Wang Xiaoyu, Pang Wendu, Hu Xin, Shu Tao, Luo Yaxin, Li Junhong, Feng Lan, Qiu Ke, Rao Yufang, Song Yao, Mao Minzi, Zhang Yuyang, Ren Jianjun, Zhao Yu
Department of Oto-Rhino-Laryngology, West China Hospital, Sichuan University, Chengdu, China.
Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
Hum Genet. 2025 Apr;144(4):391-404. doi: 10.1007/s00439-024-02725-7. Epub 2025 Jan 22.
The genetic relationship between migraine and stroke remains underexplored, particularly in the context of druggable targets. Previous studies have been limited by small sample sizes and a lack of focus on genetic-targeted therapies for these conditions. We analyzed the association and causality between migraine and stroke using multivariable logistic regression in the UK Biobank cohort and Mendelian randomization (MR) analyses based on genome-wide association study (GWAS) data. Integrating expression quantitative trait loci (eQTLs) data from blood and brain regions, we explored the phenotypic and genetic links between migraine medications, drug target, and stroke. Additionally, we explored novel druggable genes for migraine and evaluated their effects on migraine signaling molecules and stroke risk. Migraine was significantly associated with stroke, particularly ischemic stroke (IS) and intracerebral hemorrhage (ICH), with MR analysis confirming a causal link to ICH. HTR1A emerged as a potential link between antidepressants (preventive medications for migraine) and stroke. We identified 17 migraine-related druggable genes, with 5 genes (HMGCR, TGFB1, TGFB3, KCNK5, IMPDH2) associated with nine existing drugs. Further MR analysis identified correlation of CELSR3 and IMPDH2 with cGMP pathway marker PRKG1, and identified KCNK5, PLXNB1, and MDK as novel migraine-associated druggable genes significantly linked to the stroke risks. These findings established the phenotypic and genetic link between migraine, its medication and stroke, identifying potential targets for single and dual-purpose therapies for migraine and stoke, and emphasized the need for further research to validate these associations.
偏头痛与中风之间的遗传关系仍未得到充分研究，尤其是在可成药靶点方面。以往的研究受到样本量小以及缺乏针对这些病症的基因靶向治疗的关注的限制。我们使用英国生物银行队列中的多变量逻辑回归以及基于全基因组关联研究（GWAS）数据的孟德尔随机化（MR）分析，分析了偏头痛与中风之间的关联和因果关系。整合来自血液和脑区的表达定量性状位点（eQTL）数据，我们探索了偏头痛药物、药物靶点与中风之间的表型和遗传联系。此外，我们探索了偏头痛的新型可成药基因，并评估了它们对偏头痛信号分子和中风风险的影响。偏头痛与中风显著相关，尤其是缺血性中风（IS）和脑出血（ICH），MR分析证实了与ICH的因果关系。5-羟色胺受体1A（HTR1A）成为抗抑郁药（偏头痛预防性药物）与中风之间的潜在联系。我们鉴定出17个与偏头痛相关的可成药基因，其中5个基因（3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）、转化生长因子β1（TGFB1）、转化生长因子β3（TGFB3）、钾通道亚家族K成员5（KCNK5）、肌苷-5'-单磷酸脱氢酶2（IMPDH2））与9种现有药物相关。进一步的MR分析确定了钙黏蛋白表皮生长因子样受体3（CELSR3）和IMPDH2与环磷酸鸟苷（cGMP）途径标志物蛋白激酶G1（PRKG1）的相关性，并确定KCNK5、血小板/内皮细胞黏附分子1（PLXNB1）和Midkine（MDK）为与中风风险显著相关的新型偏头痛相关可成药基因。这些发现建立了偏头痛及其药物与中风之间的表型和遗传联系，确定了偏头痛和中风单用途及两用疗法的潜在靶点，并强调需要进一步研究以验证这些关联。
