TY  - JOUR
AU  - Reid, Madigan M
AU  - Menon, Shreya
AU  - Liu, Hao
AU  - Zhou, Haoyue
AU  - Hu, Zhirui
AU  - Frerich, Simon
AU  - Ding, Bella
AU  - Oveisgharan, Shahram
AU  - Zhang, Zimo
AU  - Nelson, Sophia
AU  - Apolonio, Amanda
AU  - Bennett, David A
AU  - Dichgans, Martin
AU  - Pollard, Katherine S
AU  - Corces, M Ryan
AU  - Yang, Andrew C
TI  - Human brain vascular multi-omics elucidates disease-risk associations.
JO  - Neuron
VL  - 113
IS  - 19
SN  - 0896-6273
CY  - [Cambridge, Mass.]
PB  - Cell Press
M1  - DZNE-2025-01149
SP  - 3143 - 3161.e5
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Genome-Wide Association Study
KW  - Brain: blood supply
KW  - Brain: metabolism
KW  - Alzheimer Disease: genetics
KW  - Genetic Predisposition to Disease: genetics
KW  - Cerebrovascular Disorders: genetics
KW  - Female
KW  - Male
KW  - Focal Adhesion Kinase 2: genetics
KW  - Focal Adhesion Kinase 2: metabolism
KW  - Multiomics
KW  - Alzheimer's disease (Other)
KW  - T cell (Other)
KW  - brain vasculature (Other)
KW  - cerebrovascular disease (Other)
KW  - macrophage (Other)
KW  - microglia (Other)
KW  - neurodegenerative disease (Other)
KW  - non-coding disease-risk variants (Other)
KW  - single-cell multi-omics (Other)
KW  - stroke (Other)
KW  - Focal Adhesion Kinase 2 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40730185
C2  - pmc:PMC12321221
DO  - DOI:10.1016/j.neuron.2025.07.001
UR  - https://pub.dzne.de/record/281531
ER  -