Scholarlink

Background <p>Migraine affects approximately 14% of adults, but the molecular mechanisms underlying susceptibility remain incompletely understood. Although genome-wide association studies (GWAS) have identified many migraine risk loci, translating these associations into biological insight remains challenging. Environmental and physiological migraine triggers, including hormones, diet and stress, may act partly through epigenetic mechanisms such as DNA methylation. Because many migraine risk variants are non-coding and may influence disease through regulatory effects, integrating genetic association data with DNA methylation and gene expression may help refine migraine-associated loci into candidate molecular mechanisms.</p> Methods <p>We performed a novel methylome-wide association study (meWAS) of migraine, imputing genetically regulated DNA methylation at 86,518 cytosine-phosphate-guanine (CpG) sites using GWAS summary statistics derived from 102,084 migraine cases and 771,257 controls of European ancestry. We then linked DNA methylation signals to imputed gene expression using transcriptome-wide association study (TWAS) evidence across 49 Genotype-Tissue Expression tissues. Bayesian colocalisation analyses were used to prioritise CpGs and genes supported by shared causal variants with migraine risk, and to map shared regulatory signals between methylation and expression quantitative trait loci.</p> Results <p>We identified 258 migraine-associated CpG sites after Bonferroni correction (<i>P</i> &lt; 5.78 × 10<sup>–7</sup>), of which 177 colocalised with migraine GWAS variants (PP4 &gt; 0.5) and mapped to 69 independent genomic loci, including 58 established and 11 putative novel loci. Integration with TWAS evidence prioritised 199 genes (candidate-set Bonferroni-corrected TWAS <i>P</i> &lt; 7.84 × 10<sup>–5</sup>) near these CpG sites, including 91 genes with evidence of colocalisation with migraine GWAS variants. Further colocalisation between methylation and expression quantitative trait signals mapped shared regulatory signals to 120 CpGs and 78 genes across 40 independent genomic loci, comprising 32 established and eight putative novel migraine risk loci. Protein–protein interaction analysis showed modest but significant network enrichment, with local modules implicating signalling organisation, mitochondrial function, oxidative stress, and related regulatory processes.</p> Conclusions <p>These findings show that migraine susceptibility is partly shaped by shared genetic regulation of DNA methylation and gene expression. By refining GWAS loci into candidate genes and molecular signals, this integrative multi-omic framework highlights distributed molecular pathways relevant to neuronal and vascular responsiveness and identifies candidates for future functional characterisation.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Integrative genetic analysis identifies shared regulation of DNA methylation and gene expression in migraine risk

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月31日

查看全文
  • Ammarah Ghaffar,
  • Dale R. Nyholt

摘要

Background

Migraine affects approximately 14% of adults, but the molecular mechanisms underlying susceptibility remain incompletely understood. Although genome-wide association studies (GWAS) have identified many migraine risk loci, translating these associations into biological insight remains challenging. Environmental and physiological migraine triggers, including hormones, diet and stress, may act partly through epigenetic mechanisms such as DNA methylation. Because many migraine risk variants are non-coding and may influence disease through regulatory effects, integrating genetic association data with DNA methylation and gene expression may help refine migraine-associated loci into candidate molecular mechanisms.

Methods

We performed a novel methylome-wide association study (meWAS) of migraine, imputing genetically regulated DNA methylation at 86,518 cytosine-phosphate-guanine (CpG) sites using GWAS summary statistics derived from 102,084 migraine cases and 771,257 controls of European ancestry. We then linked DNA methylation signals to imputed gene expression using transcriptome-wide association study (TWAS) evidence across 49 Genotype-Tissue Expression tissues. Bayesian colocalisation analyses were used to prioritise CpGs and genes supported by shared causal variants with migraine risk, and to map shared regulatory signals between methylation and expression quantitative trait loci.

Results

We identified 258 migraine-associated CpG sites after Bonferroni correction (P < 5.78 × 10–7), of which 177 colocalised with migraine GWAS variants (PP4 > 0.5) and mapped to 69 independent genomic loci, including 58 established and 11 putative novel loci. Integration with TWAS evidence prioritised 199 genes (candidate-set Bonferroni-corrected TWAS P < 7.84 × 10–5) near these CpG sites, including 91 genes with evidence of colocalisation with migraine GWAS variants. Further colocalisation between methylation and expression quantitative trait signals mapped shared regulatory signals to 120 CpGs and 78 genes across 40 independent genomic loci, comprising 32 established and eight putative novel migraine risk loci. Protein–protein interaction analysis showed modest but significant network enrichment, with local modules implicating signalling organisation, mitochondrial function, oxidative stress, and related regulatory processes.

Conclusions

These findings show that migraine susceptibility is partly shaped by shared genetic regulation of DNA methylation and gene expression. By refining GWAS loci into candidate genes and molecular signals, this integrative multi-omic framework highlights distributed molecular pathways relevant to neuronal and vascular responsiveness and identifies candidates for future functional characterisation.