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Migraine genes and neurobiological pathways

Final Report Summary - EUROHEAD (Migraine genes and neurobiological pathways)

Migraine is a common chronic pain syndrome with recurrent attacks of disabling headache, associated symptoms and, in one third of patients, neurological aura symptoms. Over 12 % of the general population have migraine attacks regularly (median 18 times per year). Two-thirds of this population is female. The World Health Organization (WHO) rates migraine in the highest class of most disabling chronic disorders. Migraine-related annual costs in EU amount to EUR 27 billion. Acute attack treatments are satisfactory in only less than half of patients. Effective and well-tolerated prophylactic migraine agents are dearly needed.

It is assumed that rare familial and common complex types of migraine share common genes and pathways. Focusing on families and isolated populations, integrated genome wide scans, linkage disequilibrium mapping, bioinformatics and association studies, the underlying mechanisms of onset of pain and aura by studying the causal (candidate) genes for migraine attacks were investigated. Instead of using end diagnoses of migraine, endophenotypes, more specific trait component analysis was used in some of the genetic studies.

In addition to gene identification activities, the project also investigated the functional consequences of gene mutations in cellular and animal models of migraine, and when possible in migraine patients, by using electrophysiological, neurobiological (e.g. cortical spreading depression) techniques. Thus, EUROHEAD made progress to unravel migraine pathways, achieving better opportunities for diagnosis and design of future migraine therapies.

Research on migraine is booming. In the decade preceding the project, three genes were identified in families with familial hemiplegic migraine. Functional studies in cellular and transgenic animal models pointed to a common pathway of increased potassium and glutamate conferring increased susceptibility for cortical spreading depression (CSD) as the most likely mechanism for this disorder.

There was enough evidence from clinical and basic scientific research to support the view that ionic disturbance may also play a role in the common forms of migraine. Comparison of this basic neurobiological research with clinical research using provocation paradigms in the project showed that, at least in part, migraine attacks in migraine with and without aura may occur through independent mechanisms.

European research to identify gene variants conferring migraine susceptibility was combined as a result of the project. A first project was the recently completed large case control study of thousands of deoxyribonucleic acid (DNA) variants in ion transporter genes that, unfortunately, did not yield significant, replicated, DNA variants. The same Consortium for Genetic Research aimed to tackle even larger initiatives aimed at identifying gene variants for migraine in the coming decade. The project also yielded strong, coherent groups of researchers to perform ground-breaking clinical research and basic neurobiological research in order to better understand the migraine patient and migraine pathophysiology. Such knowledge is important as migraine is one of the most common chronic pain syndromes and is associated with immense socioeconomic burden for the European Union.

The ultimate impact of the project was providing the molecular basis for therapeutic and preventative approaches for this common disabling disorder. The entire EUROHEAD project was aimed at improving the health of migraine patients and quality of life for families affected by this major neurological disease. Economic development and impact will be affected by these research achievements. Enhanced understanding of the neurobiology of migraine will influence, initiate or enhance therapeutic activities and will form the basis of clinical trials. Economic benefits were expected not only for European small and medium-sized enterprises (SMEs) and larger (European) pharmaceutical companies, but also for the patients in Europe, as the project increased the awareness that migraine and other primary headache disorders are 'true diseases' and deserve utmost priority.

The EUROHEAD project had impact in many ways:
1) for the first time a strong coherent multidisciplinary network of researchers with expertise in clinical, genetic and basic neurobiological aspects of primary headaches was formed (and will continue to exist now the project has ended);
2) this network already attracted other European and non-European researchers and continues to grow;
3) the project ensured that Europe will remain the leader in headache research worldwide (no such network existed elsewhere in and/or outside Europe);
4) the project provided European industry with a necessary concentration of high-quality headache research on the continent;
5) the project increased awareness on the importance of headache as a real, treatable disease to various stakeholders (including the scientific community, pharmaceutical companies, policymakers, patients and the general public);
6) the project - being a Specific Targeted Research Project (STREP) - had a major impact on our understanding of migraine as a disease with:
i) novel migraine genes and loci identified;
ii) novel cellular and animal models generated and characterised;
iii) novel migraine mechanisms unravelled in these models and in patients;
iv) novel pan-European tools for diagnosis of migraine established.