CLUSTER HEADACHE GENOME-WIDE ASSOCIATION STUDY AND META-ANALYSIS IDENTIFIES EIGHT LOCI AND IMPLICATES SMOKING AS CAUSAL RISK FACTOR 147 7 Genetic risk score analysis GRS for CH were associated with case-control status in leave-one-out analyses in each of the four tested independent cohorts. Among cases with CH, no association was seen between GRS and episodic vs. chronic CH, age-at-onset, sex, current smoking or ever smoking (Table S7). Figure 3 Manhattan plot showing genome-wide significant loci associated with cluster headache in transancestry meta-analysis (4,777 cases, 31,575 controls). The horizontal axis shows the chromosomal position and the vertical axis shows the significance (-log10 p value) of tested markers. Each dot represents a genetic variant. The threshold for genome-wide significance (p < 5 × 10–8) is indicated by a red dotted line, and genome-wide significance loci are shown in blue. Three genome-wide significant variants (rs9307511 on chr4 and rs338106 and rs747974 on chr 13) were considered spurious associations as they lacked a supporting LD structure, were driven by the East Asian cohort alone, and were previously interpreted as being spurious associations in this cohort.8 Genetic correlation After correcting for multiple testing, CH was genetically correlated with 84 traits (Table S8). The strongest correlation was with ‘cigarettes per day’34 (rg = 0.36, p = 6.32 x 10-18). Notably, ten (12%) of the correlated traits were related to smoking behavior. CH was also positively correlated with measures of risk-taking behavior, ADHD, mood disorders, musculoskeletal pain, migraine, and with unfavorable lifestyle factors including low physical activity, low nutritional diet and lower educational attainment (Table S8). When examining the correlation of the same 84 traits to migraine, the genetic correlations to pain, depression and ADHD were similar to those seen for CH, while no correlation was observed between migraine and smoking traits or measures of risk-taking behavior. Three of the CH loci are near previously identified risk loci for migraine (i.e. FHL5, PLCE1, LRP1).17 (Table S27). Colocalization analysis indicated that CH and migraine are caused by the
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