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Objective: Our study investigates the impact of copy number variations (CNVs) on Parkinson's disease (PD) pathogenesis using genome-wide data, aiming to uncover novel genetic mechanisms and improve the understanding of the role of CNVs in sporadic PD., Methods: We applied a sliding window approach to perform CNV-GWAS and conducted genome-wide burden analyses on CNV data from 11,035 PD patients (including 2,731 early-onset PD (EOPD)) and 8,901 controls from the COURAGE-PD consortium., Results: We identified 14 genome-wide significant CNV loci associated with PD, including one deletion and 13 duplications. Among these, duplications in 7q22.1, 11q12.3 and 7q33 displayed the highest effect. Two significant duplications overlapped with PD-related genes SNCA and VPS13C , but none overlapped with recent significant SNP-based GWAS findings. Five duplications included genes associated with neurological disease, and four overlapping genes were dosage-sensitive and intolerant to loss-of-function variants. Enriched pathways included neurodegeneration, steroid hormone biosynthesis, and lipid metabolism. In early-onset cases, four loci were significantly associated with EOPD, including three known duplications and one novel deletion in PRKN . CNV burden analysis showed a higher prevalence of CNVs in PD-related genes in patients compared to controls (OR=1.56 [1.18-2.09], p=0.0013), with PRKN showing the highest burden (OR=1.47 [1.10-1.98], p=0.026). Patients with CNVs in PRKN had an earlier disease onset. Burden analysis with controls and EOPD patients showed similar results., Interpretation: This is the largest CNV-based GWAS in PD identifying novel CNV regions and confirming the significant CNV burden in EOPD, primarily driven by the PRKN gene, warranting further investigation.

Background and Objectives: The role of body mass index (BMI) in Parkinson disease (PD) is unclear. Based on the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in PD (Courage-PD) consortium, we used 2-sample Mendelian randomization (MR) to replicate a previously reported inverse association of genetically predicted BMI with PD and investigated whether findings were robust in analyses addressing the potential for survival and incidence-prevalence biases. We also examined whether the BMI-PD relation is bidirectional by performing a reverse MR., Methods: We used summary statistics from a genome-wide association study (GWAS) to extract the association of 501 single-nucleotide polymorphisms (SNPs) with BMI and from the Courage-PD and international Parkinson Disease Genomics Consortium (iPDGC) to estimate their association with PD. Analyses are based on participants of European ancestry. We used the inverse-weighted method to compute odds ratios (OR IVW per 4.8 kg/m 2 [95% CI]) of PD and additional pleiotropy robust methods. We performed analyses stratified by age, disease duration, and sex. For reverse MR, we used SNPs associated with PD from 2 iPDGC GWAS to assess the effect of genetic liability toward PD on BMI., Results: Summary statistics for BMI are based on 806,834 participants (54% women). Summary statistics for PD are based on 8,919 (40% women) cases and 7,600 (55% women) controls from Courage-PD, and 19,438 (38% women) cases and 24,388 (51% women) controls from iPDGC. In Courage-PD, we found an inverse association between genetically predicted BMI and PD (OR IVW 0.82 [0.70-0.97], p = 0.012) without evidence for pleiotropy. This association tended to be stronger in younger participants (≤67 years, OR IVW 0.71 [0.55-0.92]) and cases with shorter disease duration (≤7 years, OR IVW 0.75 [0.62-0.91]). In pooled Courage-PD + iPDGC analyses, the association was stronger in women (OR IVW 0.85 [0.74-0.99], p = 0.032) than men (OR IVW 0.92 [0.80-1.04], p = 0.18), but the interaction was not statistically significant ( p -interaction = 0.48). In reverse MR, there was evidence for pleiotropy, but pleiotropy robust methods showed a significant inverse association., Discussion: Using an independent data set (Courage-PD), we replicate an inverse association of genetically predicted BMI with PD, not explained by survival or incidence-prevalence biases. Moreover, reverse MR analyses support an inverse association between genetic liability toward PD and BMI, in favor of a bidirectional relation.

