Genetic regulation of cell type-specific chromatin accessibility contributes to migraine etiology.

Migraine is a common and disabling neurological disorder affecting many individuals. Most causal regulatory variants remain unresolved, particularly concerning their target cell types. Disease-associated variants are found in non-coding cis-regulatory elements. This indicates they modulate gene regulation in significant ways. Researchers performed two-sample Mendelian randomization using brain cell type-specific variants. They analyzed data from 616 postmortem brain donors and large migraine GWAS samples. They identified open chromatin regions reaching significance and replicated findings in the UK Biobank and the Million Veteran Program. Multi-modal target gene annotation integrated diverse models to evaluate potential drug targets. Out of 15,334 causal estimates, 19 reached significance, with seven replicated in both cohorts. Two non-neuronal chromatin regions were prioritized as likely migraine risk contributors. NGF was nominated as the highest-priority candidate gene, with TSPAN2 as a secondary candidate. These findings highlight important regulatory elements and target genes for future research. Clinical relevance: This research identifies potential genetic targets for migraine treatment, guiding future therapies.