CHAPTER 10 210 10 Introduction In this thesis both migraine and cluster headache were investigated. For migraine, studies were performed in the fields of genomics, metabolomics but also specific molecules involved in a biological pathway were investigated. For cluster headache, the research focussed only on genomics. The aim of Part I of the thesis was to gain a better understanding of the biochemical profile of migraine. We hypothesized that individuals with migraine have a different biochemical profile, reflecting disturbances in molecular processes relevant to the pathophysiology of the disease. To this end, we investigated profiles of biochemical compounds interictally (i.e. outside an attack) and ictally (i.e. during an attack) in individuals with migraine and compared these with profiles obtained from control individuals to identify differences in metabolites and molecules relevant to the disease. Findings of the studies conducted for the thesis are discussed and put in perspective with other biochemical findings in migraine. In addition, it is shortly discussed what can be learned from such studies. The aim of Part II was to investigate the genetic underpinnings of migraine and cluster headache. The most recent findings in genome-wide association studies (GWAS) and next-generation sequencing analysis in migraine and cluster headache are presented. It is shown that cross-trait and causal analyses are beginning to identify and characterise specific biological factors that contribute to migraine and cluster headache risk, as well as their comorbid conditions. The combination of metabolomics and genomics data is discussed and followed by a short general reflection and opportunities for future research. Biochemistry of migraine Human health is dependent on the interaction of genes and environmental factors (e.g. medication and lifestyle). The metabolomic profile can be considered the endpoint of biological workings that include genomic, epigenomic, transcriptomic, proteomic, and environmental factors. A benefit of metabolomics is that it takes environmental factors into account and therefore represents a broader view of the phenotype at the molecular level than, for instance, genomics alone. In a way, metabolomics is the unbiased sum of all biochemical processes.This makes studying metabolomics very relevant when trying to elucidate the aetiology of a disease. Within biochemical research, studies can focus on different aspects of the metabolic system, as was done by either looking at specific molecules, i.e. at amines (Chapter 3), endocannabinoids (Chapter 4), and prostaglandin E2 (PGE2) (Chapter 5), or by looking at a more unbiased biochemical profile (Chapter 2). By investigating the overall system and/or by combining different aspects of the architecture of a disease the results of the studies in the end might implicate similar biological mechanisms. One step further is to combine various omics approaches by which new insights in the disease pathology can be gained and through which biological systems can be interlinked.
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