Genetic regulation of cell type-specific chromatin accessibility contributes to migraine etiology.
BACKGROUND Migraine is a common and disabling neurological disorder, yet most causal regulatory variants and their target cell types remain unresolved. Disease-associated variants are enriched in non-coding cis-regulatory elements, indicating that they act by modulating gene regulation. Chromatin accessibility quantitative trait loci (caQTLs) capture genetic effects on these regulatory elements with cell-type resolution and can pinpoint the regulatory regions and cellular contexts mediating disease risk. However, brain cell type-specific caQTLs have not previously been integrated with migraine genetics. METHODS We performed two-sample Mendelian randomization (MR) using brain cell type-specific cis-caQTLs from sorted neuronal (NeuN⁺) and non-neuronal (NeuN⁻) nuclei of 616 postmortem brain donors as exposures, with FinnGen Release 12 migraine GWAS (26,894 cases / 374,605 controls) as the discovery outcome. Open chromatin regions (OCRs) reaching Bonferroni-corrected significance were replicated in the UK Biobank (25,393 cases / 433,047 controls) and the Million Veteran Program (31,836 cases / 405,831 controls), and further evaluated by Bayesian colocalization and instrument-level phenome-wide screening. Multi-modal target gene annotation integrated Hi-C, cis-eQTL, ABC, and ENCODE-rE2G models; nominated genes were further evaluated for drug-target safety using gene-level rare-variant collapsing analyses and characterized for regional brain expression using the Human Protein Atlas. RESULTS Of 15,334 OCR-migraine causal estimates, 19 reached Bonferroni-corrected significance in FinnGen R12. Seven were Bonferroni-replicated in both replication cohorts with concordant directions, and three showed strong colocalization (PP.H4 > 0.80). After excluding one OCR with extensive cardiovascular pleiotropy, two non-neuronal OCRs were retained: Peak_7234 (chr1:115,282,554-115,283,246) and Peak_124742 (chr4:35,524,861-35,526,079). Multi-modal annotation of Peak_7234 convergently nominated NGF as the highest-priority candidate target gene, with TSPAN2 as a secondary candidate; Peak_124742 lies in a gene-poor region with insufficient regulatory annotation to confidently nominate a target gene. Neither NGF nor TSPAN2 showed associations reaching phenome-wide significance. CONCLUSIONS Two non-neuronal brain open chromatin regions are prioritized as likely causal contributors to migraine risk. At the chr1:115.3 Mb region, NGF is nominated as the highest-priority candidate downstream target, with TSPAN2 as a complementary candidate. These findings extend cell type-specific causal mapping of migraine to the regulatory layer and identify candidate regulatory elements and target genes for further mechanistic and translational investigation. CLINICAL TRIAL NUMBER Not applicable.