7 CHAPTER 7 144 3). This locus, previously reported and internally replicated within the East Asian cohort.8 was exclusively driven by the same cohort in our analysis (see Table S13). However, a nearby locus reached nominal significance in the European-ancestry meta-analysis, with lead variant rs68046706 (OR 1.76, 95% CI 1.10 - 1.26, p = 3.86 x10-6) 86 kb away from rs10916600. The WNT2 locus identified in the European-ancestry meta-analysis, for which the lead variant was not present in the East Asian cohort, fell below significance (p = 5.91 x 10-7). At the PLCE1 locus, the new lead variant was a missense variant (rs2274224) in PLCE1. Cohort-wise associations for all the identified loci are given in Tables S10 and S13. All the five previously reported GWAS-significant loci were re-identified in our study, while none of the associations reported from candidate gene studies were replicated (Table S14). Table 1 Cluster headache GWAS studies included in the meta-analysis. Study Cases (n) Controls (n) Dutch Cluster Headache Cohorta 943 1,424 UK Cluster Headache Cohortb 852 5,614 Swedish Cluster Headache Cohort 1b 591 1,134 German Cluster Headache Cohort 477 938 Danish Cluster Headache Cohort 492 9,658 Swedish Cluster Headache Cohort 2 255 241 Trondheim Cluster Headache Cohorta 144 1,800 Greek Cluster Headache Cohort 99 91 Barcelona Cluster Headache Cohort 97 482 Italian Cluster Headache Cohort 93 347 Total 4,043 21,729 a Previously published in whole or in part by Harder et al.6; b Previously published by O’Conner et al.7 The subsequent downstream analyses were based on the European-ancestry meta-analysis. To prioritize candidate genes for a causal association with CH, we applied five methods. (1) eQTL analysis found that at the MERTK locus, three variants in high LD (r2 > 0.92) with the lead variant rs13399108 modulate the expression of TMEM87B (in fibroblasts and aortic artery) and SLC20A1 (in whole blood). At the FHL5 locus, two variants (r2 > 0.84 with the lead variant rs9486725) associate with the expression of UFL1 (in whole blood, white blood cells and tibial artery). At the LRP1 locus, the T allele of lead variant rs11172113 associates with an increased LRP1 mRNA expression in aortic artery, adipose tissue and tibial artery (Table S15). (2) The transcriptome-wide association study (TWAS-FUSION) identified eight candidate genes at five loci with a significant TWAS p value ≤ 1.0 x 10-6 (Table S5). (3) Fine mapping by FOCUS identified eight candidate genes based on posterior inclusion probability (PIP) > 0.5 (Table S16). Four genes (MERTK, TMEM87B, SATB2 and CFTR) were prioritized by both TWASFUSION and FOCUS with high confidence (PIP > 0.99 in the same tissue in both analyses). (4) Using MetaMeth, 13 CpG sites at nine genes were predicted to be hypo- or hypermethylated in
RkJQdWJsaXNoZXIy MTk4NDMw