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Background <p>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).</p> Methods <p>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.</p> Results <p>We identified 11 protein targets for CH (<i>p</i> &lt; 2.41 × 10<sup>–5</sup>), 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%.</p> Conclusions <p>We identified a set of potential protein targets for CH, characterized by rare side effects and a strong association with the biological mechanisms underlying the disorder. These findings offer valuable insights for the development of targeted drug therapies in the treatment of CH.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月20日

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  • Zhonghua Xiong,
  • Zhi 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 A Chalmer,
  • Maria Carolina Dalmasso,
  • Egil Ferkingstad,
  • Kumar Parijat Tripathi,
  • Elena Bacchelli,
  • Sigrid Børte,
  • Carmen Fourier,
  • Anja S Petersen,
  • Lisanne S Vijfhuizen,
  • Sigurdur H Magnusson,
  • Emer O’Connor,
  • Gyda Bjornsdottir,
  • 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 Guerzoni,
  • Prasanth Sivakumar,
  • Janice Yip,
  • Axel Heinze,
  • Fahri Küçükali,
  • Sisse R Ostrowski,
  • Ole B Pedersen,
  • Espen S Kristoffersen,
  • Amy E Martinsen,
  • María S 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,
  • Olafur A. Sveinsson,
  • Luca Pani,
  • Michele Zoli,
  • Josep A. Ramos-Quiroga,
  • Efthimios Dardiotis,
  • Anna Steinberg,
  • Steffi Riedel-Heller,
  • Christina Sjöstrand,
  • Thorgeir E. Thorgeirsson,
  • Hreinn Stefansson,
  • Laura Southgate,
  • Richard C. Trembath,
  • Jana Vandrovcova,
  • Raymond Noordam,
  • Koen Paemeleire,
  • Kari Stefansson,
  • Cathy Shen-Jang Fann,
  • Elisabet Waldenlind,
  • Erling Tronvik,
  • Rigmor H. Jensen,
  • Shih-Pin Chen,
  • Henry 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 Ramirez,
  • John-Anker Zwart,
  • Yonggang Wang,
  • Xueying Yu

摘要

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

We identified 11 protein targets for CH (p < 2.41 × 10–5), 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, characterized by rare side effects and a strong association with the biological mechanisms underlying the disorder. These findings offer valuable insights for the development of targeted drug therapies in the treatment of CH.