Compensated Hypogonadism Identified in Males with Cluster Headache: A Prospective Case-Controlled Study.

OBJECTIVE: Androgens have been hypothesized to be involved in the pathophysiology of cluster headache due to the male predominance, but whether androgens are altered in patients with cluster headache remains unclear. METHODS: We performed a prospective, case-controlled study in adult males with cluster headache. Sera were measured for hormones including testosterone, luteinizing hormone (LH), and sex hormone-binding globulin in 60 participants with episodic cluster headache (during a bout and in remission), 60 participants with chronic cluster headache, and 60 age- and sex-matched healthy controls. Free testosterone (fT) was calculated according to the Vermeulen equation. Shared genetic risk variants were assessed between cluster headache and testosterone concentrations. RESULTS: The mean fT/LH ratio was reduced by 35% (95% confidence interval [CI]: 21%-47%, p < 0.0001) in patients with chronic cluster headache and by 24% (95% CI: 9%-37%, p = 0.004) in patients with episodic cluster headache compared to controls after adjusting for age, sleep duration, and use of acute medication. Androgen concentrations did not differ between bouts and remissions. Furthermore, a shared genetic risk allele, rs112572874 (located in the intron of the microtubule associated protein tau (MAPT) gene on chromosome 17), between fT and cluster headache was identified. INTERPRETATION: Our results demonstrate that the male endocrine system is altered in patients with cluster headache to a state of compensated hypogonadism, and this is not an epiphenomenon associated with sleep or the use of acute medication. Together with the identified shared genetic risk allele, this may suggest a pathophysiological link between cluster headache and fT. ANN NEUROL 2024;95:1149-1161.

CLOCK gene circannual expression in cluster headache.

BACKGROUND: Cluster headache is a primary headache disorder characterized by bouts with circadian and circannual patterns. The CLOCK gene has a central role in regulating circadian rhythms. Here, we investigate the circannual CLOCK expression in a population of cluster headache patients in comparison to matched controls. METHODS: Patients with cluster headache were sampled two to four times over at least one year, both in or outside bouts, one week after each solstice and equinox. The expression of CLOCK was measured by quantitative real-time polymerase chain reaction (RT-PCR) in the peripheral blood. RESULTS: This study included 50 patients and 58 matched controls. Among the patient population, composed of 42/50 males (84%) with an average age of 44.6 years, 45/50 (90%) suffered from episodic cluster headache. Two to four samples were collected from each patient adding up to 161 samples, 36 (22.3%) of which were collected within a bout. CLOCK expression for cluster headache patients was considerably different from that of the control population in winter (p-value mean = 0.006283), spring (p-value mean = 0.000006) and summer (p-value mean = 0.000064), but not in autumn (p-value mean = 0.262272). For each season transition, the variations in CLOCK expression were more pronounced in the control group than in the cluster headache population. No statistically significant differences were found between bout and non-bout samples. No individual factors (age, sex, circadian chronotype, smoking and coffee habits or history of migraine) were related to CLOCK expression. CONCLUSIONS: We observed that CLOCK expression in cluster headache patients fluctuates less throughout the year than in the control population. Bout activity and lifestyle factors do not seem to influence CLOCK expression.

The genetics and chronobiology of cluster headache.

BACKGROUND/HYPOTHESIS: Cluster headache displays uniquely rhythmic patterns in its attack manifestation. This strong chronobiological influence suggests that part of the pathophysiology of cluster headache is distinctly different from migraine and has prompted genetic investigations probing these systems. METHODS: This is a narrative overview of the cluster headache chronobiological phenotype from the point of view of genetics covering existing knowledge, highlighting the specific challenges in cluster headache and suggesting novel research approaches to overcome these. RESULTS: The chronobiological features of cluster headache are a hallmark of the disorder and while discrepancies between study results do exist, the main findings are highly reproducible across populations and time. Particular findings in subgroups indicate that the heritability of the disorder is linked to chronobiological systems. Meanwhile, genetic markers of circadian rhythm genes have been implicated in cluster headache, but with conflicting results. However, in two recently published genome wide association studies two of the identified four loci include genes with an involvement in circadian rhythm, MER proto-oncogene, tyrosine kinase and four and a half LIM domains 5. These findings strengthen the involvement of circadian rhythm in cluster headache pathophysiology. CONCLUSION/INTERPRETATION: Studying chronobiology and genetics in cluster headache presents challenges unique to the disorder. Researchers are overcoming these challenges by pooling various data from different cohorts and performing meta-analyses providing novel insights into a classically enigmatic disorder. Further progress can likely be made by combining deep pheno- and genotyping.