Background: Cluster headache is characterized by activation of the trigeminovascular pathway with subsequent pain signalling in the meningeal vessels, and inflammation has been suggested to play a role in the pathophysiology. To further investigate inflammation in cluster headache, inflammatory markers were analysed in patients with cluster headache and controls., Methods: We performed a case-control study, collecting cerebrospinal fluid and serum samples from healthy controls, cluster headache patients in remission, active bout, and during an attack to cover the dynamic range of the cluster headache phenotype. Inflammatory markers were quantified using Target 48 OLINK cytokine panels., Results: Altered levels of several cytokines were found in patients with cluster headache compared to controls. CCL8, CCL13, CCL11, CXCL10, CXCL11, HGF, MMP1, TNFSF10 and TNFSF12 levels in cerebrospinal fluid were comparable in active bout and remission, though significantly higher than in controls. In serum samples, CCL11 and CXCL11 displayed decreased levels in patients. Only one cytokine, IL-13 was differentially expressed in serum during attacks., Conclusion and Interpretation: Our data shows signs of possible neuroinflammation occurring in biological samples from cluster headache patients. Increased cerebrospinal fluid cytokine levels are detectable in active bout and during remission, indicating neuroinflammation could be considered a marker for cluster headache and is unrelated to the different phases of the disorder., (© 2024. The Author(s).)

Cluster headache, characterised by attacks of severe, recurrent, unilateral headache and ipsilateral cranial autonomic symptoms, remains a primary headache with an elusive pathophysiology. Recent advances have introduced effective treatments and broadened understanding of the clinical features of cluster headache. These features are similar in patients globally, but regional differences in prevalence and burden exist. International collaborations have led to identification of eight genetic loci associated with cluster headache. The pathophysiological mechanisms are still not fully understood but recent studies show that targeting the trigeminal autonomic reflex by neurostimulation, or targeting the neuropeptide calcitonin gene-related peptide (CGRP), might lessen the attack burden. The US Food and Drug Administration has approved galcanezumab, a monoclonal antibody targeting CGRP, as the first specific preventive treatment for episodic cluster headache. However, a preventive effect was not replicated in chronic cluster headache, and the European Medicines Agency did not approve galcanezumab, restricting its availability in Europe. Owing to the low prevalence of cluster headache, continued collaboration through multicentre clinical trials and data sharing will be imperative for further breakthroughs in understanding and management., Competing Interests: Declaration of interests ASP has received a restricted research grant (payment to their institution) and conference attendance from Lundbeck Pharma, and personal fees from Pfizer for teaching activities. NL has received a restricted research grant from Lundbeck Pharma (payment to their institution), a research grant from the Capital Region Research Foundation, support for conference attendance from Pfizer, and personal fees from teaching activities for general practitioners from Dagens Medicin and Pfizer (personal). PJG reports, over the past 36 months: grants from Celgene and Kallyope; personal fees from Aeon Biopharma, AbbVie, Amgen, eNeura, CoolTech, Dr Reddys, Eli Lilly, Epalex, Linpharma, Lundbeck, Novartis, Pfizer, Sanofi, Satsuma, Shiratronics, and Teva Pharmaceuticals; participation on a data and safety monitoring board for Aeon Biopharma and Man & Science; personal fees for advice through Gerson Lehrman Group, Guidepoint, SAI Med Partners, and Vector Metric; fees for educational materials from CME Outfitters; publishing royalties or fees from Massachusetts Medical Society, Oxford University Press, UptoDate, and Wolters Kluwer; and a patent for magnetic stimulation for headache (WO2016090333 A1) assigned to eNeura, without fee. PJG is a board member of the American Headache Society, Migraine Trust, and Organisation for Understanding Cluster Headache. ACB reports honoraria for presentations from Novartis, Teva, and Lundbeck; and research funding from the Swedish Brain Foundation and the Mellby Gård Foundation. S-JW has received honoraria as a moderator from AbbVie, Biogen, Eli Lilly, Hava Biopharma, and Pfizer; has received consulting fees from AbbVie, Eli Lilly Taiwan, Percept, and Pfizer Taiwan; and has received research grants from the Taiwan branches of Eli Lilly, Lundbeck, Novartis, and Orient Europharma. RF reports research grants from Bioprojet, Jazz Pharmaceuticals, Netherlands Brain Foundation, and ZonMW (fee for institution); educational honoraria from Novartis (fee for institution), Teva Pharmaceutical Industries, Bioprojet, and Lundbeck Pharma (personal fees); consultancy for AbbVie, Eli Lilly, and Takeda (fee for institution); and is a member of the cluster headache section of the Dutch Headache guidelines (unpaid). MB reports grant funding from the Will Erwin Headache Research Foundation; travel support for attending meetings from the American Headache Society; has served as a consultant for Lundbeck, Beckley Psytech, Praxis Precision Medicines, and PureTech Health; is a site investigator for a cluster headache clinical trial funded by Lundbeck; was a paid guest for a video podcast by the American Academy of Neurology, is a paid survey respondent for Doximetry, and is an unpaid member of the medical advisory board of Clusterbusters. S-JC was involved as a site investigator of a multicentre trial sponsored by Allergan, AbbVie, Hyundai Pharmaceutical, Ildong Pharmaceutical, Eli Lilly, Pfizer, and Lundbeck; and has received lecture fees or advisory honoraria from AbbVie Korea, Lundbeck, Eli Lilly Korea, SK Chemicals, Teva Pharmaceutical Industries, and Pfizer. MFPP reports consulting fees for AbbVie–Allergan, Ache, Eli Lilly, Eurofarma, Libbs, Lundbeck, Kenvue, Pfizer, Sanofi-Aventis, and Teva Pharmaceutical Industries; travel support from Teva; participation in advisory boards for AbbVie-Allergan, Eli Lilly, Pfizer, Kenvue, Eurofarma, and Sonofi-Aventis; and is president of the Brazilian Association for Cluster Headache and Migraine (unpaid). RHJ received a restricted research grant (for institution) for work on cluster headache from Lundbeck Pharma; received a research grant for treatment trial for idiopathic intracranial hypertension (for institution) from Novo Nordisk Foundation; is on an advisory board for Lundbeck Pharma and has received fees for participation on an advisory board (for institution); has received personal fees for educational and teaching activities from Pfizer, Teva Pharmaceutical Industries, Novartis, AbbVie, Lundbeck, and Eli Lilly; is chair of the Master of Headache Disorders at the University of Copenhagen, a director of the Danish Headache Center, and undertakes unpaid activities as a director of Lifting The Burden., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

