7 CHAPTER 7 148 same causal variant at each of the three loci (posterior probability 98.6% for FHL5 locus, 99.6% for PLCE1 locus and 100% for LRP1 locus). Effect sizes were, however, consistently higher for CH (ORs 1.29, 1.18, 1.18) than for migraine (1.09, 1.06, 1.11) with non-overlapping confidence intervals for the ORs (Table S28). Among 122 loci associated with migraine in the most recent GWAS,17 no other migraine variant was associated with CH after Bonferroni correction (Table S29). The effect sizes (beta) for association to migraine and CH were not significantly correlated (Pearson r = 0.16, p = 0.074) for the remaining 119 variants, after excluding the three overlapping loci. Figure 4 Miami plot of genetically driven DNA methylation genes in cluster headache. Computational prediction of genetically driven CpG methylation associated with cluster headache, using MetaMeth. Genes annotated to significant CpGs are shown (FDR-corrected p value < 0.05). Horizontal axis shows the chromosomal position and the vertical axis shows significance (-log10 pvalue). The top panel shows predicted hypermethylation, while the bottom panel shows predicted hypomethylation. Mendelian randomization analysis Using the random-effect inverse variant weighted (IVW) method, we observed a strong association between the instrumental variables for smoking intensity and CH (β = 1.11, SE = 0.43, p = 6.3 x 10-6 ). The direction and magnitude were similar in the MR-Egger analysis (β = 1.04, SE = 0.55, p = 4.6 x 10-4). The Cochran´s Q test statistic was significant (p = 0.03), indicative of some heterogeneity, but the MR-Egger intercept showed no evidence for bias caused by directional pleiotropy (p = 0.79). Mendelian randomization may, however, yield false positive results in the presence of genetic correlation between the two traits examined.37 To test for this, we performed a latent causal variable model, finding that smoking intensity had a nearly full (> 0.6) genetic causality with CH (pLCV = 8.57 x 10 -10, GCP = 0.74 ± 0.18). Combined, the results strongly support a causal effect of smoking intensity on CH. Full results are presented in Tables S30-32.
RkJQdWJsaXNoZXIy MTk4NDMw