APPENDICES 240 S ancestry-adjusted GWAS meta-analysis. Previously, multiple genetic risk loci for migraine have been reported by multiple studies based on ever increasing sample sizes. In Chapter 8 the sample size of the cohort was further increased to 102,084 migraine cases and 771,257 controls of European decent based on different international cohorts. In addition, the migraine subtype specificity was investigated in clinically diagnosed patients in 14,625 migraine with aura cases and 15,055 migraine without aura cases. The main meta-analysis identified 123 loci, of which 86 were novel compared to earlier studies. Remarkably the new risk loci included loci corresponding to genes transcribing calcitonin generelated peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). These are well-known migraine drug targets. This finding shows the clear potential for GWASs to identify (new) drug targets. Downstream analyses reconfirmed that neurovascular mechanisms underlie migraine pathophysiology as there was an enrichment for vascular and central nervous system tissue based on the risk loci. In a subtype analysis different risk loci were found for migraine with and without aura, and risk loci that increase disease susceptibility for both subtypes. Of note, CACNA1A a wellknown hemiplegic migraine gene was identified as one of three susceptibility loci for migraine with aura, thus now also genetically linking monogenic and polygenic forms of migraine. In continuation of the genetic studies of both monogenic and polygenic forms of migraine, in Chapter 9, genetic factors contributing to hemiplegic migraine were further investigated. For this study DNA was investigated of hemiplegic migraine patients in whom no mutation was detected in the known CACNA1A, ATP1A2 and SCN1A disease genes. Given the previous association with CACNA1A that popped up in Chapter 8 and associations of migraine with CACNA1B, CACNA1E and CACNA1H in other studies, made us consider the family of CACNA1x genes as an interesting target for burden testing (burden being the aggregation of both rare and common genetic variants as well as the increased presence of a variant in cases compared to controls). In total, the exome of 184 Australian hemiplegic migraine patients was sequenced. The subject and variant burden of missense variants in the CACNA1x genes of the hemiplegic migraine patients was compared to publicly available sequencing data from controls from gnomAD. An increase in burden in cases was found in CACNA1H and CACNA1I genes, a result that was replicated in an independent Dutch cohort of 32 patients with hemiplegic migraine. From this study it can be concluded that a burden of (non-pathogenic) missense variants in CACNA1H and CACNA1I is implicated as modifier genes that confer susceptibility to the hemiplegic migraine. Finally, Chapter 10 provides a general discussion of this thesis with considerations and suggestions for future research.
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