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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Seven markers in core clock genes\n                      <jats:italic toggle=\"yes\">BMAL1<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">NPAS2<\/jats:italic>\n                      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 (\n                      <jats:italic toggle=\"yes\">CLOCK<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">CRY1-2<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">PER1-3<\/jats:italic>\n                      ) 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results and interpretation<\/jats:title>\n                    <jats:p>\n                      Single marker analysis of the newly genotyped markers in\n                      <jats:italic toggle=\"yes\">BMAL1<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">NPAS2<\/jats:italic>\n                      found rs3789327 and rs3768984 more frequently among individuals with cluster headache (p\u2009&lt;\u20090.01 and p\u2009&lt;\u20090.05 respectively). Multiallelic analysis revealed that the median number of risk alleles was eight for controls and nine for individuals with cluster headache, which justifies the analysis of combinations of markers. The analysis of combinations of up to three markers identified 258 out of 897 combinations to be associated with significant risk. Further investigation starting from the function of genes in the molecular clock transcription-translation feedback loop (TTFL) found that 80% of the combinations had &gt;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 (\n                      <jats:italic toggle=\"yes\">NPAS2<\/jats:italic>\n                      ), as well as the enrichment in markers in\n                      <jats:italic toggle=\"yes\">BMAL1<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">CLOCK<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">NPAS2<\/jats:italic>\n                      in combinations associated with significant risk.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our data points to molecular clock dysfunction playing a central role in the manifestation of cluster headache.<\/jats:p>\n                  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