Ye Hong, Huang Yajing, Wang Cheng, Jin Jiancheng, Jiang Chaoya, Fang Junjie, Xu Qiuhan
Xiangshan Hospital of TCM Medical and Health Group, Ningbo City, Zhejiang Province, China.
Department of Obstetrics and Gynecology, Tongji Hospital Affiliated to Tongji University, Putuo District, Shanghai, China.
J Headache Pain. 2025 Dec 5;27(1):14. doi: 10.1186/s10194-025-02241-7.
Migraine is a common, disabling neurological disorder. Genome-wide association studies have mapped numerous migraine risk loci, but the causal genes and their cell-type context remain unclear. Prior work linked migraine GWAS to bulk brain eQTLs; however, tissue-average signals obscure cell-specific regulation.
We extended these findings to single-cell resolution. Cis-eQTL instruments from 183 human donors across eight brain cell types were filtered by genome-wide significance, LD pruning, and instrument strength, yielding 1,746 independent eGenes. Two-sample Mendelian randomization (MR) tested effects on migraine risk in FinnGen R12 (discovery) with replication in UK Biobank (GCST90473326). To control for multiple testing, we applied within-cell-type Bonferroni correction and global false discovery rate (FDR) adjustment. Bayesian colocalization was performed in both discovery and replication cohorts to evaluate shared causal variants. We also performed a phenome-wide association screen (PheWAS) and profiled regional brain RNA.
Eleven eGenes were significant in FinnGen. Protective associations were observed for BTBD16 in excitatory and inhibitory neurons, RRP15 in excitatory neurons, CCDC146 and GSTM3 in oligodendrocytes, and PDE4B in microglia. Risk-increasing associations were found for GSTM2 (excitatory neurons), RIMS1 and DPH1 (astrocytes), AADAC (microglia), and RBM20 (endothelium). Replication supported signals for inhibitory-neuronal BTBD16 and astrocytic RIMS1. Colocalization analyses indicated shared causal variants at both loci in the discovery cohort (PP.H4 > 0.80). PheWAS showed no genome-wide liabilities for either gene. Regional expression suggested white-matter enrichment for BTBD16 and a cerebellar peak for RIMS1.
Cell-type-specific MR sharpens migraine mechanisms beyond bulk tissue and prioritizes inhibitory-neuronal BTBD16 (protective) and astrocytic RIMS1 (risk-increasing) for mechanistic validation and therapeutic exploration.
偏头痛是一种常见的、使人丧失能力的神经系统疾病。全基因组关联研究已经定位了许多偏头痛风险基因座，但致病基因及其细胞类型背景仍不清楚。先前的研究将偏头痛全基因组关联研究与全脑表达定量性状基因座（eQTL）联系起来；然而，组织平均信号掩盖了细胞特异性调控。
我们将这些发现扩展到单细胞分辨率。通过全基因组显著性、连锁不平衡（LD）修剪和工具强度，对来自8种脑细胞类型的183名人类供体的顺式eQTL工具进行筛选，得到1746个独立的e基因。两样本孟德尔随机化（MR）在芬兰基因研究R12（发现队列）中测试对偏头痛风险的影响，并在英国生物银行（GCST90473326）中进行重复验证。为了控制多重检验，我们应用了细胞类型内的邦费罗尼校正和全局错误发现率（FDR）调整。在发现队列和重复验证队列中均进行了贝叶斯共定位分析，以评估共享的因果变异。我们还进行了全表型组关联筛选（PheWAS）并分析了区域脑RNA。
11个e基因在芬兰基因研究中具有显著性。在兴奋性和抑制性神经元中观察到BTBD16的保护关联，在兴奋性神经元中观察到RRP15的保护关联，在少突胶质细胞中观察到CCDC146和GSTM3的保护关联，在小胶质细胞中观察到PDE4B的保护关联。在兴奋性神经元中发现GSTM2（增加风险）、在星形胶质细胞中发现RIMS1和DPH1（增加风险）、在小胶质细胞中发现AADAC（增加风险）以及在内皮细胞中发现RBM20（增加风险）的风险增加关联。重复验证支持抑制性神经元BTBD16和星形胶质细胞RIMS1的信号。共定位分析表明，在发现队列中的两个基因座都存在共享的因果变异（PP.H4＞0.80）。PheWAS显示这两个基因在全基因组范围内均无相关疾病。区域表达提示BTBD16在白质中富集，而RIMS1在小脑中有表达峰值。
细胞类型特异性的MR研究深化了对偏头痛机制的认识，超越了对大块组织的研究，并确定了抑制性神经元的BTBD16（具有保护作用）和星形胶质细胞的RIMS1（增加风险），以便进行机制验证和治疗探索。
