Genetic risk variants in migraine and cardiovascular disease. The Gene HUNT study

Migraine is a common neurological disorder that leads to suffering and disability for those affected, and to a high cost for society. Those who have migraine with aura also have a moderately increased risk for developing cardiovascular disease, including stroke and heart attack. There has been an insufficient understanding of the biological and molecular mechanisms that cause migraine, and of why these individuals more often than others develop cardiovascular disease. Both migraine and cardiovascular disease are to a large extent heritable disorders, and it has been suggested that shared genetic factors may be part of the explanation why they tend to occur together. As part of this project we have participated in the completion of the largest genetic study of migraine to date, where 375,000 individuals participated, and where we identified 38 genetic risk loci for migraine. We are now finalizing an even larger study where we identify >100 gnetic risk loci. These results indicate that migraine is partially caused by dysfunction in smooth muscle of arteries. In other studes, we have showed that several genetic risk variants are shared between migraine, stroke and cardiovascular disease, and pinpointed genes that may be important for these disorders. Through genetic studies of, among others, 71,860 participants in the Nord-Trøndelag Health Survey, we will continue to work to reveal genetic causes of migraine and other headache disorders.

Prosjektet har i betydelig grad økt vår forståelse av genetiske årsaker til migrene, og sammenhengen mellom migrene og hjerte-/karsykdom. Resultatene har blitt formidlet gjennom 30 publikasjoner, blant annet i anerkjente tidsskrifter som Nature Genetics, Science, Neurology og Pain, samt gjennom foredrag og i offentlige medier. Resultatene fra prosjektet er allerede i utstrakt bruk av andre forskere, og det forventes å videre "nedstrøms" effekter av resultatene. Gjennom studien har vi konsolidert og utvidet vårt internasjonalt nettverk av forskere; lært avanserte metoder for genetiske analyser, som vi allerede benytter til analyser innen tilgrensende sykdomsfelt; og igangsatt flere studier som vil fortsettes etter dette prosjektets slutt.

Migraine is a common, chronic headache disorder affecting 6-7% of men and 18% of women. It is estimated to be one of the most costly of all neurological disorders, much due to its tendency to affect young people in their most productive years. Up to a thi rd of patients experience a migraine aura before or during headache attacks, characterized by transient neurological symptoms, most often visual in nature. Having migraine with aura is associated with a twofold increased risk of having an ischemic stroke, the risk being highest among women in younger (<45 years) age groups, and recent evidence suggests a similar risk increase also for myocardial infarction, angina, and overall cardiovascular mortality. Although many hypotheses have been put forward, the r eason why cardiovascular disease and risk factors are more common in migraineurs is unknown. It has been suggested that shared genetic factors between migraine and cardiovascular disease may be responsible for the comorbidity. The applicant spent 1,5 year s as a visiting scientist at the Wellcome Trust Sanger Institute, Cambridge UK, during his PhD period. He participated in performing the largest genome-wide meta-analysis done on migraine, which included more than 23,000 migraine patients. The results fro m this work was recently accepted for publication in Nature Genetics, with the applicant as shared first author. Our previous experience and extensive use of epidemiological and biobank data from the HUNT studies, as well as active participation within th e International Headache Genetics Consortium enable us to perform follow-up studies to elucidate the genetic mechanisms and possibly biological pathways underlying migraine and its comorbidities. Our research group will focus on the genetic basis of the c omorbidity between migraine and cardiovascular disease.