Cluster Headache Genomewide Association Study and Meta-Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor.

OBJECTIVE: The objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights. METHODS: A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses. RESULTS: The estimated single nucleotide polymorphism (SNP)-based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine. INTERPRETATION: This first genomewide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. ANN NEUROL 2023;94:713-726.

Combined genotype of HCRTR2 and CLOCK variants in a large family of cluster headache with familial periodicity phenotype.

PURPOSE: Cluster headache (CH) is a debilitating condition with severe and recurrent headaches characterized by circannual and circadian rhythms. A genetic contingent was suggested, and several loci were described in large cohorts. However, no variant associated with CH for multiplex families has been described. The purpose of our study was to examine candidate genes and new genetic variants in a multigenerational family of cluster headaches in which two members have original chronobiological characteristics that we have called the phenomenon of "family periodicity". METHODS AND RESULTS: We performed a whole genome sequencing in four patients in a large multigenerational family of cluster headache to identify additional loci associated with CH. This allowed us to replicate the genomic association of HCRTR2 and CLOCK as candidate genes. In two family members with the same phenotypic circadian pattern (familial periodicity) the association of polymorphism NM_001526.4:c.922G > A was shown in the HCRTR2 gene, and NM_004898.4:c.213T > C in the CLOCK gene. INTERPRETATION: This whole genome sequencing reproduced two genetic risk loci for CH already involved in its pathogenicity. This is the first time that the combination of HCRTR2 and CLOCK gene variants is identified in a multigenerational family of CH with striking periodicity characteristics. Our study supports the hypothesis that the combination of HCRTR2 and CLOCK gene variants can contribute to the risk of cluster headache and offer the prospect of a new area of research on the molecular circadian clock.

Circadian Features of Cluster Headache and Migraine: A Systematic Review, Meta-analysis, and Genetic Analysis.

BACKGROUND AND OBJECTIVES: Cluster headache and migraine have circadian features at multiple levels (cellular, systems, and behavioral). A thorough understanding of their circadian features informs their pathophysiologies. METHODS: A librarian created search criteria in MEDLINE Ovid, Embase, PsycINFO, Web of Science, and Cochrane Library. Two physicians independently performed the remainder of the systematic review/meta-analysis using Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. Separate from the systematic review/meta-analysis, we performed a genetic analysis for genes with a circadian pattern of expression (clock-controlled genes or CCGs) by cross-referencing genome-wide association studies (GWASs) of headache, a nonhuman primate study of CCGs in a variety of tissues, and recent reviews of brain areas relevant in headache disorders. Altogether, this allowed us to catalog circadian features at the behavioral level (circadian timing, time of day, time of year, and chronotype), systems level (relevant brain areas where CCGs are active, melatonin and corticosteroid levels), and cellular level (core circadian genes and CCGs). RESULTS: For the systematic review and meta-analysis, 1,513 studies were found, and 72 met the inclusion criteria; for the genetic analysis, we found 16 GWASs, 1 nonhuman primate study, and 16 imaging reviews. For cluster headache behavior, meta-analyses showed a circadian pattern of attacks in 70.5% (3,490/4,953) of participants across 16 studies, with a clear circadian peak between 21:00 and 03:00 and circannual peaks in spring and autumn. Chronotype was highly variable across studies. At the systems level, lower melatonin and higher cortisol levels were reported in cluster headache participants. At the cellular level, cluster headache was associated with core circadian genes CLOCK and REV-ERBα, and 5 of the 9 cluster headache susceptibility genes were CCGs. For migraine behavior, meta-analyses showed a circadian pattern of attacks in 50.1% (2,698/5,385) of participants across 8 studies, with a clear circadian trough between 23:00 and 07:00 and a broad circannual peak between April and October. Chronotype was highly variable across studies. At the systems level, urinary melatonin levels were lower in participants with migraine and even lower during an attack. At the cellular level, migraine was associated with core circadian genes CK1δ and RORα, and 110 of the 168 migraine susceptibility genes were CCGs. DISCUSSION: Cluster headache and migraine are highly circadian at multiple levels, reinforcing the importance of the hypothalamus. This review provides a pathophysiologic foundation for circadian-targeted research into these disorders. TRIAL REGISTRATION INFORMATION: The study was registered with PROSPERO (registration number CRD42021234238).

