Migraine-driven causal genes in ischemic stroke
- 1Ningbo Key Laboratory of Nervous System and Brain Function, Department of Neurosurgery, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, China
- 2Ningbo Hangzhou Bay Hospital, Ningbo, Zhejiang 315336, China
- 3Ningbo Key Laboratory of Nervous System and Brain Function, Department of Neurosurgery, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang 315010, China; Corresponding author.
Abstract
Migraine, most notably migraine with aura, elevates the risk of ischaemic stroke, though the underlying causal molecular connections have not been fully elucidated. This study sought to uncover migraine-associated causal genes that confer susceptibility to ischaemic stroke and to dissect their cell-type-specific functional mechanisms operating within the neurovascular unit. We combined publicly available human transcriptomic resources, genetics-driven causal inference, machine-learning-assisted biomarker screening, mouse-derived single-cell and spatial transcriptomic atlases, immune-cell deconvolution, and in-silico molecular docking. Twenty migraine-related genes were detected with causal associations to ischaemic-stroke risk. We prioritised three consensus hub genes: CD79A, PKN2, and PRKDC. In stroke patients, CD79A was significantly downregulated, while PKN2 and PRKDC exhibited elevated expression; their reliable diagnostic capacity was further confirmed in an independent external cohort. Single-cell and spatial transcriptomic profiling mapped these hub genes to endothelial, myeloid and glial cell populations residing within a dynamic inflammatory-vascular pathological niche in mouse ischaemic brain lesions. Mechanistic analyses pointed to perturbed mitochondrial energy homeostasis and dysregulated adaptive immune responses as downstream consequences modulated by these hub genes. Molecular-docking simulations demonstrated high-affinity interactions between Tamibarotene, Dirithromycin and the three encoded hub proteins, highlighting these compounds as promising candidates for drug repurposing. Collectively, our multi-omics analysis pinpoints CD79A, PKN2 and PRKDC as migraine-derived causal targets for ischaemic stroke, delivers cell- and spatial-resolved mechanistic perspectives on neurovascular-unit injury, and puts forward lead compounds awaiting further pre-clinical validation.
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BibTeX
@article{zhang2026migrainedriven,
title = {{Migraine-driven causal genes in ischemic stroke}},
author = {Zhimeng Zhang and Pengyu Lin and Haojin Ni and Yong Li and Jie Wei and Junjun Zhang and Zifeng Dai and Yuchun Liu and Liyuan Han and Jinghui Lin},
journal = {Neurotherapeutics},
year = {2026},
month = nov,
doi = {10.1016/j.neurot.2026.e01113},
url = {https://doi.org/10.1016/j.neurot.2026.e01113},
note = {CC BY},
}
RIS
TY - JOUR
TI - Migraine-driven causal genes in ischemic stroke
AU - Zhimeng Zhang
AU - Pengyu Lin
AU - Haojin Ni
AU - Yong Li
AU - Jie Wei
AU - Junjun Zhang
AU - Zifeng Dai
AU - Yuchun Liu
AU - Liyuan Han
AU - Jinghui Lin
PY - 2026
DA - 2026/11/05
JO - Neurotherapeutics
DO - 10.1016/j.neurot.2026.e01113
UR - https://doi.org/10.1016/j.neurot.2026.e01113
AB - Migraine, most notably migraine with aura, elevates the risk of ischaemic stroke, though the underlying causal molecular connections have not been fully elucidated. This study sought to uncover migraine-associated causal genes that confer susceptibility to ischaemic stroke and to dissect their cell-type-specific functional mechanisms operating within the neurovascular unit. We combined publicly available human transcriptomic resources, genetics-driven causal inference, machine-learning-assisted biomarker screening, mouse-derived single-cell and spatial transcriptomic atlases, immune-cell deconvolution, and in-silico molecular docking. Twenty migraine-related genes were detected with causal associations to ischaemic-stroke risk. We prioritised three consensus hub genes: CD79A, PKN2, and PRKDC. In stroke patients, CD79A was significantly downregulated, while PKN2 and PRKDC exhibited elevated expression; their reliable diagnostic capacity was further confirmed in an independent external cohort. Single-cell and spatial transcriptomic profiling mapped these hub genes to endothelial, myeloid and glial cell populations residing within a dynamic inflammatory-vascular pathological niche in mouse ischaemic brain lesions. Mechanistic analyses pointed to perturbed mitochondrial energy homeostasis and dysregulated adaptive immune responses as downstream consequences modulated by these hub genes. Molecular-docking simulations demonstrated high-affinity interactions between Tamibarotene, Dirithromycin and the three encoded hub proteins, highlighting these compounds as promising candidates for drug repurposing. Collectively, our multi-omics analysis pinpoints CD79A, PKN2 and PRKDC as migraine-derived causal targets for ischaemic stroke, delivers cell- and spatial-resolved mechanistic perspectives on neurovascular-unit injury, and puts forward lead compounds awaiting further pre-clinical validation.
SN - 1878-7479
SN - 1933-7213
ER -