6 CHAPTER 6 116 Abstract Objective: Identifying common genetic variants that confer genetic risk for cluster headache. Methods: We conducted a case-control study in the Dutch Leiden University Cluster headache neuro-Analysis program (LUCA) study population (n = 840) and controls from the Netherlands Epidemiology of Obesity Study (NEO) (n = 1,457), representing the general population. Replication was performed in a Norwegian sample of 144 cases from the Trondheim Cluster headache sample and 1,800 controls from the Nord-Trøndelag Health Survey (HUNT). Gene set and tissue enrichment analyses, blood cell-derived RNA-sequencing of genes around the risk loci and linkage disequilibrium score regression were part of the downstream analyses. Results: An association was found with cluster headache for four independent loci (r2 < 0.1) with genome-wide significance (p < 5 x 10-8), rs11579212 (odds ratio (OR) = 1.51, 95% CI 1.33-1.72 near RP11-815M8.1), rs6541998 (OR = 1.53, 95% CI 1.37-1.74 near MERTK), rs10184573 (OR = 1.43, 95% CI 1.26-1.61 near AC093590.1), and rs2499799 (OR = 0.62, 95% CI 0.54-0.73 near UFL1/FHL5), collectively explaining 7.2% of the variance of the phenotype. SNPs rs11579212, rs10184573 and rs976357, as proxy SNP for rs2499799 (r2 = 1.0), replicated in the Norwegian sample (p < 0.05). Gene-based mapping yielded ASZ1 as possible fifth locus. RNA-sequencing indicated differential expression of POLR1B and TMEM87B in cluster headache. Interpretation: This GWAS identified and replicated genetic risk loci for cluster headache with effect sizes larger than those typically seen in complex genetic disorders.
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