GENERAL DISCUSSION 221 10 causal relationship, and one found a protective influence of large artery stroke on migraine.122-124 One study showed that an increase in blood pressure leads to an increase in migraine risk.125 A similar result was observed in another study where both a raise in systolic blood pressure and diastolic blood pressure increased migraine susceptibility.126 In addition, another study showed that migraine leads to an increased coronary artery disease risk.127 Combining these results with what is already found in metabolomics studies supports a role of lipids in migraine pathophysiology. Apart from disease traits a some MR studies in migraine have investigated behavioural traits, such as smoking and coffee and alcohol consumption.128, 129 Chapter 6 was one of the first GWASs that resulted in risk loci for cluster headache. By the benefit of this study the genetic relationship of cluster headache with other traits and diseases could further be explored. The most notable, the long debated relationship between smoking and cluster headache, as a large proportion of cluster headache patients are known to smoke (70-90%).130-132 Given that up to 40-60% of smoking addiction is due to genetic factors it may well be that there is a genetic link predisposing to both cluster headache and smoking.133, 134 In addition, tobacco-smoking might cause cluster headache, for instance as a result of tobacco leading to excessive trigeminal autonomic pathway and hypothalamic activation.135 This is supported by the observation that a majority of cluster headache patients (~80%) started smoking prior to cluster headache debut.131 This could be explained by smoking causing cluster headache or by the sharing of genetic architecture and/or other causal risk factors. Contrary to this, is the fact that there is a long latency (>15 years) between smoking onset and cluster headache debut and additionally smoking cessation does not lead to changes in disease severity.130-132 In Chapter 6 the relationship between smoking and cluster headache was investigated with a genetic correlation analysis. We found a positive genetic correlation between smoking and cluster headache, indicating a genetic overlap. In Chapter 7 the relationship was further unravelled, this time we analysed the causality of smoking on cluster headache. It was found that smoking and cluster headache not only have a shared genetic architecture, but also that smoking is one of the factors that causes cluster headache. As the positive correlation between two traits could lead to bias, an additional analysis, the latent causal variable (LCV) analysis was performed to verify the causality between smoking and cluster headache, this analysis reconfirmed the causality.136 With GWAS data many genetic aspects of a disease can be unravelled. It is, however, important to note that MR studies are still in their infancy therefore it is critical and necessary to replicate the results of different studies to reach robust conclusions. Combining genetic data: the full spectrum of migraine from polygenic to monogenic forms In the search for a “fourth” hemiplegic migraine gene sequencing was applied to cohorts of hemiplegic migraine patients that are negative for mutations in CACNA1A, ATP1A2, and SCN1A. Thus far no “fourth” gene has been found, however, there are indications,137 that the heritability of hemiplegic in mutation-negative patients is more complex (i.e. more oligogenic or even polygenic). A number of genes including PRRT2,138 PNKD,139 SLC4A4,140 SLC1A3,141 and SLC2A1,142 are primarily associated with movement or solute transport disorders, but some patients with mutations in these genes were reported to display signs of hemiplegic migraine, suggesting an
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