GENERAL DISCUSSION 219 10 that the effect of these overlapping risk loci in cluster headache is much larger than it ever was in migraine, even though the sample size is smaller. This result also disputes that the overlapping loci are merely a result of contamination of migraine cases. In addition, cluster headache also showed a correlation with pain, depression, but above all with smoking and risk-taking behaviour traits, but this was different from what was seen in migraine. Migraine did also show a correlation with pain and depression, but not with smoking and risk-taking behaviour (Chapter 7). This suggest that migraine and cluster headache have a partly shared and a partly distinct genetic basis, which reflects the partly shared and partly distinct biological mechanisms. Giving meaning to GWAS data Over the last decade or so, GWAS have also been able to identify many low-effect risk DNA variants for common migraine. With each study, the sample size steadily increased as did the number of associated DNA variants. In 2016 the at the time most recent migraine GWAS (59,674 cases and 316,078 controls) produced 44 LD-independent SNPs generating 38 distinct genomic loci associated with migraine.108 Downstream bioinformatics analysis showed that the genes associated with these loci were primarily linked to arterial and smooth muscle function. This was in agreement with the shared polygenic genetic risk between migraine, stroke and cardiovascular diseases that had been described previously.109, 110 In Chapter 8 we performed the latest (2022) migraine GWAS with almost twice as many cases and controls (102,084 cases and 771,257 controls).108 We were able to identify 123 distinct genomic regions associated with migraine, of which 86 loci were novel compared to the 2016 migraine GWAS.108 Given that many of the loci replicate provides proof for the robustness of the loci. In addition, with downstream analysis an additional 44 genome-wide significant independent variants were identified resulting in a total of 167 independent SNPs in Chapter 8. Enrichment analyses suggested the involvement of vascular and central nervous system tissue/cell types, this is in concordance with the concept that migraine is a neurovascular disorder. In addition, risk loci that encode genes associated with migraine drug targets (calcitonin gene-related peptide; CGRP encoded by CALCA/CALCB and serotonin 1F receptor encoded by HTR1F) were identified.111, 112 This clearly illustrates the potential of genetic studies to identify future drug targets. Additionally, migraine subtype analysis in clinically well diagnosed cases resulted in three risk variants (in MPPED2, CACNA1A and HMOX2) that were specific for migraine with aura and two (one near FECH and one near SPINK2) that were specific for migraine without aura. Most notably is CACNA1A, which is known as one of the three genes (CACNA1A, ATP1A2 or SCN1A) in which a single high-penetrant mutation could lead to hemiplegic migraine.113-115 Taken together mutations in CACNA1A can lead to hemiplegic migraine, but variants in CACNA1A contribute also to the risk for common migraine, linking CACNA1A to both monogenetic and polygenetic forms of migraine. In 2021 a migraine GWAS (28,852 cases and 525,717 controls) with more ethnically diverse individuals (East Asian, African American, and Hispanic/Latino
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