Journal Article

DZNE-2025-01149

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Human brain vascular multi-omics elucidates disease-risk associations.

Reid, M. M. ; Menon, S. ; Liu, H. ; Zhou, H. ; Hu, Z. ; Frerich, S. ; Ding, B. ; Oveisgharan, S. ; Zhang, Z. ; Nelson, S. ; Apolonio, A. ; Bennett, D. A. ; Dichgans, M.DZNE* ; Pollard, K. S. ; Corces, M. R. ; Yang, A. C.

2025
Cell Press [Cambridge, Mass.]

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Please use a persistent id in citations: doi:10.1016/j.neuron.2025.07.001

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.

Keyword(s): Humans (MeSH) ; Genome-Wide Association Study (MeSH) ; Brain: blood supply (MeSH) ; Brain: metabolism (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Genetic Predisposition to Disease: genetics (MeSH) ; Cerebrovascular Disorders: genetics (MeSH) ; Female (MeSH) ; Male (MeSH) ; Focal Adhesion Kinase 2: genetics (MeSH) ; Focal Adhesion Kinase 2: metabolism (MeSH) ; Multiomics (MeSH) ; Alzheimer's disease ; T cell ; brain vasculature ; cerebrovascular disease ; macrophage ; microglia ; neurodegenerative disease ; non-coding disease-risk variants ; single-cell multi-omics ; stroke ; Focal Adhesion Kinase 2

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Contributing Institute(s):

1. Vascular Cognitive Impairment & Post-Stroke Dementia (AG Dichgans)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 15 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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