To identify pan-ancestry and ancestry-specific genetic variants, as well as cell-type specific gene functions associated with migraine in the Million Veteran Program (MVP) Study. 

Migraine pathophysiology is complex and involves interplay between genetic and environmental risk factors. MVP is an ongoing national cohort launched in 2011 to investigate how genetics, lifestyle and military exposures contribute to diseases. It is one of the largest and most diverse biorepositories in the world.

We performed a genome-wide association study (GWAS) of genetic variations in Veterans with migraine. A diagnosis of migraine vs non-migraine was ascertained using questionnaire and ICD codes. GWAS was performed in four different ancestry groups: European (EUR), African (AA), Hispanic (HIS), and Asian (ASN). Sex, Age, and 3 principal components were adjusted as covariates. Pan-ancestry GWAS was performed using METAL. Cell-type specific enrichment analyses were performed using enrichR. Pathways analyses were performed using Web-based Gene Set analysis Toolkit.

A total of 90,600 migraine cases and were identifie d. Prevalence rates of migraine in this cohort (648,172) by ancestry were: EUR n=60,957 (13.1%), AA n=19,709 (16.0%), ASN n=1,267 (15.2%) and HIS n=8,667 (16.6%). Ancestry specific risk loci were identified: 624 SNPs in EUR, 3 SNPs in AA, 8 SNPs in HIS, and 59 SNPs in ASN. Meta-Analysis across all four ancestries identified a total of 789 SNPs, of which 778 SNPs represent novel variants (p-value < 5E-8). Pathway analysis suggests involvement of interleukin signaling, ionotropic glutamate receptor, synaptic vesicle trafficking, JAK/STAT, EFGR and PDGF signaling pathways. These genetic risk variants are near genes whose expression are enriched in neurons, immune cells, fibroblast, microglia, and astrocytes.

Novel genetic risk variants and their functional consequences, as well as cell-type specific enrichment associated with migraine have been identified. Our findings underscore the critical need for more inclusive participation in migraine research.