Genetic regulation of cell type-specific chromatin accessibility contributes to migraine etiology.
TL;DR
Two non-neuronal brain open chromatin regions are prioritized as likely causal contributors to migraine risk and identified candidate regulatory elements and target genes for further mechanistic and translational investigation.
Abstract
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.