Shared genetic basis for migraine and ischemic stroke: A genome-wide analysis of common variants.
Malik R., Freilinger T., Winsvold BS., Anttila V., Vander Heiden J., Traylor M., de Vries B., Holliday EG., Terwindt GM., Sturm J., Bis JC., Hopewell JC., Ferrari MD., Rannikmae K., Wessman M., Kallela M., Kubisch C., Fornage M., Meschia JF., Lehtimäki T., Sudlow C., Clarke R., Chasman DI., Mitchell BD., Maguire J., Kaprio J., Farrall M., Raitakari OT., Kurth T., Ikram MA., Reiner AP., Longstreth WT., Rothwell PM., Strachan DP., Sharma P., Seshadri S., Quaye L., Cherkas L., Schürks M., Rosand J., Ligthart L., Boncoraglio GB., Davey Smith G., van Duijn CM., Stefansson K., Worrall BB., Nyholt DR., Markus HS., van den Maagdenberg AM., Cotsapas C., Zwart JA., Palotie A., International Headache Genetics Consortium None., Dichgans M., METASTROKE Collaboration of the International Stroke Genetics Consortium None.
OBJECTIVE: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation. METHODS: We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping. RESULTS: We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p = 6.4 × 10(-28) for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p = 2.7 × 10(-20) for the CE score in MO). CONCLUSIONS: Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype.