| Title: | A phenome-wide association study reveals novel phenotypic determinants of migraine risk in the UK Biobank |
| Journal: | Headache The Journal of Head and Face Pain |
| Published: | 10 Jun 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42267619/ |
| DOI: | https://doi.org/10.1111/head.70079 |
Publication 20759
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Abstract
OBJECTIVE: To identify genetic and phenotypic determinants of migraine susceptibility and progression using a large-scale, hypothesis-free approach.</p>
BACKGROUND: Migraine is a common neurological disorder with a substantial individual and societal burden. While risk factors are known, hypothesis-driven approaches may overlook contributors.</p>
METHODS: We analyzed data from 502,364 UK Biobank participants (aged 37-73 years; recruited 2006-2010) to assess associations between migraine and 2824 phenotypes, including observational associations and associations with migraine polygenic risk scores. Time-dependent associations were evaluated, and causality was assessed. Follow-up extended from baseline through to November 30, 2024, with a median of ~14.7 years.</p>
RESULTS: Our analyses identified 253 phenotypes significantly associated with migraine risk, 191 phenotypes associated with migraine PRS, and 87 overlapping between the two approaches. Cox regression analysis confirmed 84 robust time-dependent associations and highlighted novel risk factors, such as oral ulcers (adjusted hazard ratio [aHR] = 1.14, 95% confidence interval [CI]: 1.02-1.28, q = 2.54 × 10-2), lower limb obesity (aHR = 1.01, 95% CI: 1.00-1.02, q = 3.52 × 10-4), and hormone replacement therapy (aHR = 1.39, 95% CI: 1.29-1.50, q = 1.95 × 10-17). MR analysis also revealed causal associations with emotional fluctuations (inverse-variance weighting odds ratio [IVW OR] 4.10, 95% CI = 1.76-9.53, q = 1.00 × 10-2), neuroticism (IVW OR = 1.12, 95% CI = 1.07-1.08, q = 1.24 × 10-5), general health ratings (IVW OR = 1.81, 95% CI = 1.43-2.29, q = 3.30 × 10-2), and fatigue (IVW OR = 1.94, 95% CI = 1.35-2.79, q = 5.73 × 10-36). However, the association with paracetamol use (IVW OR = 9.65 × 104, 95% CI = 1.67 × 104-5.57 × 105, q = 5.73 × 10-36) had uncertain directionality on Steiger testing and should be interpreted cautiously. In total, 87 genetic and phenotypic determinants of migraine were identified, offering new therapeutic targets involving inflammatory and insulin-like growth factor 1 (IGF-1) -related pathways.</p>
CONCLUSIONS: This comprehensive analysis provides new insights into the genetic and phenotypic factors that influence migraine. The findings suggest new targets for therapeutic intervention and provide a basis for the development of precision prevention and clinical management strategies.</p>
16 Keywords
- Adult
- Aged
- Biological Specimen Banks
- Female
- Genetic Predisposition to Disease
- Genetic Risk Score
- Genome-Wide Association Study
- Humans
- Male
- Middle Aged
- Migraine Disorders
- Phenomics
- Phenotype
- Risk Factors
- UK Biobank
- United Kingdom
20 Authors
- Changhe Shi
- Shuangjie Li
- Yuanyuan Liang
- Dongrui Ma
- Zhengwei Hu
- Yunchao Wang
- Zhiyun Wang
- Shasha Qi
- Xiaoyan Hao
- Mengjie Li
- Chunyan Zuo
- Chenwei Hao
- Yanmei Feng
- Yuemeng Sun
- Chen Wang
- Ruwei Yang
- De Yang
- Yonggang Wang
- Chengyuan Mao
- Shilei Sun
Enabling scientific discoveries that improve human health