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001     281531
005     20251109002047.0
024 7 _ |a 10.1016/j.neuron.2025.07.001
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024 7 _ |a pmid:40730185
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024 7 _ |a pmc:PMC12321221
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024 7 _ |a 0896-6273
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024 7 _ |a 1097-4199
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024 7 _ |a altmetric:179712296
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037 _ _ |a DZNE-2025-01149
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Reid, Madigan M
|b 0
245 _ _ |a Human brain vascular multi-omics elucidates disease-risk associations.
260 _ _ |a [Cambridge, Mass.]
|c 2025
|b Cell Press
336 7 _ |a article
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336 7 _ |a ARTICLE
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520 _ _ |a 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.
536 _ _ |a 353 - Clinical and Health Care Research (POF4-353)
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650 _ 7 |a Alzheimer's disease
|2 Other
650 _ 7 |a T cell
|2 Other
650 _ 7 |a brain vasculature
|2 Other
650 _ 7 |a cerebrovascular disease
|2 Other
650 _ 7 |a macrophage
|2 Other
650 _ 7 |a microglia
|2 Other
650 _ 7 |a neurodegenerative disease
|2 Other
650 _ 7 |a non-coding disease-risk variants
|2 Other
650 _ 7 |a single-cell multi-omics
|2 Other
650 _ 7 |a stroke
|2 Other
650 _ 7 |a Focal Adhesion Kinase 2
|0 EC 2.7.10.2
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650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Genome-Wide Association Study
|2 MeSH
650 _ 2 |a Brain: blood supply
|2 MeSH
650 _ 2 |a Brain: metabolism
|2 MeSH
650 _ 2 |a Alzheimer Disease: genetics
|2 MeSH
650 _ 2 |a Genetic Predisposition to Disease: genetics
|2 MeSH
650 _ 2 |a Cerebrovascular Disorders: genetics
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Focal Adhesion Kinase 2: genetics
|2 MeSH
650 _ 2 |a Focal Adhesion Kinase 2: metabolism
|2 MeSH
650 _ 2 |a Multiomics
|2 MeSH
700 1 _ |a Menon, Shreya
|b 1
700 1 _ |a Liu, Hao
|b 2
700 1 _ |a Zhou, Haoyue
|b 3
700 1 _ |a Hu, Zhirui
|b 4
700 1 _ |a Frerich, Simon
|b 5
700 1 _ |a Ding, Bella
|b 6
700 1 _ |a Oveisgharan, Shahram
|b 7
700 1 _ |a Zhang, Zimo
|b 8
700 1 _ |a Nelson, Sophia
|b 9
700 1 _ |a Apolonio, Amanda
|b 10
700 1 _ |a Bennett, David A
|b 11
700 1 _ |a Dichgans, Martin
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700 1 _ |a Pollard, Katherine S
|b 13
700 1 _ |a Corces, M Ryan
|b 14
700 1 _ |a Yang, Andrew C
|b 15
773 _ _ |a 10.1016/j.neuron.2025.07.001
|g Vol. 113, no. 19, p. 3143 - 3161.e5
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|t Neuron
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|y 2025
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856 4 _ |u https://pub.dzne.de/record/281531/files/DZNE-2025-01149%20SUP.zip
856 4 _ |u https://pub.dzne.de/record/281531/files/DZNE-2025-01149_Restricted.pdf
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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