Department of Radiology, The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China.
The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China.
J Headache Pain. 2024 Nov 22;25(1):202. doi: 10.1186/s10194-024-01922-z.
Migraine is a prevalent neurological disorder affecting 14.1% of the global population. Despite advances in genetic research, further investigation is needed to identify therapeutic targets and better understand its mechanisms. In this study, we aimed to identify drug targets and explore the relationships between gene expression, protein levels, and migraine pathophysiology.
We utilized cis-pQTL data from deCODE Genetics, combined with migraine GWAS data from the GERA + UKB cohort as the discovery cohort and the FinnGen R10 cohort as the replication cohort. SMR and MR analyses identified migraine-associated protein loci. Brain eQTL data from GTEx v8 and BrainMeta v2 were used to explore causal relationships between gene expression, protein levels, and migraine risk. Mediation analysis assessed the role of metabolites, and PheWAS evaluated potential side effects.
Four loci were identified: PNKP, MRVI1, CALCB, and INPP5B. PNKP and MRVI1 showed a high level of evidence and opposing effects at the gene and protein levels. PNKP gene expression in certain brain regions was protective against migraine, while its plasma protein levels were positively associated with migraine risk. MRVI1 showed protective effects at the protein level but had the opposite effect at the gene expression level. Mediation analysis revealed that the glutamate to pyruvate ratio and 3-CMPFP mediated PNKP's effects on migraine. PheWAS indicated associations between PNKP and body composition traits, suggesting drug safety considerations.
PNKP and MRVI1 exhibit dual mechanisms of action at the gene and protein levels, potentially involving distinct mechanistic pathways. Among them, PNKP emerges as a promising drug target for migraine treatment, supported by multi-layered validation.
偏头痛是一种常见的神经系统疾病，影响全球 14.1%的人口。尽管在遗传研究方面取得了进展，但仍需要进一步的研究来确定治疗靶点，更好地了解其机制。在这项研究中，我们旨在确定药物靶点，并探索基因表达、蛋白质水平与偏头痛病理生理学之间的关系。
我们利用 deCODE 遗传学的顺式 pQTL 数据，结合 GERA + UKB 队列的偏头痛 GWAS 数据作为发现队列，以及 FinnGen R10 队列作为复制队列。SMR 和 MR 分析确定了与偏头痛相关的蛋白质位点。我们使用 GTEx v8 和 BrainMeta v2 的脑 eQTL 数据来探索基因表达、蛋白质水平与偏头痛风险之间的因果关系。中介分析评估了代谢物的作用，而 pheWAS 则评估了潜在的副作用。
确定了四个位点：PNKP、MRVI1、CALCB 和 INPP5B。PNKP 和 MRVI1 在基因和蛋白质水平上都具有高水平的证据和相反的作用。特定脑区的 PNKP 基因表达对偏头痛具有保护作用，而其血浆蛋白水平与偏头痛风险呈正相关。MRVI1 在蛋白质水平上表现出保护作用，但在基因表达水平上则相反。中介分析表明，谷氨酸到丙酮酸的比值和 3-CMPFP 介导了 PNKP 对偏头痛的作用。pheWAS 表明 PNKP 与身体成分特征之间存在关联，这表明需要考虑药物安全性。
PNKP 和 MRVI1 在基因和蛋白质水平上表现出双重作用机制，可能涉及不同的机制途径。其中，PNKP 作为偏头痛治疗的一个有前途的药物靶点，得到了多层次的验证。
