Uncovering drug targets for cluster headache through proteome-wide Mendelian randomization analysis

作者：Zhonghua Xiong, Zhi Kai Guo, Lei Zhao, Dong Qiu, Yanliang Mei, Xiaoshuang Li, Peng Zhang, Mantian Zhang, Geyu Liu, Tianshuang Gao, Bendik S Winsvold, Aster V. E. Harder, Caroline Ran, Mona Ameri Chalmer, Carolina Dalmasso, Egil Ferkingstad, Kumar Parijat Tripathi, Elena Bacchelli, Sigrid Børte, Carmen Fourier, Anja Sofie Petersen, Lisanne S. Vijfhuizen, Sigurður H. Magnússon, Emer O’Connor, Gyða Björnsdóttir, Paavo Häppölä, Yen‐Feng Wang, Ida Callesen, Tim Kelderman, Victor J Gallardo, Irene de Boer, Felicia Jennysdotter Olofsgård, Katja Heinze, Nunu Lund, Laurent F. Thomas, Chia‐Lin Hsu, Matti Pirinen, Heidi Hautakangas, Marta Ribasés, Simona Guérzoni, Prasanth Sivakumar, Janice Yip, Axel Heinze, Fahri Küçükali, Sisse Rye Ostrowski, Ole Birger Pedersen, Espen Saxhaug Kristoffersen, Amy E. Martinsen, María Soler Artigas, Susie Lagrata, Maria Michela Cainazzo, Joycee Adebimpe, Olivia Quinn, Carl Göbel, Anna Cirkel, Alexander E. Volk, Stefanie Heilmann‐Heimbach, Anne Heidi Skogholt, Maiken E. Gabrielsen, Leopoldine A. Wilbrink, Daisuke Danno, Dwij Mehta, Daníel F. Guðbjartsson, Frits R. Rosendaal, Ko Willems van Dijk, Rolf Fronczek, Michael Wagner, Martin Scherer, Hartmut Göbel, Kristel Sleegers, Ólafur Á. Sveinsson, Luca Pani, Michele Zoli, Josep A. Ramos-Quiroga, Efthimios Dardiotis, Anna Steinberg, Steffi Riedel-Heller, Christina Sjöstrand, Thorgeir E. Thorgeirsson, H Stefansson, Laura Southgate, Richard C. Trembath, Jana Vandrovcová, Raymond Noordam, Koen Paemeleire, Kari Stefansson, Cathy Shen-Jang Fann, Elisabet Waldenlind, Erling Tronvik, Rigmor H. Jensen, Shih-Pin Chen, H Houlden, Gisela M. Terwindt, Christian Kubisch, Elena Maestrini, Michail Vikelis, Patricia Pozo-Rosich, Andrea C. Belin, Manjit Matharu, Arn M.J.M. van den Maagdenberg, Thomas F. Hansen, Alfredo Ramı́rez, John-Anker Zwart, Yonggang Wang, Xueying Yu · 发表于：The Journal of Headache and Pain · 年份：2025 · DOI：10.1186/s10194-025-01999-0 · 被引用次数：5 · 研究领域：Migraine and Headache Studies、Cerebrovascular and genetic disorders、Connective Tissue Growth Factor Research

BACKGROUND: Cluster headache (CH) is a highly disabling primary headache disorder with a complex underlying mechanism. However, there are currently no effective targeted therapeutic drugs available. Existing medications often have limited efficacy and numerous side effects, which frequently fail to meet clinical needs. This study aims to identify potential new therapeutic targets for CH through proteome-wide mendelian randomization (PWMR). METHODS: We used PWMR to estimate the causal effects of plasma proteins on CH. This analysis integrated plasma protein quantitative trait loci (pQTL) data with genome-wide association study (GWAS) results of CH phenotypes. In addition, we conducted various sensitivity analyses, enrichment analyses, phenome-wide MR assessments, protein-protein interaction network construction, and mediation MR analyses to further validate the drug potential of the identified protein targets. RESULTS: ), with high-priority candidates exhibiting minimal side effects. Phenome-wide MR revealed novel targets-PXDNL, CCN4, PKD1, LGALS9, and MRC1-that show no significant disease-related adverse effects and interact with established preventive CH drug targets. Notably, PXDNL interacts with both acute and preventive CH drug targets. Furthermore, the causal effect of plasma proteins on CH is partially mediated by cortical surface area, with mediation proportions ranging from 3.2% to 10.0%. CONCLUSIONS: We identified a set of potential protein targets for CH, characteri...