GENERAL INTRODUCTION 19 1 94). Endocannabinoids were measured using a previously validated micro-liquid chromatographytandem mass spectrometry (micro-LC-MS/MS) technique. In Chapter 5 the role of PGE2 in the (early) phase of an induced migraine attack was investigated.To this end, PGE2 plasma levels were measured towards in the (pre)ictal state of a glyceryl trinitrate (GTN) provoked attack in women with and without migraine. Part II Genetics of different headache forms In Chapter 6 a GWAS in cluster headache is described. This study aims to demonstrate whether there are robust genetic associations for cluster headache. The study investigated 840 Dutch patients and a replication was performed in 144 Norwegian patients. In Chapter 7 a metaanalysis of multiple GWAS studies of cluster headache with patients from Norway, Sweden, UK Germany, Denmark, Greece, Spain, Italy and the Netherlands (in total 4,043 patients) is conducted to not only confirm previous risk loci but also identify new disease risk loci. Using a Mendelian randomization approach it is investigated whether the intensity of cigarette smoking has a causal effect on cluster headache. Chapter 8 describes a meta-analysis of multiple GWAS studies in migraine (102,084 migraine cases and 771,257 controls). Specific risk loci for migraine subtypes are investigated in a clinical sample. The aim of Chapter 9 is to investigate whether there is an increased burden in hemiplegic migraine of missense variants in CACNA1X genes in patients without a high-penetrant disease-causing mutation in one of the well-known hemiplegic migraine genes (CACNA1A, ATP1A2, and SCN1A). The study illustrates the genetic complexity of hemiplegic migraine and the possibility of a spectrum ranging from high-risk rare mutations to low-risk common variants contributing to the risk for all forms of migraine. Finally, Chapter 10 provides a general discussion of the thesis together with suggestions for future research.
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