Genomic Architecture of Migraine: A Multi-ancestry GWAS Meta-analysis of 2.5 Million Participants
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Migraine is a leading cause of disability 1 , yet preventive treatment remains largely empirical despite the availability of several mechanistically distinct therapies 2 . Genetic data can clarify mechanisms and therapeutic hypotheses when association signals are integrated with molecular and clinical data 3 . We meta-analyzed migraine GWAS data from 12 European ancestry cohorts (206,893 cases and 2,093,175 controls) and four African ancestry cohorts (22,115 cases and 178,626 controls). We identified 311 lead variants in European-ancestry analyses and 316 lead variants in trans-ancestry analysis. Fine-mapping and transcriptome-wide analyses prioritized variants and genes implicated in sensory neuronal signaling, vascular tone, and immune regulation, with convergent evidence at several established loci including TRPM8 and PHACTR1 4 . Drug-repurposing analyses identified therapeutic targets and compounds, including established migraine treatments and candidates requiring experimental validation. Genetic correlations, Mendelian randomization, and a phenome-wide scan linked migraine liability to psychiatric, pain, and gastrointestinal phenotypes. Together, these findings expand the known genetic architecture of migraine across ancestries and provide a genetics-led map connecting association signals with biological pathways, multimorbidity and candidate therapeutic mechanisms, providing a foundation for future functional and translational studies.
Source: medRxiv
Authors: Cassie Overstreet, Marco Galimberti, Kazi Tanvir Hasan, Sarah Beck, Jack Hirsch, Sanjeev Sariya, Brian Ferolito, Yu Zhou, Yingzhe Zhang, Ellen I. Weinheimer, AnnMarie Lacobelle, Yaira Nunez, The VA Million Veteran Program, Henry R. Kranzler, J. Michael Gaziano, Murray B. Stein, Christopher Gottschalk, Karmel Choi, Alexandre C. Pereira, Joseph D. Deak, Gita A Pathak, Daniel F. Levey, Joel Gelernter
Institutions: Yale University, VA Connecticut Healthcare System, Icahn School of Medicine at Mount Sinai, VA Boston Healthcare System, Massachusetts General Hospital, Philadelphia VA Medical Center, University of Pennsylvania, Harvard University, Mass General Brigham, University of California San Diego, VA San Diego Healthcare System, Brigham and Women's Hospital
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: U.S. Department of Defense, U.S. Department of Veterans Affairs, Alzheimer's Association, Yale University, Office of Research and Development, University of Pennsylvania, National Institutes of Health, National Center for PTSD, U.S. Department of Veterans Affairs, National Institute on Alcohol Abuse and Alcoholism, National Institute on Aging, National Institute of Mental Health, National Institute on Drug Abuse
Awards: G2242242560, G2905247291, G2924140200, G342784211, G3809296745, G4704345230, Epigenomic burden of alcohol use disorder on polygenic risk of Alzheimer’s, G605948636, Expanding Genetic Understanding of Depression, Anxiety, and their Treatments, Multi-modal intersection of depression and genetic liability to Alzheimers disease, Psychiatric Genomics Consortium for PTSD, Using novel data sources across genetic, biological, and social domains to refine genome-wide investigations of substance use disorders, Collaborative Study on the Genetics of Alcoholism (COGA).
OpenAlex ID: W7204801223