Epigenome-wide DNA methylation profiling reveals risk genes for migraine and its subtypes

Nov 29, 2025The journal of headache and pain

DNA methylation patterns linked to migraine and its types

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Abstract

A total of 169 CpG sites were identified with causal effects on migraine, mapping to 68 genes.

Migraine risk is associated with changes, suggesting a potential causal role.
Ten additional genes related to migraine subtypes were identified, including specific genes for migraine with aura (MA) and migraine without aura (MO).
Twelve high-confidence genes were prioritized, with three genes (CFDP1, ICA1L, SERPING1) consistently supported by multiple analytical approaches.
Functional analyses revealed significant involvement of calcitonin-like ligand receptors, axon development, and neurovascular regulation in migraine pathology.
Drug-gene interaction analyses indicate potential therapeutic targets such as MAPT and CALCA for migraine treatment.

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BACKGROUND: Migraine is a highly disabling neurovascular disorder, yet its underlying molecular mechanisms remain incompletely understood. Emerging evidence implicates epigenetic modifications, particularly , in migraine pathophysiology, but whether these changes play a causal role has not been established.

METHODS: We integrated large-scale brain and blood methylation quantitative trait loci (mQTL) datasets with genome-wide association study (GWAS) data to investigate the causal role of DNA methylation in migraine and its subtypes. Two-sample (MR) was applied to evaluate the effects of cytosine-phosphate-guanine (CpG) methylation on migraine risk. Significant CpG sites were annotated to genes and refined through a multi-step prioritization framework incorporating colocalization, expression QTL (eQTL)-MR, two-step MR, and gene-based association analyses. Functional enrichment, protein-protein interaction, and drug-gene analyses were then performed to explore biological mechanisms and therapeutic potential.

RESULTS: We identified 169 CpG sites with causal effects on migraine, mapping to 68 genes. Subtype analyses revealed 10 additional genes associated with MA and MO, including three genes specific to MA and one to MO, expanding the total to 72 non-overlapping migraine risk genes. Integrative prioritization highlighted 12 high-confidence genes, among which CFDP1, ICA1L and SERPING1 was supported by all five analytical approaches. Functional characterization indicated significant enrichment in calcitonin-like ligand receptors, axon development and neurovascular regulation, while drug-gene interaction analyses suggested therapeutic potential for targets such as MAPT and CALCA.

CONCLUSION: Our findings provide robust evidence that DNA methylation contributes causally to migraine risk and its subtypes, identify genes of biological and therapeutic relevance, and offer novel insights into the epigenetic mechanisms underlying migraine pathophysiology.

Key numbers

169

Causal CpG Sites Identified

Total number of unique CpG sites linked to migraine risk.

Unique Genes Associated with Migraine

Total number of unique genes linked to migraine and its subtypes.

High-Confidence Genes Prioritized

Number of genes prioritized based on comprehensive analytical approaches.

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Epigenome-wide DNA methylation profiling reveals risk genes for migraine and its subtypes

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