Investigating Vitamin D Receptor Genetic Markers in a Cluster Headache Meta-Analysis.

Patients diagnosed with the primary headache disorder known as cluster headache (CH) commonly report that their headache attacks occur in patterns of both circadian and seasonal rhythmicity. Vitamin D is essential for a variety of bodily functions and vitamin D levels are largely regulated by daylight exposure in connection with seasonal variation. For this Sweden-based study, the association between CH and three single-nucleotide polymorphisms in the vitamin D receptor gene, rs2228570, rs1544410, and rs731236, were investigated, as well as CH bouts and trigger factors in relation to seasonal and weather changes. Over 600 study participants with CH and 600 controls were genotyped for rs2228570, and genotyping results for rs1544410 and rs731236 were obtained from a previous genome-wide association study. The genotyping results were combined in a meta-analysis, with data from a Greek study. No significant association was found between rs2228570 and CH or the CH subtype in Sweden, nor did the meta-analysis show significant results for any of the three markers. The most common period of the year to experience CH bouts in Sweden was autumn, and conditions linked to weather or weather changes were also identified as potential triggers for CH bouts for a quarter of the responders who reported bout triggers. Though we cannot rule out vitamin D involvement in CH, this study does not indicate any connection between CH and the three vitamin D receptor gene markers.

Cluster headache polygenetic risk and known functional variants of CYP3A4 are not associated with treatment response.

BACKGROUND AND PURPOSE: The response to cluster headache treatments has a high interindividual variation. To date, treatment response has only been assessed by a candidate gene approach and no investigations into metabolic pathways have been performed. Our aim was to investigate the association between the polygenetic risk of cluster headache and treatment response to first-line cluster headache treatments as well as known functional variants of CYP3A4 and the response to verapamil. Further, it was aimed to replicate previous single nucleotide polymorphisms found to be associated with treatment response in cluster headache and/or migraine. METHODS: In, 508 cluster headache patients diagnosed according to the International Classification of Headache Disorders were genotyped and participated in a semi-structured interview to evaluate treatment response. Polygenetic risk scores were calculated by the effect retrieved from a meta-analysis of the latest two genome-wide association studies on cluster headache. RESULTS: Inferior treatment response to oxygen, triptans and verapamil is associated with chronicity of cluster headache were confirmed but no evidence was found that a response could be predicted by a high genetic risk of cluster headache. Likewise, verapamil response was not associated with functional variants of CYP3A4. No support of the genetic variants previously reported to be associated with treatment response to triptans or verapamil was found. CONCLUSION: The clinically relevant variation in treatment response for cluster headache was not influenced by genetic factors in the present study.

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

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.

No significant association between SNPs in the CLOCK and ADH4 genes and susceptibility to cluster headaches: A systematic review and meta-analysis.

BACKGROUND: The circadian locomotor output cycles kaput (CLOCK) gene and the alcohol dehydrogenase 4 (ADH4) gene are promising candidates for susceptibility to cluster headaches (CH). Associations of the three single nucleotide polymorphisms (SNPs)-CLOCK SNP rs1801260 and ADH4 SNPs rs1800759, and rs1126671-with CH were studied previously, but the results were inconsistent. METHODS: Associations between the three SNPs (rs1801260, rs1126671, and rs1800759) and CH risk were separately assessed by pooled odds ratios (ORs) along with 95% confidence intervals (95% CIs) based on five different genetic models. Methodological quality was assessed using the Newcastle-Ottawa Quality Assessment Scale (NOS). All statistical analyses were carried out with RevMan 5.3 software. RESULTS: Eight studies involving 1437 CH patients and 2541 healthy controls were selected for quantitative synthesis, from five studies on CLOCK rs1801260, five on ADH4 rs1800759, and three on ADH4 rs1126671. Our pooled data did not support associations between the three SNPs (rs1801260 in the CLOCK gene, rs1800759 and rs1126671 in the ADH4 gene) and susceptibility to CH (rs1801260: OR 1.10, 95% CI: 0.95-1.28; p = 0.19; rs1800759: OR 1.06, 95% CI: 0.93-1.22; p = 0.37; and rs1126671: OR 1.09, 95% CI: 0.92-1.28; p = 0.32). CONCLUSION: We found no significant associations between the three SNPs (rs1801260 in the CLOCK gene and rs1800759 and rs1126671 in the ADH4 gene) and the susceptibility to CH across both Caucasian and Asian ethnicities in our meta-analysis.

