A multi-ancestry meta [GWAS] of migraine among veterans: associations with traumatic brain injury, depression, and [PTSD], 2025, Gasperi et al

[forestglip]

A multi-ancestry meta genome-wide association study of migraine among veterans: associations with traumatic brain injury, depression, and post-traumatic stress disorder

Spoiler: Authors

Gasperi, Marianna; Rosenthal, Sara Brin; Maihofer, Adam X.; Gerstenberger, Armand; Dochtermann, Daniel; Choquet, Hélène; Pressman, Alice; Panizzon, Matthew S.; Stein, Murray B.; Schuster, Nathaniel M.; Pyarajan, Saiju; Afari, Niloofar; Nievergelt, Caroline M.

Abstract
Migraine is a neurovascular disorder that poses a high burden to Veterans, who face a greater risk than sex-matched individuals in the general population. Genetic research on migraine in Veterans and its link to psychiatric comorbidities is limited.

We present a meta-analysis of a genome-wide association study (GWAS) of migraine in a predominantly male sample of over 433,000 Veterans, including 87,859 cases, from the Million Veteran Program (MVP), identifying 49 genome-wide significant loci, with 36 novel to this study, of which 7 replicated in an independent prior GWAS (after Bonferroni correction for number of loci tested).

Our analyses revealed 283 genes, including some newly associated with migraine: MAML3, CELF4, IRX1, ASXL1, SPOCD1, CXCL , and TLR4 . In silico analyses showed enrichment in brain and uterine tissues, which may reflect broader hormonal or neuroendocrine pathways. Compared to previous migraine GWAS, our results show minimal vascular tissue enrichment, potentially reflecting the sample composition, which was predominantly men and Veterans.

Migraine SNP-based heritability was 10% for men and 16% for women, and several sex-specific loci were identified through sex-stratified analyses. Despite high genetic correlations with neuropsychiatric disorders – including post-traumatic stress disorder, depression, and traumatic brain injury – Mendelian randomization analyses found no causal links.

Finally, we prioritized potential migraine drug targets, including losmapimod (which reduces production of toxic DUX4 protein) and TLR4 antagonists.

Web | DOI | PMC | PDF | Molecular Psychiatry | Open Access

 

[forestglip]

I previously saw that the MAGMA results in an anxiety GWAS showed the same top four enriched tissues as DecodeME:

Interestingly, the top four significantly enriched tissues based on MAGMA are the same four tissues as DecodeME, in the same order:
Frontal Cortex, Cortex, Anterior Cingulate Cortex BA24, Nucleus Accumbens.

This migraine study also matches for those top four tissues:

 

[forestglip]

They did a lot of comparing their findings to a previous migraine GWAS: New and sex-specific migraine susceptibility loci identified from a multiethnic genome-wide meta-analysis (2021, Communications Biology)

I took a look at that paper, and interestingly, in the MAGMA analysis in that study, brain tissues were not even close to significant:

 

[forestglip]

The first MAGMA plot above is for 54 specific tissues. For the more general tissue grouping, there were two significant tissues showing enrichment of GWAS genes, both in the full cohort, and in the men-only cohort: brain and uterus. Here is the plot for men:


This is interesting, because males do not have uteruses. So they suggest that it may instead be indicating importance in migraine of pathways which are similar to those in the uterus, but found elsewhere in the body.

Enrichment was also observed in the uterus, suggesting a possible link with hormone regulation and sex-specific mechanisms in migraine etiology and potentially reflecting shared pathways with neurovascular and endocrine function.

Because several loci responsible for uterine enrichment (e.g., CELF4, TLR4) also show significant expression in endocrine and neuroendocrine regions, including the hypothalamus and adrenal gland in GTEx, it is possible that the uterus functions primarily as a sentinel tissue within a broader domain of endocrine regulation that is active in both men and women, rather than signaling a women-specific mechanism.

Because the MVP cohort is over 90% men, the uterine enrichment is more likely to reflect shared neuroendocrine pathways instead of direct influences on female reproductive organs. This finding was seen in both the multi-ancestry meta-analysis (META_C) and the men-only trans-ancestry META_Men analysis, highlighting the possibility that the uterine tissue enrichment may be a proxy for a broader biological process that remains unmeasured but is central to migraine pathophysiology.