Headache Center, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.
CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, 16 Lincui Road, Beijing, China.
J Headache Pain. 2024 Sep 11;25(1):148. doi: 10.1186/s10194-024-01853-9.
Migraine is a highly prevalent and complex neurovascular disease. However, the currently available therapeutic drugs often fall to adequately meet clinical needs due to limited effectiveness and numerous undesirable side effects. This study aims to identify putative novel targets for migraine treatment through proteome-wide Mendelian randomization (MR).
We utilized MR to estimate the causal effects of plasma proteins on migraine and its two subtypes, migraine with aura (MA) and without aura (MO). This analysis integrated plasma protein quantitative trait loci (pQTL) data with genome-wide association studies (GWAS) findings for these migraine phenotypes. Moreover, we conducted a phenome-wide MR assessment, enrichment analysis, protein-protein interaction networks construction, and mediation MR analysis to further validate the pharmaceutical potential of the identified protein targets.
We identified 35 protein targets for migraine and its subtypes (p < 8.04 × 10), with prioritized targets showing minimal side effects. Phenome-wide MR identified novel protein targets-FCAR, UBE2L6, LATS1, PDCD1LG2, and MMP3-that have no major disease side effects and interacted with current acute migraine medication targets. Additionally, MMP3, PDCD1LG2, and HBQ1 interacted with current preventive migraine medication targets. The causal effects of plasma protein on migraine were partly mediated by plasma metabolites (proportion of mediation from 3.8% to 21.0%).
A set of potential protein targets for migraine and its subtypes were identified. These proteins showed rare side effects and were responsible for biological mechanisms involved in migraine pathogenesis, indicating priority for the development of migraine treatments.
偏头痛是一种高发且复杂的神经血管性疾病。然而，由于疗效有限且存在诸多不良反应，目前可用的治疗药物往往无法充分满足临床需求。本研究旨在通过全蛋白质组孟德尔随机化（MR）寻找偏头痛治疗的潜在新靶点。
我们利用 MR 来估计血浆蛋白对偏头痛及其两种亚型（有先兆偏头痛和无先兆偏头痛）的因果效应。该分析整合了血浆蛋白数量性状基因座（pQTL）数据和这些偏头痛表型的全基因组关联研究（GWAS）结果。此外，我们进行了全表型 MR 评估、富集分析、蛋白质-蛋白质相互作用网络构建和中介 MR 分析，以进一步验证鉴定的蛋白质靶标的药物潜力。
我们确定了 35 个偏头痛及其亚型的蛋白质靶点（p<8.04×10-8），其中优先靶点显示出最小的副作用。全表型 MR 确定了新的蛋白质靶点-FCAR、UBE2L6、LATS1、PDCD1LG2 和 MMP3-这些靶点没有主要疾病的副作用，并且与当前急性偏头痛治疗药物的靶点相互作用。此外，MMP3、PDCD1LG2 和 HBQ1 与当前预防性偏头痛治疗药物的靶点相互作用。血浆蛋白对偏头痛的因果效应部分由血浆代谢物介导（介导比例为 3.8%至 21.0%）。
确定了一组潜在的偏头痛及其亚型的蛋白质靶点。这些蛋白显示出罕见的副作用，并且负责偏头痛发病机制中涉及的生物学机制，表明它们是偏头痛治疗开发的优先靶点。
