CLUSTER HEADACHE GENOME-WIDE ASSOCIATION STUDY AND META-ANALYSIS IDENTIFIES EIGHT LOCI AND IMPLICATES SMOKING AS CAUSAL RISK FACTOR 145 7 CH (Table S17, Figure 4). (5) At two loci, the lead variant was in high LD with protein-altering missense variants. That is, at the FHL5 locus, the intronic lead variant rs9486725 is in strong LD (r2 ≥ 0.98) with p.Arg204Gly (rs2273621) and p.Ser243Arg (rs9373985 in FHL5; and at the PLCE1 locus the intronic lead variant rs57866767 is in strong LD (r2 = 1) with a p.Arg1267Pro (rs2274224) in PLCE1 (Table S18). Table 2 Summary of the genomic loci associated with cluster headache. Locus name Lead variant (Chr:Pos) EA/ NEA (EAF) OR (95% CI) p value (Het p) Variant type [Prioritized genes] DUSP10 rs17011182 (1:222164327) A/G (0.793) 1.38 (1.29-1.48) 7.76 x 10-21 (0.58) regulatory region [DUSP10] MERTK rs13399108 (2:112747123) A/G (0.373) 1.41 (1.33-1.50) 1.74 x 10-30 (0.16) intron [MERTK, TMEM87B, FBLN7, SLC20A1] FTCDNL1 rs6714578 (2:200485487) A/G (0.655) 1.53 (1.43-1.63) 2.83 x 10-37 (0.65) intergenic [SATB2] FHL5 rs9486725 (6:97061159) T/C (0.346) 1.29 (1.21-1.36) 2.50 x 10-17 (0.29) intron [UFL1, FHL5, KLHL32, NDUFAF4] WNT2 rs2402176 (7:116908448) C/G (0.291) 1.20 (1.12-1.27) 2.61 x 10-8 (0.51) intergenic [CFTR, CAPZA2, ST7] PLCE1 rs57866767 (10:96023077) T/C (0.588) 1.18 (1.12-1.25) 4.45 x 10-9 (0.51) intron [PLCE1] LRP1 rs11172113 (12:57527283) T/C (0.600) 1.18 (1.12-1.25) 5.15 x 10-9 (0.52) intron [LRP1] Locus name = the closest protein-coding gene within a 250-Kb window. Chr = chromosome. Pos = position (hg19). EA = effect allele, which here is set to correspond with the risk allele. NEA = non-effect allele. EAF = effect allele frequency. OR = odds ratio. CI = confidence interval. Het p = p value from Cochran’s Q-test for heterogeneity. Prioritized genes = genes prioritized by at least one of five complementary methods: (1) expression quantitative trait (eQTL) analysis, (2) transcriptome-wide association analysis using FUSION, (3) fine mapping of causal gene sets (FOCUS), (4) association to genetically driven DNAm (MetaMeth), and (5) protein-altering variants in high LD (r2 > 0.8) with index variant. Genes identified by ≥ 2 of the methods are marked in bold.Candidate gene mapping and functional characterization Twenty genes were prioritized by at least one of the five methods. A summary of the gene prioritization results is given in Table S19. When considering the 20 prioritized genes, FUMA24 found a significant enrichment for genes differentially expressed in artery (tibial artery) and brain (substantia nigra) (Figure 5 and Table S20), and a significant overlap with genes reported in the GWAS catalog for 10 traits, most significantly for headache and migraine (Table S21). The summary statistics-based enrichment analyses DEPICT and LDSC-SEG did not yield significant enrichment for gene sets or tissues after correcting for multiple testing (Tables S22-26). Of the 20 prioritized genes (Table S19), ten are highlighted as druggable in the druggable genome database.28 Of these, five encode targets of 33 existing drugs registered in DrugBank29 (Table S6), including three genes that were implicated in CH by at least two gene prioritization methods (i.e. MERTK, CFTR and LRP1). Calpain 2, encoded by CAPN2 in the trans-ancestry locus, was not registered in DrugBank.
RkJQdWJsaXNoZXIy MTk4NDMw