7 CHAPTER 7 150 Discussion In a GWAS meta-analysis for CH in European-ancestry cohorts we identified nine independent associations in seven risk loci and confirm the strong associations at four loci (ORs 1.29 - 1.53) reported in recent smaller GWAS.6-8 One additional locus, previously reported and internally replicated in the East Asian cohort,8 was identified in a subsequent trans-ancestry GWAS metaanalysis that included this cohort. We estimate that common genetic variants explain 14.5% of CH’s phenotypic variance. Twenty genes were prioritized as candidates for being involved in CH. These showed enrichment for arterial tissue, in addition to brain, fueling the idea that CH may have a vascular involvement.1 Still, since no significant tissues were identified by summary statistics-based enrichment analyses (using DEPICT and LDSC-SEG), more evidence is needed to draw definite conclusions. Several of the 20 prioritized genes encode targets for existing drugs, and may represent candidates for repurposing studies. The clinical utility of GRS remains to be explored. We found no association between GRS and specific clinical phenotypes, suggesting that the signal is not driven by any of the subgroups. Differences in CH clinical presentation between Asian and European populations, such as reduced restlessness and circadian rhythmicity, may indicate distinct genetic predispositions.38 The CAPN2 locus was selectively driven by the East Asian cohort, and may exemplify how the contribution of individual risk loci varies between populations. Future well-powered trans-ancestral studies should further explore ancestry-related risk loci, and whether these are related to differences in clinical presentation. In our hypothesis-free genetic correlation analysis CH was correlated with several traits, including smoking, risk-taking behavior, ADHD, mood disorders, musculoskeletal pain and migraine. The strongest genetic correlation was with smoking, which is consistent with the observation that as many as 70 - 90% of patients with CH smoke,1, 3, 39 seen also in our cohorts (Table S1). The high proportion of smokers among patients with CH may theoretically be explained by smoking causing CH or vice versa, or because they have shared causal factors. Whether smoking is causing CH is heavily debated. On the one hand, smoking initiation typically predates the onset of CH3 and among those with CH who have never smoked the majority were exposed to parental smoking in childhood.40 Furthermore, it seems that smoking is associated with more severe manifestations of CH1 and some data suggest that the prevalence of CH has followed trends in smoking prevalence.39 On the other hand, arguments against a causal effect of smoking include the typically long latency between smoking onset and CH debut (> 15 years).3 Also, in retrospective studies patients with CH who stopped smoking several years earlier did not experience an improvement in their CH.1, 39 To investigate the potential causality of smoking on CH, we performed a Mendelian randomization and LCV analysis.41 The analyses indicated a causal effect of smoking intensity on CH, with
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