The trigeminal system is key to the pathophysiology of migraine and cluster headache, two primary headache disorders that share many features. Recently, MER proto-oncogene tyrosine kinase (MERTK), a cell surface receptor, was strongly associated with cluster headache through genetic studies. Further, the MERTK ligand galectin-3 has been found to be elevated in serum of migraine patients. In this study, MERTK and MERTK ligands were investigated in key tissue to better understand their potential implication in the pathophysiology of primary headache disorders. Immunohistochemistry was used to map MERTK and galectin-3 expression in rat trigeminal ganglia. RT-qPCR was used to assess MERTK gene expression in blood, and ELISA immunoassays were used for MERTK ligand quantification in serum from study participants with and without cluster headache. MERTK gene expression was elevated in blood samples from study participants with cluster headache compared to controls. In addition, MERTK ligand galectin-3 was found at increased concentration in the serum of study participants with cluster headache, whereas the levels of MERTK ligands growth arrest specific 6 and protein S unaffected. MERTK and galectin-3 were both expressed in rat trigeminal ganglia. Galectin-3 was primarily localized in smaller neurons and to a lesser extent in C-fibres, while MERTK was found in satellite glia cells and in the outer membrane of Schwann cells. Interestingly, a strong MERTK signal was found specifically in the region proximal to the nodes of Ranvier. The overexpression of MERTK and galectin-3 in tissue from study participants with cluster headache, as well as the presence of MERTK in rat peripheral satellite glia cells and Schwann cells in the trigeminal ganglia, further highlights MERTK signalling as an interesting potential future therapeutic target in primary headache., (© 2024. The Author(s).)

Up to 25% of individuals who live with cluster headache (CH), an extremely painful primary headache disorder, do not adequately respond to the first-line treatment, triptans. Studies have indicated that genetic variants can play a role in treatment response. Likewise, differences in clinical characteristics can give clues to mechanisms underlying triptan non-response. Our aim was to investigate five genetic variants previously implicated in triptan response and their relation to triptan usage in our Swedish CH cohort and to investigate potential distinctions in clinical characteristics. 545 CH patients were screened for the genetic variants rs1024905, rs6724624, rs4795541, rs5443, and rs2651899 with a case control design based on triptan usage. Analysis of clinical characteristics was based on self-reported questionnaire data from 893 patients. One genetic variant, rs1024905, was significantly associated with triptan non-usage in CH (Pc = 0.010). In addition, multi-allele effector analysis showed that individuals with a higher number of effector variants were less likely to use triptans (P = 0.007). Analysis of clinical characteristics showed that triptan users were more likely to have alcohol as a trigger (57.4% vs 43.4%, P = 0.002), have autonomic symptoms (95.1% vs 88.1%, P = 0.002), and be current smokers (27.0% vs 21.9%, P = 0.033) compared to non-users. These results support the hypothesis that genetic variants can play a role in triptan usage in CH and that patients with a typical CH phenotype are more likely to use triptans., (© 2024. The Author(s).)

