6 CHAPTER 6 124 Genetic correlation of cluster headache with migraine The observed h2 for migraine was 17.1% (SE 1.56%). The genetic correlation between CH and migraine was 0.33 (SE 0.021, p = 0.12). Next, we examined the 38 migraine-associated loci reported in Gormley et al.34 Of the 37 migraine loci that were represented in our data set directly or by variants in high LD, one, located on chromosome 6, was associated with CH rs2971606, a proxy (r2 = 1.0) for the migraine index variant rs67338227, in FHL5, p = 1.39 x 10-8 (Bonferroni corrected pcorr = 0.5 x 10-6). The association had the same effect direction for migraine and CH. There was also moderate LD between the lead SNP for migraine and CH (r2 = 0.64 in data from 1000 Genomes Project Phase 3 CEU). Still, colocalization analysis revealed a 67.5% posterior probability for the hypothesis (H3) that the causal variants for CH and migraine are distinct, higher than the 32.5% posterior probability for hypothesis (H4) that CH and migraine share a causal variant in this region. The other 36 migraine loci were not associated with CH (data not shown), with the second strongest association seen for rs10786156 in PLCE1 (p = 2.82 x 10-3, pcorr = 0.10). The migraine locus near MED14 on chromosome X (rs12845494) was not represented in our dataset. The effect sizes for the 37 loci combined correlated with those of CH, Pearson’s r(35) = 0.59 (p = 1.36 x 10-4), even disregarding the overlapping FHL5 locus (Pearson’s r(34) = 0.58, p = 2.18 x 10-4). Sex-stratified analyses The low number of female cases gave limited power for the women-only analysis. Rs6541998was genome-wide significant in men using sex-stratified analyses; all other loci were nominally significant (p < 1 x 10-3) for both men and women with effects in the same direction. Using the method suggested by Clogg et al.,37 we found no significant differences for the regression coefficients between men and women at the four lead SNPs (p-value 0.54 for rs11579212; p-value 0.62 for rs6541998; p-value 0.57 for rs10184573; p-value 0.59 for rs2499799). Previously reported cluster headache loci Of the 9 different SNPs previously associated with CH, one replicated, rs1800759 in ADH4 (p = 0.00039, Bonferroni corrected pcorr = 0.0035) (Table 4). In contrast, none of the previously reported associations in HCRTR2, ADCYAP1R1, CLOCK, CHRNA3-CHRNA5, and MME were replicated in our sample (Table 4). Table 1 Clinical characteristics of the discovery samplea Characteristics CH patients (n = 840) Controls (n = 1,457) P-valueb Men 579 (68.9) 636 (43.7) < 0.001 Current daily smoking 440 (52.4) 202 (13.9) < 0.001 Episodic cluster headache 577 (68.7) - - Chronic cluster headache 233 (27.7) - - Migraine co-morbidity 106 (12.6) - - Data are expressed as numbers (percentages) unless otherwise stated. a Numbers and proportions may not add up to total of 100 due to rounding or missing values. b P-values of chi-square test for categorical variables. CH = cluster headache
RkJQdWJsaXNoZXIy MTk4NDMw