Effects of cluster headache preventatives on mouse hypothalamic transcriptional homeostasis.

OBJECTIVE: To investigate how cluster headache preventatives verapamil, lithium and prednisone affect expression of hypothalamic genes involved in chronobiology. METHODS: C57Bl/6 mice were exposed to daily, oral treatment with verapamil, lithium, prednisone or amitriptyline (as negative control), and transcripts of multiple genes quantified in the anterior, lateral and posterior hypothalamus. RESULTS: Verapamil, lithium or prednisone did not affect expression of clock genes of the anterior hypothalamus (Clock, Bmal1, Cry1/2 and Per1/2). Prednisone altered expression of hypothalamic neuropeptides melanin-concentrating hormone and histidine decarboxylase within the lateral and posterior hypothalamus, respectively. The three preventatives did not affect expression of the neurohypophyseal hormones oxytocin and arginine-vasopressin in the posterior hypothalamus. Conversely, amitriptyline reduced mRNA levels of Clock, oxytocin and arginine-vasopressin. CONCLUSION: Data suggest that cluster headache preventatives act upstream or downstream from the hypothalamus. Our findings provide new insights on hypothalamic homeostasis during cluster headache prophylaxis, as well as neurochemistry underlying cluster headache treatment.

The clinical characteristics of familial cluster headache.

BACKGROUND: A positive family history predisposes to the development of cluster headache. The distinct characteristics of familial cluster headache have yet to be confirmed, however, evidence suggests a younger age of onset and higher proportion of females in this subgroup. OBJECTIVES: To assess the rate and mode of inheritance of familial cluster headache in a tertiary referral centre for headache. To describe the clinical features of familial cluster headache. METHODS: A retrospective study conducted between 2007 and 2017. Cluster headache was confirmed in probands and affected relatives. Differences in demographics, clinical characteristics, and response-to-treatment in familial cluster headache were delineated through multivariate analysis using a control cohort of 597 patients with sporadic cluster headache. RESULTS: Familial cluster headache was confirmed in 48 (7.44%) patients and predominantly reflected an autosomal dominant mode of inheritance with reduced penetrance. Familial cases were more likely to report nasal blockage (OR 4.06, 95% CI; 2.600-6.494, p < 0.001) during an attack and a higher rate of concurrent short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (OR 3.76, 95% CI; 1.572-9.953, p = 0.004). CONCLUSION: These findings add to evidence suggesting a genetic component to cluster headache. Here, we demonstrated prominent nasal blockage, and a higher occurrence of concomitant short-lasting unilateral neuralgiform headache with conjunctival injection and tearing in this subgroup, further delineating the phenotype.

VDR Gene Polymorphisms and Cluster Headache Susceptibility: Case-Control Study in a Southeastern European Caucasian Population.

Cluster headache (CH) is a severe primary headache disorder with a genetic component, as indicated by family and twin studies. Diurnal and seasonal rhythmicity are key features of the disease and might be related to vitamin D, as low vitamin D levels have been observed in patients with cluster headache. In addition, the vitamin D receptor (VDR) occurs in brain areas and particularly in the hypothalamus. The aim of the present case-control study was to investigate the association of cluster headache susceptibility and clinical phenotypes with the VDR gene polymorphisms FokI, BsmI and TaqI in a Southeastern European Caucasian population. DNA was extracted from 131 unrelated CH patients and 282 non-headache controls and genotyped using real-time PCR (melting curve analysis). Linkage disequilibrium (LD) analysis confirmed that BsmI and TaqI, both located in the 3'UTR of the VDR gene, are in strong LD. Genotype and allele frequency distribution analysis of the VDR FokI, BsmI, and TaqI polymorphisms showed no statistically significant difference between cases and controls, whereas haplotype analysis indicated that the TAC haplotype might be associated with decreased cluster headache susceptibility. Intra-patient analysis according to diverse clinical phenotypes showed an association of the BsmI GG and TaqI TT genotypes with more frequent occurrence of CH attacks in this cohort. Therefore, a possible association was observed between VDR gene polymorphisms BsmI and TaqI or a linked locus and susceptibility for cluster headache development and altered clinical phenotypes in the Southeastern European Caucasian study population. Further large-scale replication studies are needed to validate these findings.

