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Genes identified by genome wide association studies are likely to be involved in the pathophysiological mechanisms underlying the disease. In this study, we performed validation and characterization of eight loci corresponding to nine genes identified in previous genome wide association studies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Genetic loci were validated by means of a case-control study using TaqMan genotyping in 671 individuals, and a meta-analysis using previously genotyped data. Pyrosequencing methylation analysis and reverse transcription quantitative PCR gene expression studies was performed in a subset of individuals with cluster headache and healthy controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Genetic associations were found with functional variants in two genes;\n                      <jats:italic>FHL5<\/jats:italic>\n                      and\n                      <jats:italic>MERTK.<\/jats:italic>\n                      The minor allele of the\n                      <jats:italic>FHL5<\/jats:italic>\n                      variant rs2273621 was associated with an increased risk of cluster headache in the genotyped samples (odds ratio\u2009=\u20091.42,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.03) and in a meta-analysis (odds ratio\u2009=\u20091.29, confidence interval: 1.09\u20131.52), and the minor allele of the rs2230515 variant in\n                      <jats:italic>MERTK<\/jats:italic>\n                      was associated with lower risk in the meta-analysis (odds ratio\u2009=\u20090.69, confidence interval: 0.52\u20130.92). Methylation analysis further revealed altered methylation status of\n                      <jats:italic>MERTK<\/jats:italic>\n                      . Moreover, changes in relative gene expression were found for several candidate genes: a decrease in the mRNA expression of\n                      <jats:italic>DUSP10<\/jats:italic>\n                      (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.001),\n                      <jats:italic>CAPN2<\/jats:italic>\n                      (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.001),\n                      <jats:italic>UFL1<\/jats:italic>\n                      (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.001) and\n                      <jats:italic>LRP1<\/jats:italic>\n                      (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.007) in blood, and a decrease of\n                      <jats:italic>CAPN2<\/jats:italic>\n                      (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009&lt;\u20090.001) as well as an increase in the mRNA expression of\n                      <jats:italic>FTCDNL1\/FONG<\/jats:italic>\n                      (\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.004) in fibroblasts in CH vs. controls. Only two genes;\n                      <jats:italic>PLCE1<\/jats:italic>\n                      and\n                      <jats:italic>WNT2,<\/jats:italic>\n                      could not be validated in the biological tissue studied;\n                      <jats:italic>WNT2<\/jats:italic>\n                      , possibly due to limited power, while\n                      <jats:italic>PLCE1<\/jats:italic>\n                      was not expressed in the available tissue.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These results confirm the validity of seven candidate genes for cluster headache identified through GWAS. Furthermore, five of the candidate genes are abundantly expressed in both immune and blood cells, converge functionally on inflammatory signalling pathways and suggest a potential role for inflammasomes in cluster headache.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s10194-026-02485-x","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T15:54:34Z","timestamp":1785858874000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genome-wide association susceptibility loci for cluster headache support a role for inflammation in the pathophysiology"],"prefix":"10.1186","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0239-9871","authenticated-orcid":false,"given":"Caroline","family":"Ran","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cl\u00e9mence","family":"Deborgies Sanches","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Swedblom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Wellfelt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Antoniazzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Lloyd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felicia","family":"Jennysdotter Olofsg\u00e5rd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Spulber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabet","family":"Waldenlind","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Lantz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Steinberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Sundholm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Sj\u00f6strand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea Carmine","family":"Belin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"2485_CR1","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1001\/jamaneurol.2020.0682","volume":"77","author":"MW Waung","year":"2020","unstructured":"Waung MW, Taylor A, Qualmann KJ, Burish MJ (2020) Family history of cluster headache: a systematic review. 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