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
Neuron. 2025 Jul 23. doi: 10.1016/j.neuron.2025.07.001.
Cerebrovascular dysfunction underlies many neurological disorders, yet how genetic variants in brain vascular cells drive disease risk remains unknown. We developed MultiVINE-seq to simultaneously profile RNA and chromatin accessibility in vascular, perivascular, and immune cells from 30 human brains. Mapping genome-wide association study (GWAS) data to our multi-omic atlas linked thousands of GWAS disease-risk variants to target cell types and genes, including 2,605 previously unmapped. We found cerebrovascular and neurodegenerative disease variants have distinct mechanisms: cerebrovascular disease variants disrupt extracellular matrix genes in endothelial, mural, and fibroblast cells important for vessel structural integrity, while Alzheimer's disease (AD) variants dysregulate inflammatory adaptor proteins in endothelial and immune cells. Notably, a lead AD variant enhances PTK2B expression in brain CD8 T cells, providing genetic evidence for adaptive immunity in AD pathogenesis. This work provides a key resource for interpreting genetic risk and reveals how variants in vascular cells drive divergent pathogenic mechanisms across neurological diseases.
脑血管功能障碍是许多神经系统疾病的基础，但脑血管细胞中的基因变异如何驱动疾病风险仍不清楚。我们开发了MultiVINE-seq，以同时分析来自30个人类大脑的血管、血管周围和免疫细胞中的RNA和染色质可及性。将全基因组关联研究（GWAS）数据映射到我们的多组学图谱，将数千个GWAS疾病风险变异与靶细胞类型和基因联系起来，其中包括2605个以前未映射的变异。我们发现脑血管疾病和神经退行性疾病变异具有不同的机制：脑血管疾病变异破坏了对血管结构完整性至关重要的内皮细胞、壁细胞和成纤维细胞中的细胞外基质基因，而阿尔茨海默病（AD）变异则在内皮细胞和免疫细胞中失调炎症衔接蛋白。值得注意的是，一个主要的AD变异增强了脑CD8 T细胞中的PTK2B表达，为AD发病机制中的适应性免疫提供了遗传学证据。这项工作为解释遗传风险提供了关键资源，并揭示了血管细胞中的变异如何驱动不同神经系统疾病的不同致病机制。
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Front Cardiovasc Med. 2023-11-24
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