Cluster headache is a severe primary headache disorder affecting 0.1% of the population and occurring four times more frequently in men than in women. It is characterized by episodes of extremely excruciating, one-sided pain centered around the eye or temple.

Much remains unknown about the causes and development of cluster headaches, but disturbances of the hypothalamus, trigeminovascular system, and autonomic nervous system are likely involved. Previous twin and family studies have suggested the involvement of genetic factors. Two recent genome-wide association studies (GWAS) in individuals of European descent 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). A third GWAS in Han Chinese individuals replicated two of these loci (MERTK and SATB2) and reported an additional locus in the CAPN2 gene.<sup>8</sup>

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

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

We estimate that shared genetic variants explain 14.5% of the phenotypic variance in cluster headache. Twenty genes were prioritized as candidates for cluster headache involvement. These showed enrichment for arterial tissue, supporting the hypothesis that cluster headache may have vascular involvement. Several of the 20 prioritized genes encode targets for existing drugs. Differences in the clinical presentation of cluster headache between Asian and European populations, such as reduced restlessness and circadian rhythms, may indicate different genetic predispositions. The CAPN2 locus was selectively driven by the East Asian cohort and may exemplify how the contribution of individual risk loci varies. To investigate the potential causality of smoking on cluster headache, we performed Mendelian randomization and LCV analysis. The analyses indicated a causal effect of smoking intensity on cluster headache with high statistical confidence.

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.
https://doi.org/10.1002/ana.26743