Human brain vascular multi-omics elucidates disease-risk associations.

IF 15 1区医学 Q1 NEUROSCIENCES

Neuron Pub Date : 2025-07-23 DOI:10.1016/j.neuron.2025.07.001

Madigan M Reid, Shreya Menon, Hao Liu, Haoyue Zhou, Zhirui Hu, Simon Frerich, Bella Ding, Shahram Oveisgharan, Zimo Zhang, Sophia Nelson, Amanda Apolonio, David A Bennett, Martin Dichgans, Katherine S Pollard, M Ryan Corces, Andrew C Yang

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引用次数: 0

Abstract

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.

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人类脑血管多组学阐明疾病风险关联。

脑血管功能障碍是许多神经系统疾病的基础，但脑血管细胞的遗传变异如何驱动疾病风险仍不清楚。我们开发了MultiVINE-seq同时分析来自30个人类大脑的血管、血管周围和免疫细胞的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，将数千种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种以前未映射的基因。我们发现脑血管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内皮细胞、壁细胞和成纤维细胞中对血管结构完整性重要的细胞外基质基因，而阿尔茨海默病（AD）变异调节内皮细胞和免疫细胞中的炎症适应蛋白。值得注意的是，AD的一个先导变体增强了PTK2B在脑CD8 T细胞中的表达，为AD发病机制中的适应性免疫提供了遗传证据。这项工作为解释遗传风险提供了关键资源，并揭示了血管细胞的变异如何驱动神经系统疾病的不同致病机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neuron 医学-神经科学

CiteScore

24.50

自引率

3.10%

发文量

382

审稿时长

1 months

期刊介绍： Established as a highly influential journal in neuroscience, Neuron is widely relied upon in the field. The editors adopt interdisciplinary strategies, integrating biophysical, cellular, developmental, and molecular approaches alongside a systems approach to sensory, motor, and higher-order cognitive functions. Serving as a premier intellectual forum, Neuron holds a prominent position in the entire neuroscience community.