83: Sex-stratified genome-wide association analysis finds a novel female-specific migraine locus in CAP2

Topic: Basic Science
Subtopic: Pain category (ICD-11), Chronic primary headache, , , Omics (Proteomics/Metabolomics/Transcriptomics/Genomics), , , , , ,

Background and Aims: Migraine is a debilitating, chronic disease that disproportionately affects females, with prevalence three to four times higher than in males. While the genetic architecture of migraine has been explored extensively, few studies have investigated whether sex-dependent genetic effects contribute to this disparity. We therefore sought to characterize differences in the genetic architecture of migraine between females and males using genome-wide association study (GWAS) approaches, and to identify alleles that may contribute to sex differences in migraine phenotypes.

Methods: We performed sex-stratified GWAS in European-ancestry participants from the All of Us (AoU) database [1] using SAIGE, comprising 4,835 male cases (83,198 controls) and 20,300 female cases (113,164 controls). Migraine was defined using SNOMED-CT concept codes encompassing migraine, migraine with and without aura, chronic migraine, and migraine variants. Summary statistics from the two strata were compared using Cochran's Q as a per-variant index of heterogeneity, with significance defined as P_het < 0.05; the magnitude of heterogeneity was indexed by I². Functional and regulatory annotations of identified variants were examined for relevance to sex-dependent etiological pathways. To prioritize findings, we focused on variants that additionally reached genome-wide significance (p < 5 × 10⁻⁸) in at least one stratum.

Results: Of variants tested in both strata, 840,386 showed nominally significant sex heterogeneity, and two reached genome-wide significance in one sex. The top heterogeneous variant, rs150235640 (chr6:17393872; intronic to CAP2), showed a genome-wide significant association with migraine in women (BETA = −0.072, p = 7.43 × 10⁻⁹) with no detectable effect in men (BETA = 0.043, p = 0.065), yielding P_het = 1.4 × 10⁻⁵ and I² = 94.7%. CAP2 encodes a brain-enriched cyclase-associated actin regulator involved in dendritic spine morphology and synaptic plasticity, with eQTL evidence for CAP2 expression in cerebellum, tibial nerve, and arterial tissues. We also identified sex-heterogeneous effects at the known migraine and vascular risk locus PHACTR1, rs6458545 (chr6:12934070; P_het = 0.04, I² = 76.2%), a phosphatase and actin regulator previously implicated in migraine, coronary artery disease, and cervical artery dissection, with a larger effect in women (BETA = 0.067, p = 3.43 × 10⁻⁹) than in men (BETA = 0.017, p = 0.44).

Conclusions: Sex-stratified GWAS identified CAP2 as a novel female-specific migraine locus, with a protective effect observed exclusively in women. Rather than contradicting the higher female prevalence of migraine, this finding suggests the variant may buffer against a subset of sex-dependent etiological pathways operating in women but not in men. The overall sex disparity in migraine prevalence reflects the aggregate of many genetic and non-genetic risk factors, and female-specific protective variants are consistent with a complex genetic architecture in which individual loci may act in opposing directions relative to net population-level risk. These findings highlight the value of systematic sex-heterogeneity testing in complex trait genetics and support a neurovascular mechanism with possible sex-dependent regulation at the CAP2 locus.

References: 1. All of Us Research Program Genomics Investigators. Genomic data in the All of Us Research Program. Nature. 2024

Presenting Author: Matthew Seebald
Submitting Author: Matthew Seebald

Senior Author: Ian R. Gizer

IASP 2026 Global Year theme of Neuropathic Pain: No

• Ellen Wanheung Yeung: PhD - Department of Psychological and Brain Sciences, Columbian College of Arts and Sciences, The George Washington University
• Ian Robert Gizer: PhD - College of Arts and Science Psychological Sciences, University of Missouri