Li Da-Peng, Feng Chun-Bo, Wang Li, Tao Ye, Han Yan-Xun
Department of Otolaryngology, Head and Neck Surgery, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, China.
Scientific Research and Experiment Center, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, China.
J Headache Pain. 2025 Nov 13;26(1):255. doi: 10.1186/s10194-025-02179-w.
Migraine, a complex neurovascular disorder, is closely associated with neuroinflammation and immune dysregulation. However, the high heterogeneity of immune cell populations means that the specific cellular immune mechanisms driving migraine susceptibility remain unclear.
We integrated single-cell expression quantitative trait locus (sc-eQTL) data by applying single-cell Mendelian randomization (Mendelian randomization applied at single-cell resolution, scMR) and colocalization analyses to systematically explore immune-mediated regulatory mechanisms underlying migraine and to identify potential therapeutic targets.
We assessed the causal effects of 9,117 unique sc-eQTLs on migraine across 14 immune cell types. Four genes (PRDM11, VIM, FGFRL1, C6orf25) were identified as high-priority targets. Colocalization analysis revealed a high probability (posterior probability PP.H4 > 0.90) that these genes share causal variants with migraine genome-wide association study (GWAS) signals. Single-cell RNA sequencing (scRNA-seq) analyses revealed differential expression patterns of these genes across cell types and migraine-related states. Safety assessments based on phenome-wide association studies (PheWAS) showed a low risk of off-target effects in multiple body systems, thus supporting their safety as therapeutic targets. Mapping these targets to a database of known drugs identified three repurposable drug candidates (one approved and two investigational) with therapeutic potential for migraine.
This study establishes an extensible multi-omics analytical framework, providing novel insights into the immunogenetic basis of migraine. Furthermore, it successfully identified repurposable candidate drugs targeting key pathogenic genes, offering new perspectives for developing novel immunomodulatory therapeutic strategies for migraine.
偏头痛是一种复杂的神经血管疾病，与神经炎症和免疫失调密切相关。然而，免疫细胞群体的高度异质性意味着驱动偏头痛易感性的特定细胞免疫机制仍不清楚。
我们通过应用单细胞孟德尔随机化（在单细胞分辨率下应用的孟德尔随机化，scMR）和共定位分析来整合单细胞表达定量性状位点（sc-eQTL）数据，以系统地探索偏头痛潜在的免疫介导调节机制，并确定潜在的治疗靶点。
我们评估了14种免疫细胞类型中9117个独特sc-eQTL对偏头痛的因果效应。确定了四个基因（PRDM11、VIM、FGFRL1、C6orf25）为高优先级靶点。共定位分析显示，这些基因与偏头痛全基因组关联研究（GWAS）信号共享因果变异的可能性很高（后验概率PP.H4>0.90）。单细胞RNA测序（scRNA-seq）分析揭示了这些基因在不同细胞类型和偏头痛相关状态下的差异表达模式。基于全表型组关联研究（PheWAS）的安全性评估表明，这些基因在多个身体系统中产生脱靶效应的风险较低，因此支持它们作为治疗靶点的安全性。将这些靶点映射到已知药物数据库中，确定了三种具有偏头痛治疗潜力的可重新利用的候选药物（一种已获批，两种正在研究中）。
本研究建立了一个可扩展的多组学分析框架，为偏头痛的免疫遗传学基础提供了新的见解。此外，它成功地确定了针对关键致病基因的可重新利用的候选药物，为开发新的偏头痛免疫调节治疗策略提供了新的视角。
