GENETIC SUSCEPTIBILITY LOCI IN GENOME-WIDE ASSOCIATION STUDY OF CLUSTER HEADACHE 129 6 and controls were genotyped using the same platform, genotyping was performed in different laboratories possibly introducing batch effects.Therefore, we made significant efforts to circumvent possible problems arising from our design by rigorous quality control. Overall, our case sample was representative of the general CH population with a ~2:1 male-female ratio, chronic CH of ~30% and without any familial confounder, as familial cases were removed in the QC steps.1 The difference in the percentage of men and women for cases and controls was corrected for in the statistical analysis. Among previously suggested loci to be involved in CH, we found evidence for significant association to the alcohol dehydrogenase 4 gene (ADH4) although the effect identified is opposite to what was previously reported and at the genome wide level it was not significant.31 In previous studies, ADH4 was investigated mainly because alcohol is considered both a trigger and possible risk factor for transformation from episodic to chronic CH.30, 31 Of note, we did not find evidence for an association of HCRTR2, as reported previously,8-10 nor for any of the other previously reported loci in CH. A remarkable finding in our study was that one of the leading loci, represented by rs2499799, which covers both FHL5 and UFL, has previously been identified as a migraine risk locus.34 FHL5 encodes a transcription factor that regulates cAMP-responsive elements CREB6 and CREM, which play a role in synaptic plasticity and memory formation.39 UFL1 codes for the ubiquitinfold modifier 1 (UFM1)-specific ligase 1, an ubiquitin-like protein that allows UFL1 to conjugate to its substrates.40 The ubiquitin protease system (UPS) has been associated as a pathway in neuropsychiatric and neurodegenerative disorders.41 In the latest migraine GWAS meta-analysis, the UFL1/FHL5 locus had an odds ratio (OR) of 1.09 [1.08-1.11] based on the primary signal (rs67338227).34 The direction of the effect in the UFL1/FHL5 locus in our dataset was the same in both migraine and CH and, the lead SNPs for migraine and CH were in LD (r2 = 0.64). Our colocalization analysis suggests that CH and migraine are more likely caused by distinct variants at this locus. Admittedly this finding could also be a result of different LD patterns in the samples that were compared in the colocalization analysis. The other 36 independent loci implicated in migraine showed no association with CH. Our results suggest though that the UFL1/FHL5 locus is ‘specific’ for CH and that the association is not due to the mere presence of comorbid migraine among patients with CH. This is further supported by the similar prevalence of migraine among cases in our discovery sample (13%) and the expected population prevalence (10-17%), although the number of migraine cases in controls was not collected.42 While no other migraine locus reached significance in our study individually there was a moderate correlation between association effect sizes of CH and migraine for the 37 examined migraine loci. This may reflect a shared genetic architecture underlying both disorders, which is not surprising given that they share pathophysiological features such as the involvement of the trigeminovascular system and efficacy of calcitonin gene-related peptide (CGRP) monoclonal antibodies and triptans.4 It is possible that future studies with larger sample sizes may identify the involvement of more migraine loci in CH.
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