6 CHAPTER 6 128 Table 5 RNA-seq expression data Gene Expression in blood Locus number CH P-value CH Pcorr valuea M P-value POLR1B Yes 2 7.50 x 10-5 8.3 x 10-4 0.50 TMEM87B Yes 2 0.014 0.15 0.45 ZC3H8 Yes 2 0.084 0.92 - DUSP10 Yes 1 0.725 1 - MERTK Yes 2 0.527 1 - TTL Yes 2 0.465 1 - MMS22L Yes 4 0.424 1 - FBLN7 Yes 2 0.361 1 - ZC3H6 Yes 2 0.285 1 - FTCDNL1 Yes 3 0.123 1 - UFL1 Yes 4 0.123 1 - FHL5 No 4 - - - FUT9 No 4 - - - GPR63 No 4 - - - RGPD8 No 2 - - - SATB2 No 3 - - - Genes were selected based in the eQTL mapping in FUMA.22 a P-values were Bonferroni corrected for 11 tests. CH = cluster headache; M = migraine. Discussion We performed a GWAS in CH and identified four independent genetic risk loci, of which three replicated in an independent sample. The association effect sizes, with ORs around 1.5, are high compared to those usually observed in GWAS (https://www.ebi.ac.uk/gwas/).38 Whereas this may indicate that the risk for CH is driven by a limited number of loci with strong associations with CH, it is likely to be expected that follow-up studies with larger sample sizes also will identify loci with smaller effect sizes. Except for the MERTK locus (rs6541998), all loci replicated in our replication sample, suggesting that the signals are genuine. Gene-based mapping additionally found that expression of the ASZ1 gene may be influenced by one or more CH loci, providing a possible additional locus. RNA-seq results show altered expression in CH patients of POLR1B and TMEM87B, suggesting their involvement in CH. Although there seems to be a considerable SNP-based heritability for CH, a robust estimation of SNP-based heritability is not possible given the small sample size, hence heritability estimates should be interpreted with caution. The main limitations of our study are that, (1) although we identified and replicated genomewide significant loci, the relatively small number of cases in the discovery sample will leave loci with smaller effect sizes or lower allele frequencies hidden; (2) it is unclear to what extent the present results can be extrapolated to ancestries other than European ancestry; (3) although cases
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