SYSTEMATIC REVIEW article
Front. Neurol.
Sec. Headache and Neurogenic Pain
Volume 16 - 2025 | doi: 10.3389/fneur.2025.1660995
Causal Factors for Migraine in Mendelian Randomization Studies: A Systematic Review and Meta‐analysis
Provisionally accepted- 1West China School of Pharmacy, Sichuan University, Chengdu, China
- 2Department of Pharmacy/Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, China
- 3Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, West China School of Pharmacy, Sichuan University, Chengdu, China
- 4Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China
- 5Department of Public Health and Medicinal Administration, University of Macau, Macau, China
- 6Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, China
- 7Center for Primary Health Care Research, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden
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Background: Migraine is a familial, episodic disorder characterized by complex sensory processing dysfunction, with headache serving as its hallmark feature. While numerous risk factors have been proposed, the causal nature of these associations often remains ambiguous. Mendelian randomization (MR) represents a robust epidemiological framework that leverages genetic variants to infer causal relationships, thereby overcoming limitations of observational studies. This study systematically reviews and meta-analyzes MR evidence to elucidate bidirectional causal relationships between migraine and systemic diseases, identify novel risk determinants, and highlight critical gaps for future mechanistic investigations. Methods: A comprehensive literature search was conducted across seven databases using predefined search strategies and exclusion criteria. The search time limit was from the construction of the database to July 3, 2024. Study eligibility was independently assessed by two reviewers, with data extraction processes adhering to STROBE-MR guidelines. Included studies were evaluated for quality using validated criteria, and relevant data were systematically extracted. Data synthesis involved meta-analytical pooling of effect estimates using Review Manager 5.4, with forest plots generated to visualize results. Causal relationships were interpreted according to the WHO ICD-11 disease classification system, with subgroup analyses. Results: A total of 60 studies involving 331 MR analyses were included, revealing bidirectional causal relationships between migraine and multiple phenotypes: migraine was identified as a causal factor for 6 diseases and 7 non-diseases factors. Conversely, 6 diseases, 23 non-disease factors were causal determinants of migraine risk. Subtype-specific analyses showed MOA was causally associated with 4 diseases and 1 non-disease factor as an exposure, and influenced by 2 diseases and 3 non-disease factors as an outcome; MWA demonstrated causal relationships with 2 diseases as an exposure, and associations with 3 diseases and 3 non-disease factors as an outcome (p<0.05 for all). Conclusions: This systematic review provides robust genetic evidence supporting bidirectional causal relationships between migraine and multiple phenotypes. Subtype-specific analyses highlight distinct causal pathways for MOA and MWA, underscoring the clinical heterogeneity of migraine. These findings advance our understanding of migraine pathogenesis and inform precision medicine approaches. More data will be needed in the future to obtain a more specific assessment.
Keywords: Migraine, Mendelian randomization, causal relationship, Systematic review, Meta-analysis
Received: 07 Jul 2025; Accepted: 14 Aug 2025.
Copyright: © 2025 LI, Liu, Ni, Ni, Yang and Ji. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Jiaqi Ni, West China School of Pharmacy, Sichuan University, Chengdu, China
Shu Yang, West China School of Pharmacy, Sichuan University, Chengdu, China
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