7 CHAPTER 7 152 of the same medications.47, 48 Future studies with deep phenotyping should explore if the shared genetic risk factors are directly related to shared clinical features, such as prominent autonomic symptoms in some migraine patients.49 We note that for all three shared loci, the effect sizes were higher for CH (ORs 1.18 - 1.29) than for migraine (1.06 - 1.11) with non-overlapping confidence intervals. Even for the most consistently identified migraine risk locus, LRP1 (p value 1.38 x10-90 in the latest migraine GWAS),17 the effect size was higher for CH (1.18 vs. 1.11). This holds true also when comparing to GWAS of clinic-based migraine cohorts (OR = 1.11).50 The larger effect sizes suggest that the three shared loci are stronger drivers of disease susceptibility in CH than in migraine, and also makes it unlikely that the observed associations are a result of misclassification of migraine patients as having CH. A major strength of our study is the substantially larger sample size compared to previous studies, which allows for downstream functional analyses, and clinical diagnoses made according to ICHD criteria.2, 10 This was made possible through the establishment of the International Consortium for Cluster Headache Genetics (CCG), which has brought together 16 headache research groups from 13 countries (www.clusterheadachegenetics.org). A limitation of the current study is that it included only a single non-European cohort, from east Asia, limiting, the possibility for conducting ancestry-specific meta-analyses and downstream analyses, for non-European ancestries. This highlights the need for future, well-powered trans-ancestry genetic studies in CH. In conclusion, in this GWAS meta-analysis we identify nine independent associations in seven risk loci for CH in European-ancestry samples and one additional locus in East Asian samples. The prioritized genes show enrichment in arterial and brain tissues. CH shares certain risk loci with migraine, and is most strongly genetically correlated with smoking. Of clinical interest, Mendelian randomization analysis indicates a causal effect of cigarette smoking on the development of CH.
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