Evidence That HFE H63D Variant Is a Potential Disease Modifier in Cluster Headache.

Cluster headache (CH) is a primary headache disorder with a complex genetic background. Several studies indicate a potential link between iron homeostasis and the pathophysiology of primary headaches. The HFE gene encodes for a protein involved in iron metabolism, while genetic variants in HFE have been associated with hereditary hemochromatosis (HH), an iron overload disorder. The objective of the current study was to examine the association of the more common HFE H63D variant, with the susceptibility to develop CH and diverse clinical phenotypes in a population of Southeastern European Caucasian (SEC) origin. Genomic DNA samples from 128 CH patients and 294 neurologically healthy controls were genotyped for the HFE rs1799945 (H63D) variant. H63D genotypic and allelic frequency distribution did not differ significantly between patients and controls (p > 0.05). Subgroup analysis revealed a significantly more frequent occurrence of the variant G allele in chronic compared to episodic CH patients, indicative for a possible correlation of the HFE gene with the susceptibility for disease chronification. Although homozygosity for the less prevalent H63D variant G allele was minimal in the CH cohort, the results of the present study are in accordance with previous studies in CH and migraine patients, suggesting that HFE H63D variant modifies the disease clinical characteristics. Hence, despite the absence of a per se association with CH susceptibility in the current SEC cohort, variability in HFE gene may be potentially regarded as a disease modifier genetic factor in CH.

The molecular clock gene cryptochrome 1 (CRY1) and its role in cluster headache.

BACKGROUND: Cluster headache is a severe primary headache disorder commonly featuring a strikingly distinct circadian attack pattern. Therefore, the circadian system has been suggested to play a crucial role in the pathophysiology of cluster headache. Cryptochromes are key components of the molecular clock generating circadian rhythms and have previously been shown to be associated with several psychiatric disorders, including seasonal affective disorder, bipolar disorder, and depression. METHODS: In this case-control study, we investigated the role of cryptochrome (CRY) genes in cluster headache by screening 628 cluster headache patients and 681 controls from Sweden for four known genetic variants in the CRY1 (rs2287161 and rs8192440) and CRY2 (rs10838524 and rs1554338) genes. In addition, we analyzed CRY1 gene expression in primary fibroblast cell lines from eleven patients and ten controls. RESULTS: The exonic CRY1 variant rs8192440 was associated with cluster headache on allelic level (p=0.02) and this association was even more pronounced in a subgroup of patients with reported diurnal rhythmicity of attacks (p=0.002). We found a small significant difference in CRY1 gene expression between cluster headache patients and control individuals (p=0.04), but we could not identify an effect of the associated variant rs8192440 on CRY1 expression. CONCLUSIONS: We discovered a disease-associated variant in the CRY1 gene and slightly increased CRY1 gene expression in tissue from cluster headache patients, strengthening the hypothesis of circadian dysregulation in cluster headache. How this gene variant may contribute to the pathophysiology of the disease remains subject to further studies.

Gene polymorphism association studies in cluster headache: A field synopsis and systematic meta-analyses.

