Cluster headache is a severe primary headache disorder affecting 0.1% of the population and is four times more common in men than women. It is characterized by episodes of extremely distressing, unilateral pain centered around the eye or temple.

Much is not known about the causes and development of cluster headaches, but disorders of the hypothalamus, trigeminovascular and autonomic nervous systems are probably involved. Previous twin and family studies have suggested the involvement of genetic factors. Two recent genome-wide association studies (GWAS) in individuals of European ancestry have demonstrated robust genetic associations for cluster headaches and independently identified four genetic risk loci on chromosome 1 (near the DUSP10 gene), chromosome 2 (within MERTK and near SATB2), and Chromosome 6 (within FHL5) identified. A third GWAS in Han Chinese replicated two of these loci (MERTK and SATB2) and reported an additional locus in the CAPN2.8 gene

To identify additional genetic factors and increase the power for the functional interpretation of the genetic signals, we founded the International Consortium for Cluster Headache Genetics (CCG) and analyzed data from 10 European and one East Asian cluster headache cohort, i.e. from the cohorts used in the four previous CH6-9 GWAS, as well as five additional cohorts, increasing the sample size for analysis by 3.2-fold compared to the largest previous CH GWAS.

In this GWAS meta-analysis for cluster headache in cohorts of European ancestry, we identified 9 independent associations at 7 risk loci and confirmed the strong associations at 4 loci reported in smaller GWAS.

We estimate that common genetic variants explain 14.5% of the phenotypic variance in cluster headaches. Twenty genes were prioritized as candidates for involvement in cluster headache. These showed enhancement for arterial tissue, supporting the notion that cluster headaches may have vascular involvement. Several of the 20 prioritized genes encode targets for existing drugs. Differences in the clinical presentation of cluster headaches between Asian and European populations, such as: B. reduced agitation and circadian rhythmicity, could indicate different genetic predispositions. The CAPN2 locus was selectively driven by the East Asian cohort and could be an example of how the contribution of individual risk loci varies. To investigate the possible causality of smoking on cluster headache, we performed Mendelian randomization and LCV analysis. The analyzes indicated a causal effect of smoking intensity on cluster headaches with high statistical certainty.

Source :
Winsvold BS, Harder AVE, Ran C, Chalmer MA, Dalmasso MC, Ferkingstad E, Tripathi KP, Bacchelli E, Børte S, Fourier C, Petersen AS, Vijfhuizen LS, Magnusson SH, O'Connor E, Bjornsdottir G, Häppölä P, Wang YF, Callesen I, Kelderman T, Gallardo VJ, de Boer I, Olofsgård FJ, Heinze K, Lund N, Thomas LF, Hsu CL, Pirinen M, Hautakangas H, Ribasés M, Guerzoni S, Sivakumar P, Yip J , Heinze A, Küçükali F, Ostrowski SR, Pedersen OB, Kristoffersen ES, Martinsen AE, Artigas MS, Lagrata S, Cainazzo MM, Adebimpe J, Quinn O, Göbel C, Cirkel A, Volk AE, Heilmann-Heimbach S, Skogholt AH , Gabrielsen ME, Wilbrink LA, Danno D, Mehta D, Guðbjartsson DF;
HUNT All-In Headache, The International Headache Genetics Consortium, DBDS Genomic Consortium; Rosendaal FR, Willems van Dijk K, Fronczek R, Wagner M, Scherer M, Göbel H, Sleegers K, Sveinsson OA, Pani L, Zoli M, Ramos-Quiroga JA, Dardiotis E, Steinberg A, Riedel-Heller S, Sjöstrand C , Thorgeirsson TE, Stefansson H, Southgate L, Trembath RC, Vandrovcova J, Noordam R, Paemeleire K, Stefansson K, Fann CS, Waldenlind E, Tronvik E, Jensen RH, Chen SP, Houlden H, Terwindt GM, Kubisch C, Maestrini E, Vikelis M, Pozo-Rosich P, Belin AC, Matharu M, van den Maagdenberg AMJM, Hansen TF, Ramirez A, Zwart JA; International Consortium for Cluster Headache Genetics. Cluster Headache Genomewide Association Study and Meta-Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor. Ann Neurol. 2023 Jul 24. doi: 10.1002/ana.26743. Epub ahead of print. PMID: 37486023.