Abstract

Genome-wide association studies of migraine have yielded 123 genetic variants with different functions, suggesting that migraine is a heterogenous disorder with different underlying mechanisms. 

The aim of this PhD was to dissect migraine sub-phenotypes and their genetic component to learn more about the incompletely understood biology of migraine.

The hypothesis was that the most severe form of migraine, chronic migraine (CM), and a very specific symptom of migraine, osmophobia (aversion towards smell during migraine attack), are migraine sub-phenotypes. Here, the diagnosis CM and osmophobia accompanied by migraine were refined and their genetic component was assessed. Refined criteria for CM were proposed, extending them to include patients with a significant disease burden. Utilising genotype data and whole-genome sequencing data, results showed that CM does not have a genetic component. 

Results from our nosographic analysis of osmophobia showed that osmophobia is a migraine specific symptom that can help differentiate tension type-headache from migraine. However, it was not favourable to include osmophobia in the diagnostic criteria of migraine. Since, osmophobia was very specific for migraine, polygenic risk score analysis was done. Patients with osmophobia had a higher genetic load for migraine compared with patients without osmophobia, indicating that osmophobia may be a candidate migraine endophenotype. 

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