Genetic Susceptibility Loci in Genomewide Association Study of Cluster Headache

Harder, Aster V. E.; Winsvold, Bendik S.; Noordam, Raymond; Vijfhuizen, Lisanne S.; Børte, Sigrid; Kogelman, Lisette J. A.; Boer, Irene de; Tronvik, Erling; Rosendaal, Frits R.; Dijk, Ko Willems van; O’Connor, Emer; Fourier, Carmen; Thomas, Laurent F.; Kristoffersen, Espen Saxhaug; Fronczek, Rolf; Pozo‐Rosich, Patricia; Jensen, Rigmor Højland; Ferrari, Michel D.; Hansen, Thomas Folkmann; Zwart, John‐Anker; Terwindt, Gisela M.; Maagdenberg, Arn M. J. M. van den

doi:10.1002/ana.26146

Cited by 30 publications

(48 citation statements)

References 50 publications

(128 reference statements)

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“…The first genome-wide association study (GWAS) investigating 99 Italian patients with cluster reported suggestive associations with genetic variants in ADCYAP1R1 (ADCYAP receptor type I) and MME (membrane metalloendopeptidase) [ 5 ]; however, these findings were not replicated subsequently. Two recent studies provided the first evidence to demonstrate genome-wide significant variants contributing to the predisposition of cluster headache in European cohorts [ 6 , 7 ]. The Dutch and Norwegian study identified rs11579212 near RP11-815 M8.1 , rs6541998 near MERTK (MER Proto-Oncogene, Tyrosine Kinase) , rs10184573 near AC093590.1 , and rs2499799 near UFL1 (UFM1 specific ligase 1)/FHL5 (four and a half LIM domains 5) [ 6 ] whereas the combined United Kingdom (UK) and Swedish cohorts identified rs113658130 near LINC01877/SATB2 (SATB homeobox 2) , rs4519530 in MERTK , rs12121134 near LINC01705/DUSP10 ( Dual Specificity Phosphatase 10 ), and rs11153082 in FHL5 to be associated with cluster headache [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…Two recent studies provided the first evidence to demonstrate genome-wide significant variants contributing to the predisposition of cluster headache in European cohorts [ 6 , 7 ]. The Dutch and Norwegian study identified rs11579212 near RP11-815 M8.1 , rs6541998 near MERTK (MER Proto-Oncogene, Tyrosine Kinase) , rs10184573 near AC093590.1 , and rs2499799 near UFL1 (UFM1 specific ligase 1)/FHL5 (four and a half LIM domains 5) [ 6 ] whereas the combined United Kingdom (UK) and Swedish cohorts identified rs113658130 near LINC01877/SATB2 (SATB homeobox 2) , rs4519530 in MERTK , rs12121134 near LINC01705/DUSP10 ( Dual Specificity Phosphatase 10 ), and rs11153082 in FHL5 to be associated with cluster headache [ 7 ]. Considering the inter-ethnic variability of clinical characteristics [ 3 ], it is uncertain whether these novel loci are replicable in other populations.…”

Section: Introductionmentioning

confidence: 99%

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Genome-wide analyses identify novel risk loci for cluster headache in Han Chinese residing in Taiwan

et al. 2022

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Background Cluster headache is a highly debilitating neurological disorder with considerable inter-ethnic differences. Genome-wide association studies (GWAS) recently identified replicable genomic loci for cluster headache in Europeans, but the genetic underpinnings for cluster headache in Asians remain unclear. The objective of this study is to investigate the genetic architecture and susceptibility loci of cluster headache in Han Chinese resided in Taiwan. Methods We conducted a two-stage genome-wide association study in a Taiwanese cohort enrolled from 2007 through 2022 to identify the genetic variants associated with cluster headache. Diagnosis of cluster headache was retrospectively ascertained with the criteria of International Classification of Headache Disorders, third edition. Control subjects were enrolled from the Taiwan Biobank. Genotyping was conducted with the Axiom Genome-Wide Array TWB chip, followed by whole genome imputation. A polygenic risk score was developed to differentiate patients from controls. Downstream analyses including gene-set and tissue enrichment, linkage disequilibrium score regression, and pathway analyses were performed. Results We enrolled 734 patients with cluster headache and 9,846 population-based controls. We identified three replicable loci, with the lead SNPs being rs1556780 in CAPN2 (odds ratio = 1.59, 95% CI 1.42‒1.78, p = 7.61 × 10–16), rs10188640 in MERTK (odds ratio = 1.52, 95% CI 1.33‒1.73, p = 8.58 × 10–13), and rs13028839 in STAB2 (odds ratio = 0.63, 95% CI 0.52‒0.78, p = 2.81 × 10–8), with the latter two replicating the findings in European populations. Several previously reported genes also showed significant associations with cluster headache in our samples. Polygenic risk score differentiated patients from controls with an area under the receiver operating characteristic curve of 0.77. Downstream analyses implicated circadian regulation and immunological processes in the pathogenesis of cluster headache. Conclusions This study revealed the genetic architecture and novel susceptible loci of cluster headache in Han Chinese residing in Taiwan. Our findings support the common genetic contributions of cluster headache across ethnicities and provide novel mechanistic insights into the pathogenesis of cluster headache.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Genome-wide analyses identify novel risk loci for cluster headache in Han Chinese residing in Taiwan

et al. 2022

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“…This could indicate the presence of a slightly more 'migrainous' phenotype in women with cluster headache (20,21). Interestingly, in two recent parallel genome-wide association studies of cluster headache, among other gene loci, the migraine risk FHL5-locus was identified as well and with a remarkably large effect size, indicating a partially overlapping genetic basis between these two types of paroxysmal headache (22,23).…”

