# Unraveling the Cross-Tissue Neuroimmune–Vascular Genetic Architecture of Migraine Using Integrated Multi-Omics, Single-Cell, and Spatial Transcriptomics: Prioritizing T-Cell Regulatory Networks and Peripheral Targets

## TL;DR

This study identifies genetic and cellular networks linking immune and vascular systems to migraine, highlighting T-cell and vascular targets.

## Contribution

Integrates multi-omics data to reveal systemic neuroimmune-vascular architecture and prioritize T-cell regulatory pathways in migraine.

## Key findings

- Genetic signals are enriched in peripheral arteries, heart, and blood, with mucosal-smooth muscle organs implicated.
- T-cell co-expression modules in PBMCs reveal migraine-related immune activation pathways, including PTK2B.
- Spatial transcriptomics links migraine risk to craniofacial/meningeal and visceral smooth muscle-mucosal interfaces.

## Abstract

Migraine is a complex neurovascular disorder in which immune signaling intersects with vascular and neural circuits, yet the tissue and cell-type context of common genetic risk remains incompletely defined. We integrated large-scale migraine genome-wide association study (GWAS) summary statistics with Genotype-Tissue Expression (GTEx) v8 expression and splicing quantitative trait loci (eQTLs and sQTLs), Bayesian co-localization, single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from migraine cases and controls, a healthy single-cell multi-omics atlas (assay for transposase-accessible chromatin (ATAC) plus RNA), high-dimensional weighted gene co-expression network analysis (hdWGCNA), and embryo-level spatial transcriptomics. Genetic signals were enriched in peripheral arteries, heart, and blood, and gene-level enrichment highlighted mucosal–smooth muscle organs including the bladder and the cervix endocervix. Cell-type prioritization consistently implicated endothelial and vascular smooth muscle lineages, with additional support for inhibitory interneurons and bladder epithelium. In PBMC T cells, co-expression modules capturing cytotoxic/activation and T-cell receptor signaling programs contained migraine-prioritized genes, including PTK2B, nominating immune activation circuitry as a component of genetic susceptibility. Spatial projection further localized risk concordance to craniofacial/meningeal interfaces and visceral smooth muscle–mucosal structures. Together, these analyses delineate a systemic neuroimmune–vascular architecture for migraine and provide genetically anchored candidate pathways and targets for mechanistic and therapeutic follow-up.