CLUSTER HEADACHE GENOME-WIDE ASSOCIATION STUDY AND META-ANALYSIS IDENTIFIES EIGHT LOCI AND IMPLICATES SMOKING AS CAUSAL RISK FACTOR 151 7 high statistical confidence. Of note, the high observed proportion of smokers among cases with CH is expected if smoking is a causal risk factor. Since cases were recruited independently of smoking status, and the proportion of smokers is similar to previous reports, we find it unlikely that recruitment bias explains the results. While our study cannot give definite answers regarding mechanisms linking smoking to CH, we note that several of the prioritized genes are influenced by smoking. Cigarette smoking leads to overexpression of MERTK42 and reduced expression and function of CFTR in airway tissues.43 Notably, our TWAS also revealed an increased expression for MERTK and reduced expression for CFTR in CH. It has been shown that smoking can induce epigenetic changes that persist even 30 years after smoking cessation,44 therefore, the observation that patients who stop smoking do not experience an improvement of their CH might be explained by stable epigenetic modifications. In a large study, DNA methylation at 2,568 CpG sites related to 1,450 genes were found to be associated with former smoking at FDR < 0.05.44 Four of our prioritized genes are among these (i.e. FBLN7, SLC20A1, KDM4B, ST7), that is 4 of 20 vs. 1,450 of 23,300 genes (post hoc one-tailed binomial p = 0.033). More detailed molecular studies in relevant tissues are needed to identify mechanisms linking smoking to CH. The suggestion that smoking is a causal risk factor for CH has potential clinical implications. Smoking is a modifiable risk factor, and it gives a further impetus to promoting smoking cessation in this group of patients. The long-term effect of smoking cessation on CH should be carefully revisited by well-designed prospective studies. Notably, CH was to some extent genetically correlated with measures of risk-taking behavior apart from smoking. While our results support a causal effect of smoking on the development of CH, it is possible that patients with CH are also more likely to start smoking because of a tendency toward risk-taking, as has been suggested.39, 45 The genetic correlations to smoking and risk-taking behavior were not seen for migraine. While primary headache disorders are among the top causes of disability worldwide,46 it is unknown to what extent they represent biologically distinct disorders or rather variations in clinical presentation with a shared biological basis.47 Migraine is the only other primary headache disorder that has been explored in well-powered GWAS.17 We found that three of the eight risk loci for CH are shared with migraine, and colocalization analyses give a high probability that the same causal variants in these loci give rise to both disorders. Notably, the remaining five CH loci show no association to migraine (p values > 0.10). Likewise, apart from the three overlapping loci, none of the other 119 known migraine loci17 show association with CH. Our results suggest, therefore, that CH and migraine have a partly shared and partly distinct genetic basis, likely reflecting partly shared and partly distinct biological mechanisms. This corresponds well with the clinical impression of the two disorders as being distinct entities, but with certain shared clinical characteristics, including unilateral headache cranial autonomic symptoms, and response to some
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