Version: 1.0.0 | Published: 24 Sep 2026 | Updated: 0 days ago
Documentation
Description:
Cerebrovascular dysfunction is implicated in diverse neurological disorders, but how genetic variation in brain vascular, perivascular, and immune cell types may contribute to disease risk remains poorly understood. This gap arises in part because, while genome-wide association studies (GWASs) have identified numerous non-coding variants linked to neurological diseases, their cell type-specific effects and target genes in the human brain vasculature remain largely unknown. To address this, we developed a multi-omic vessel isolation and nuclei extraction for sequencing (MultiVINE-seq) approach to profile the paired transcriptomes and epigenomes of human brain vascular cells across 30 individuals with varying cognitive statuses. By integrating single-nucleus transcriptomic and epigenomic data, we identified key transcriptional regulators and gene networks that define human brain vascular cell specialization. Mapping GWAS variants onto our multi-omic atlas revealed that many disease risk variants lie within putative regulatory regions in vascular, perivascular, and immune cell types. Capturing these previously unaccounted-for cell types allowed us to newly map 2,605 disease-associated variants to their target cell types and genes. Cerebrovascular disease risk variants converged on vascular endothelial, mural, and perivascular fibroblast cells, disrupting extracellular matrix (ECM) gene regulation. In contrast, Alzheimer"s disease (AD) risk variants were overrepresented in endothelial cells, microglia, and perivascular immune cells, perturbing the expression of adaptor proteins that fine-tune pathology-induced inflammatory responses. Notably, we uncovered a genome-wide significant AD variant predicted to enhance the expression of the T cell receptor adaptor gene PTK2B in brain CD8 T cells, potentially amplifying their infiltration, effector functions, and cytotoxicity. This finding provides genetic evidence supporting the role of adaptive immunity in AD pathogenesis. Variant-to-function relationships were validated through the integration of orthogonal epigenomic (in-silico ChIP-Seq models, Activity-By-Contact modeling), transcriptomic (eQTL), and protein-level (immunohistochemistry) data. Our work expands our view of gene regulatory networks and risk variants to include those active in the human brain vasculature, highlighting their contributions to diverse neurological disorders.
Coverage
Spatial:
US
Follow Up:
Unknown
Provenance
Temporal
Accrual Periodicity:
Static
Start Date:
01 January 2026
Time Lag:
Not applicable
Accessibility
Access
Access Rights:
See dataset for details. Access data at:
Observations
Statistical Population
Population Description
Population Size
Measured Property
Observation Date
Persons
0
Count
01 January 2026