Migraine genetics : from monogenic to complex forms

Migraine has a strong genetic component, but the identification of these factors has proven difficult mainly because of the complex interaction of multiple loci and environmental factors. Unraveling its molecular basis and deciphering pathways leading to migraine attacks will help identifying novel treatment targets. For this thesis different genetic approaches were applied. Families with hemiplegic migraine (FHM), a rare monogenic subtype of migraine, were studied. Three genes were identified, all involved in modulation of ion influxes across neuronal and glial cell membranes. We identified many mutations in these genes and performed assays in cellular models to understand their functional consequences. In addition, we investigated the role of these genes in sporadic hemiplegic migraine (SHM). Importantly, we expanded the clinical spectrum associated with FHM genes, and established the link between migraine and epilepsy. We also performed genetic studies in common migraine families using two different approaches; the first was an outbred linkage approach with MO families, the second a family-based association approach with severe MA patients from a genetic isolate. Our results supported that, most likely, the intrinsic genetic heterogeneity in migraine families seriously hampers the identification of migraine loci and ultimately migraine genes.The studies presented in this thesis were performed at the Center for Human and Clinical Genetics of the Leiden University Medical Center (LUMC). This work was supported by grants of the Netherlands Organisation for Scientific Research (NWO) (ZonMW 912-02-085 and VICI 918.56.602); by the EU Research Network (grant HPRN-CT-2000-00082) and EU sixth framework programme (FP6) “EUROHEAD” (grant LSHM-CT-2004-504837); and the Centre for Medical Systems Biology (CMSB) established by the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research (NGI/NWO).UBL - phd migration 201