Aster Harder

GENETIC SUSCEPTIBILITY LOCI IN GENOME-WIDE ASSOCIATION STUDY OF CLUSTER HEADACHE 117 6 Introduction Cluster headache (CH) is a primary headache disorder characterized by attacks of intense unilateral orbital, supraorbital and/or temporal pain that lasts for 15-180 minutes and is associated with ipsilateral facial autonomic symptoms and/or restlessness. The majority of patients have episodic CH, with periods of cluster headache of weeks to months, alternating with attack-free periods of at least 3 months. In 10-15% of patients cluster periods never remit for longer than three months for at least one year, classifying them as chronic CH. The male-to-female ratio is 2:1.1 Smoking and psychiatric co-morbidities are prevalent.2 Current treatment strategies include aborting acute attacks and aim to reduce attack frequency with preventive treatment.3 CH shows some phenotypic overlap with other trigeminal neuralgias, but also with migraine, e.g. in that some patients with migraine may also report autonomic features. Certain similar pathophysiological pathways are hypothesized to be involved in both CH and migraine.4 Although these disorders share prominent features, they are clinically well distinguishable.5 The pathophysiology of CH is poorly understood, although vasomotor changes, inflammation, hypothalamic dysfunction, and dysregulation of the autonomic nervous system have been implicated as potential disease mechanisms.6 Twin and family studies have highlighted the involvement of genetic factors in CH.7 Thus far, most genetic studies used a hypothesis-driven approach and have examined a limited number of variants in genes linked to presumed pathways in CH. Most studied are variants in HCRTR2, which encodes the hypocretin (orexin) type 2 receptor that binds neuropeptides hypocretin-1 and -2 in the central nervous system. Still, initially positive genetic findings for HCRTR2 associations8-10 were not replicated in better-powered studies.11, 12 Finally, the first, though very small hypothesis-free, Italian genome-wide association study (GWAS) investigating 99 patients with CH reported suggestive associations with genetic variants in ADCYAP1R1 and MME,13 but these findings were not replicated in a larger Swedish sample.14 To detect genetic variants for CH, we conducted a GWAS in a Dutch sample of 840 patients with CH and 1,457 controls from the same geographical region. Results were replicated in a Norwegian sample. Downstream analyses further assessed genes and mechanisms contributing to the pathogenesis of CH. Methods Patient recruitment and sample collection The Dutch cluster headache study included 862 Dutch CH patients from the clinic-based Leiden University Cluster headache neuro-Analysis program (LUCA) that were recruited between 2010 and 2015 via the project’s website. CH patients aged 18 years or older were included. Participants

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