2026/04/01 by Clémence Deborgies Sanches, Stefan Spulber, Felicia Jennysdotter Olofsgård +10 · 1 citation
paper · doi:10.1177/03331024261440136
published in Cephalalgia 46(4) (SAGE Publications)
crossref issued 2026/04/01 · crossref published 2026/04/01 · crossref published-print 2026/04/01 · crossref published-online 2026/04/12 · crossref created 2026/04/13 · crossref deposited 2026/04/28 · crossref indexed 2026/08/05
Background / Hypothesis Headache attacks are reported to occur with circadian rhythmicity by 2/3 of individuals with cluster headache, hinting to potential dysfunctions of the molecular clock. The aim of this study was to investigate the contribution of genetic markers in core clock genes, alone or in combinations, to the genetic risk for cluster headache. Methods Seven markers in core clock genes BMAL1 and NPAS2 were genotyped using TaqMan qPCR in 707 individuals with cluster headache and 682 controls. Genetic data from eleven additional markers located in six other core clock genes ( CLOCK , CRY1-2 , and PER1-3 ) was obtained from the database of the Centre for Cluster Headache at Karolinska Institutet. Genotype analysis was applied for risk analysis for combinations of up to three markers. For validation we used a cluster headache cohort from the National Hospital for Neurology and Neurosurgery, London, UK. Results and interpretation Single marker analysis of the newly genotyped markers in BMAL1 and NPAS2 found rs3789327 and rs3768984 more frequently among individuals with cluster headache (p 50% markers located in the positive arm of the TTFL. The comparison between Swedish and UK cohorts identified 39 concordant combinations, which confirmed the risk associated with rs3768984 ( NPAS2 ), as well as the enrichment in markers in BMAL1 , CLOCK , and NPAS2 in combinations associated with significant risk. Conclusion Our data points to molecular clock dysfunction playing a central role in the manifestation of cluster headache.