Section: Discussionmentioning

confidence: 99%

Unilateral increased visual sensitivity in cluster headache: a cross-sectional study

et al. 2022

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Background and Objectives Increased sensitivity to light and patterns is typically associated with migraine, but has also been anecdotally reported in cluster headache, leading to diagnostic confusion. We wanted to assess whether visual sensitivity is increased ictally and interictally in cluster headache. Methods We used the validated Leiden Visual Sensitivity Scale (L-VISS) questionnaire (range 0-36 points) to measure visual sensitivity in people with episodic or chronic cluster headache: (i) during attacks; (ii) in-between attacks; and in episodic cluster headache (iii) in-between bouts. The L-VISS scores were compared with the L-VISS scores obtained in a previous study in healthy controls and participants with migraine. Results Mean L-VISS scores were higher for: (i) ictal vs interictal cluster headache (episodic cluster headache: 11.9 ± 8.0 vs. 5.2 ± 5.5, chronic cluster headache: 13.7 ± 8.4 vs 5.6 ± 4.8; p < 0.001); (ii) interictal cluster headache vs controls (5.3 ± 5.2 vs 3.6 ± 2.8, p < 0.001); (iii) interictal chronic cluster headache vs interictal ECH in bout (5.9 ± 0.5 vs 3.8 ± 0.5, p = 0.009), and (iv) interictal episodic cluster headache in bout vs episodic cluster headache out-of-bout (5.2 ± 5.5 vs. 3.7 ± 4.3, p < 0.001). Subjective visual hypersensitivity was reported by 110/121 (91%; 9 missing) participants with cluster headache and was mostly unilateral in 70/110 (64%) and ipsilateral to the ictal pain in 69/70 (99%) participants. Conclusion Cluster headache is associated with increased ictal and interictal visual sensitivity. In contrast to migraine, this is mostly unilateral and ipsilateral on the side of the ictal pain.

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“…A better understanding of the sources of heterogeneity may lead to more effective treatment strategies according to patient profiles. We think that our approach with cluster analysis will be of help in unraveling underlying genetic mechanisms of CH, which seems to bear some heterogeneity within its clinical phenotype ( 43 , 44 ).…”

Section: Discussionmentioning

confidence: 99%

Cluster Analysis Revealed Two Hidden Phenotypes of Cluster Headache

et al. 2022

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ObjectiveTo investigate the possible subgroups of patients with Cluster Headache (CH) by using K-means cluster analysis.MethodsA total of 209 individuals (mean (SD) age: 39.8 (11.3) years), diagnosed with CH by headache experts, participated in this cross-sectional multi-center study. All patients completed a semi-structured survey either face to face, preferably, or through phone interviews with a physician. The survey was composed of questions that addressed sociodemographic characteristics as well as detailed clinical features and treatment experiences.ResultsCluster analysis revealed two subgroups. Cluster one patients (n = 81) had younger age at diagnosis (31.04 (9.68) vs. 35.05 (11.02) years; p = 0.009), a higher number of autonomic symptoms (3.28 (1.16) vs. 1.99(0.95); p < 0.001), and showed a better response to triptans (50.00% vs. 28.00; p < 0.001) during attacks, compared with the cluster two subgroup (n = 122). Cluster two patients had higher rates of current smoking (76.0 vs. 33.0%; p=0.002), higher rates of smoking at diagnosis (78.0 vs. 32.0%; p=0.006), higher rates of parental smoking/tobacco exposure during childhood (72.0 vs. 33.0%; p = 0.010), longer duration of attacks with (44.21 (34.44) min. vs. 34.51 (24.97) min; p=0.005) and without (97.50 (63.58) min. vs. (83.95 (49.07) min; p = 0.035) treatment and higher rates of emergency department visits in the last year (81.0 vs. 26.0%; p< 0.001).ConclusionsCluster one and cluster two patients had different phenotypic features, possibly indicating different underlying genetic mechanisms. The cluster 1 phenotype may suggest a genetic or biology-based etiology, whereas the cluster two phenotype may be related to epigenetic mechanisms. Toxic exposure to cigarettes, either personally or secondarily, seems to be an important factor in the cluster two subgroup, inducing drug resistance and longer attacks. We need more studies to elaborate the causal relationship and the missing links of neurobiological pathways of cigarette smoking regarding the identified distinct phenotypic classes of patients with CH.

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Genetic Susceptibility Loci in Genomewide Association Study of Cluster Headache

Cited by 30 publications

References 50 publications

Genome-wide analyses identify novel risk loci for cluster headache in Han Chinese residing in Taiwan

Genome-wide analyses identify novel risk loci for cluster headache in Han Chinese residing in Taiwan

Unilateral increased visual sensitivity in cluster headache: a cross-sectional study

Cluster Analysis Revealed Two Hidden Phenotypes of Cluster Headache

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