Background: Cluster headache (CH) is a debilitating condition, but current therapies leave CH patients in pain. The extent of this problem in Sweden is unknown., Methods: An anonymized questionnaire was sent to 479 Swedish CH patients to investigate patterns and perceived effects of treatments., Results: Three hundred fourteen answers were analyzed. The population was representative regarding age of onset and sex. Less than half (46%) were satisfied with their abortive treatments, 19% terminated functioning abortive treatments due to side effects. Additionally, 17% of chronic CH patients had not tried the first-line preventive drug verapamil. A small subset had tried illicit substances to treat their CH (0-8% depending on substance). Notably, psilocybin was reported effective as an abortive treatment by 100% ( n = 8), and with some level of effect as a preventive treatment by 92% ( n = 12). For verapamil, some level of preventive effect was reported among 68% ( n = 85)., Conclusions: Our descriptive data illustrate that many Swedish CH patients are undertreated, lack functional therapies, and experience side effects. Further studies are warranted to search for new treatment strategies as well as a revision of current treatment guidelines with the aim of reducing patient disease burden to the greatest extent possible.

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., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

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.

Aim: Treatment for cluster headache is currently based on a trial-and-error approach. The available preventive treatment is unspecific and based on few and small studies not adhering to modern standards. Therefore, the authors collaborated to discuss acute and preventive treatment in cluster headache, addressing the unmet need of safe and tolerable preventive medication from the perspectives of people with cluster headache and society, headache specialist and cardiologist., Findings: The impact of cluster headache on personal life is substantial. Mean annual direct and indirect costs of cluster headache are more than 11,000 Euros per patient. For acute treatment, the main problems are treatment response, availability, costs and, for triptans, contraindications and the maximum use allowed. Intermediate treatment with steroids and greater occipital nerve blocks are effective but cannot be used continuously. Preventive treatment is sparsely studied and overall limited by relatively low efficacy and side effects. Neurostimulation is a relevant option for treatment-refractory chronic patients. From a cardiologist's perspective use of verapamil and triptans may be worrisome and regular follow-up is essential when using verapamil and lithium., Conclusion: We find that there is a great and unmet need to pursue novel and targeted preventive modalities to suppress the horrific pain attacks for people with cluster headache., (© 2023. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Background: Cluster headache (CH) is a primary headache disorder which is characterized by circadian timing of headache attacks, usually at nighttime, in around two thirds of patients. Patients with CH often report sleep difficulties, though it is unknown whether this is a cause or a consequence of nightly headache attacks., Objective: In this case-control study we have assessed sleep quality in study participants with CH in cluster bout respectively in remission, compared to a control group of neurologically healthy individuals to investigate the potential connection between sleep and CH., Methods: Fifty study participants with CH and 42 controls were recruited for sleep assessment. Sleep was recorded using MotionWatch 8 actigraphs (CamNTech) for a period of two weeks. Study participants were instructed to wear the unit during rest and sleep and to fill out a sleep diary daily through the two-weeks period., Results: Results from actigraphy recordings and sleep diaries suggested that patients with CH spend longer time in bed than controls (CH 8.1 hours vs. Controls 7.7 hours, p=0.03), but do not sleep more than controls (CH 6.7 hours vs. controls 6.5 hours, p=0.3). In addition, CH patients reported increased sleep latency (p=0.003), particularly during, but not restricted to, cluster bouts. Study participants with CH further reported higher levels of stress at bedtime (p=0.01), and they felt less well rested than controls (p=0.001)., Conclusion: Our analysis suggests that sleep is negatively affected in CH both in cluster bout and in remission, manifesting in symptoms consistent with insomnia such as prolonged sleep latency and increased time in bed., (© 2023. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Background: Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties., Objective: We used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors., Methods: We used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses., Results: We confirmed a previously reported positive genetic correlation of PD with melanoma (G corr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (G corr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of the NSF gene (17q21.31)., Conclusions: We show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background and Objectives: Cluster headache is considered a male-dominated disorder, but we have previously suggested that female patients may display a more severe phenotype. Studies on sex differences in cluster headache have been conflicting; therefore, this study, with the largest validated cluster headache material at present, gives more insights into sex-specific characteristics of the disease. The objective of this study was to describe sex differences in patient demographics, clinical phenotype, chronobiology, triggers, treatment, and lifestyle in a Swedish cluster headache population., Methods: Study participants were identified by screening medical records from 2014 to 2020, requested from hospitals and neurology clinics in Sweden for the ICD-10 code G44.0 for cluster headache. Each study participant answered a detailed questionnaire on clinical information and lifestyle, and all variables were compared with regard to sex., Results: A total of 874 study participants with a verified cluster headache diagnosis were included. Of the participants, 575 (66%) were male and 299 (34%) were female, and biological sex matched self-reported sex for all. Female participants were to a greater extent diagnosed with the chronic cluster headache subtype compared with male participants (18% vs 9%, p = 0.0002). In line with this observation, female participants report longer bouts than male participants ( p = 0.003) and used prophylactic treatment more often (60% vs 48%, p = 0.0005). Regarding associated symptoms, female participants experienced ptosis (61% vs 47%, p = 0.0002) and restlessness (54% vs 46%, p = 0.02) more frequently compared with male participants. More female than male study participants had a positive family history of cluster headache (15% vs 7%, p = 0.0002). In addition, female participants reported diurnal rhythmicity of their attacks more often than male participants (74% vs 63%, p = 0.002). Alcohol as a trigger occurred more frequently in male participants (54% vs 48%, p = 0.01), whereas lack of sleep triggering an attack was more common in female participants (31% vs 20%, p = 0.001)., Discussion: With this in-depth analysis of a well-characterized cluster headache population, we could demonstrate that there are significant differences between male and female participants with cluster headache, which should be regarded at the time of diagnosis and when choosing treatment options. The data suggest that female patients generally may be more gravely affected by cluster headache than male patients., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

