CHAPTER 1 18 1 Another way in which GWAS data can be used is by investigating the genetic relationships between traits, one of these analysis is Mendelian randomisation (MR). MR is able to entangle the pleiotropy that exists across many traits. In an MR analysis, genetic variants associated with an exposure are identified and regressed upon an outcome measurement to infer causality (i.e., direction) of the association. Given the random assortment of alleles at gametogenesis in early life, this method is less likely to suffer from issues of confounding and reverse causation than methods used in conventional observational epidemiological studies.118 For a successful MR analysis, three assumptions need to be fulfilled.119 (I) Variants used as instrumental variables (IVs) need to be associated with the exposure. (II) The IVs only affect the outcome through the exposure, not through any other causal pathway. Factors that may lead to violation of this assumption include population stratification, LD and horizontal pleiotropy, the latter means that there is an (in)direct independent association of the IV (or another SNP in LD with the IV) with another trait that is not in the causal pathway of the investigated relation. (III) The IVs must not be associated with confounders. In one-directional MR the possible causal relation between trait X on trait Y is investigated, in bidirectional MR studies the directional effect from trait Y on trait X is also investigated. Outline of this thesis The research conducted for this thesis is divided in two parts. Part 1 of the thesis focuses on biochemical studies in migraine. Here the biochemistry of migraine is investigated in: (i) a targeted approach, focusing on one or more related selected pathways of interest or, (ii) an untargeted approach aiming to simultaneously measure as many metabolites as possible from a biological sample. Part 2 of the thesis focusses on genetical studies in both migraine and cluster headache using next-generation sequencing data and array genotyping data. Part I Biochemistry of migraine In Chapter 2 we investigated whether the overall metabolic profile in blood of patients with migraine differed from those without migraine. Close to 100 metabolites were measured with 1H-NMR spectroscopy in blood serum of 289 individuals with migraine and 1,360 individuals without migraine, all derived from a genetic isolate in the South-West of the Netherlands. Chapter 3 describes whether CSF levels of amines, measured using an untargeted approach correlate with blood plasma levels in healthy volunteers. The study was then extrapolated to migraine patients. This chapter illustrates to what extent amine levels of CSF and blood relate to each other and seems to emphasize the role of blood-brain-barrier transport. Chapter 4 investigates whether the endocannabinoid system is disrupted in interictal patients with migraine. To this end, the levels of three endocannabinoids in CSF were investigated in interictal (e.g. outside an attack) individuals with migraine with aura (n = 97) and without aura (n = 97) compared to healthy volunteers (n =
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