BACKGROUND: A plethora of studies have attempted to identify genetic determinants of disease susceptibility and treatment response of patients with cluster headache (CH), but results are often conflicting, and no comprehensive overview with a quantitative summary of the evidence in this field is available. METHODS: A systematic search of relevant publications was performed without any language restrictions on PubMed, Web of Knowledge, Cochrane Library, and OpenGrey, up to December 2020. A standardized data extraction form was used to collect relevant data from each included study. Meta-analyses were conducted for gene polymorphisms investigated in at least two studies and the Bayesian false discovery probability (BFDP) test was applied to the pooled odds ratios (ORs) to assess the credibility of the observed associations. RESULTS: Among the 27 articles identified by the systematic review, 17 studies evaluating 12 single nucleotide polymorphisms (SNPs) were included in the quantitative data analysis. The pooled results showed no significant association with CH risk of 10 SNPs, including five SNPs of HCRTR2 (rs2653349, rs2653342, rs3122156, rs10498801, and rs3800539), two SNPs of ADH4 (rs1800759 and rs1126671), CLOCK rs1801260, and two SNPs (rs1006417 and ADCYAP1R1 rs12668955) previously identified by a genome-wide association study (GWAS). Conversely, the pooled results revealed the association of the HCRTR2 rs9357855 A allele with a higher risk of CH (A vs. G, OR: 1.33, 95% CI: 1.04-1.72, p = 0.026), and of GNB3 rs5443 with a higher response rate of patients with CH to triptan drugs (CT+TT vs. CC, OR: 1.96, 95% CI: 1.04-3.72, p = 0.038). However, assuming a prior probability of 0.001, the respective BFDP values being higher than 0.8 (BFDPrs9357855  = 0.998; BFDPrs5443  = 0.998) revealed lack of noteworthy results. CONCLUSIONS: Well-designed GWASs and large replication studies are still needed to identify reliable genetic variants of disease susceptibility and treatment response of patients with CH.

Genome-Wide Association Study Identifies Risk Loci for Cluster Headache.

OBJECTIVE: This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways. METHODS: We carried out a genome-wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model for each cohort. The 2 cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene-set enrichment, functional variant annotation, prediction and pathway analyses, were performed. RESULTS: Initial independent analysis identified 2 replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 × 10-17 , odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.37-1.66) and rs4519530 (p = 6.98 × 10-17 , OR = 1.47, 95% CI = 1.34-1.61) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 × 10-8 , OR = 1.36, 95% CI = 1.22-1.52), and rs11153082 (p = 1.85 × 10-8 , OR = 1.30, 95% CI = 1.19-1.42) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache. INTERPRETATION: We identified and replicated several genome-wide significant associations supporting a genetic predisposition in cluster headache in a genome-wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype-phenotype correlations and the pathophysiological pathways underlying cluster headache. ANN NEUROL 2021;90:193-202.

Genetic Susceptibility Loci in Genomewide Association Study of Cluster Headache.

OBJECTIVE: Identifying common genetic variants that confer genetic risk for cluster headache. METHODS: We conducted a case-control study in the Dutch Leiden University Cluster headache neuro-Analysis program (LUCA) study population (n = 840) and unselected controls from the Netherlands Epidemiology of Obesity Study (NEO; n = 1,457). Replication was performed in a Norwegian sample of 144 cases from the Trondheim Cluster headache sample and 1,800 controls from the Nord-Trøndelag Health Survey (HUNT). Gene set and tissue enrichment analyses, blood cell-derived RNA-sequencing of genes around the risk loci and linkage disequilibrium score regression were part of the downstream analyses. RESULTS: An association was found with cluster headache for 4 independent loci (r2 < 0.1) with genomewide significance (p < 5 × 10-8 ), rs11579212 (odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.33-1.72 near RP11-815 M8.1), rs6541998 (OR = 1.53, 95% CI = 1.37-1.74 near MERTK), rs10184573 (OR = 1.43, 95% CI = 1.26-1.61 near AC093590.1), and rs2499799 (OR = 0.62, 95% CI = 0.54-0.73 near UFL1/FHL5), collectively explaining 7.2% of the variance of cluster headache. SNPs rs11579212, rs10184573, and rs976357, as proxy SNP for rs2499799 (r2  = 1.0), replicated in the Norwegian sample (p < 0.05). Gene-based mapping yielded ASZ1 as possible fifth locus. RNA-sequencing indicated differential expression of POLR1B and TMEM87B in cluster headache patients. INTERPRETATION: This genomewide association study (GWAS) identified and replicated genetic risk loci for cluster headache with effect sizes larger than those typically seen in complex genetic disorders. ANN NEUROL 2021;90:203-216.