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.

Background and Objectives: Multimorbidity among patients with cluster headache (CH) is considered to be high, but large studies are lacking. The aims were to explore the occurrence of diagnosis-specific multimorbidity among patients with CH and matched references and possible associations of this with their sickness absence and disability pension., Methods: We performed a register-based study of patients with CH and matched references, regarding their multimorbidity, sickness absence, and disability pension. Data were obtained from 2 nationwide registers: Statistics Sweden's Longitudinal Integration Database for Health Insurance and Labor Market Studies (LISA) (for sociodemographics in 2009, sickness absence, and disability pension in 2010) and The National Board of Health and Welfare's specialized outpatient and inpatient registers for diagnosis-specific health care in 2001-2010 (for identifying patients with CH and multimorbidity, defined by ICD-10 codes). The prevalence and number of net days of sickness absence and/or disability pension in 2010 were calculated, in general and by multimorbidity. Odds ratios (OR) with 95% confidence intervals (CIs) were calculated for comparison of each diagnostic group with references without the chosen morbidity., Results: We analyzed 3,240 patients with CH, aged 16-64 years, and living in Sweden in 2010 and 16,200 matched references. A higher proportion of patients with CH had multimorbidity (91.9%) than of references (77.6%), OR 3.263 (95% CI 2.861-3.721), both in general and regarding all analyzed diagnostic groups. Differences were particularly high for diagnoses relating to the nervous (CH 51.8% vs references 15.4%), OR 5.922 (95% CI 5.461-6.422), and musculoskeletal (CH 39.0% vs references 23.7%), OR 2.057 (95% CI 1.900-2.227), systems. Multimorbidity rates were overall higher among women in patients with CH (96.4% vs men 89.6%). Patients with CH had a higher mean number of days of sickness absence and disability pension compared with references, 63.15 vs 34.08 days. Moreover, multimorbidity was associated with a higher mean number of such days in patients with CH, 67.25, as compared with references, 40.69 days., Discussion: The proportions of multimorbidity were high in both patients with CH and references, however, higher in the patients with CH, who also had higher sickness absence and disability pension levels. In particular, CH patients with multimorbidity and of female sex had high sickness absence and disability pension levels., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Two studies that examined the interaction between HLA-DRB1 and smoking in Parkinson's disease (PD) yielded findings in opposite directions., Objective: To perform a large-scale independent replication of the HLA-DRB1 × smoking interaction., Methods: We genotyped 182 single nucleotide polymorphism (SNPs) associated with smoking initiation in 12 424 cases and 9480 controls to perform a Mendelian randomization (MR) analysis in strata defined by HLA-DRB1., Results: At the amino acid level, a valine at position 11 (V11) in HLA-DRB1 displayed the strongest association with PD. MR showed an inverse association between genetically predicted smoking initiation and PD only in absence of V11 (odds ratio, 0.74, 95% confidence interval, 0.59-0.93, P Interaction  = 0.028). In silico predictions of the influence of V11 and smoking-induced modifications of α-synuclein on binding affinity showed findings consistent with this interaction pattern., Conclusions: Despite being one of the most robust findings in PD research, the mechanisms underlying the inverse association between smoking and PD remain unknown. Our findings may help better understand this association. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background and Objectives: Considerable heterogeneity exists in the literature concerning genetic determinants of the age at onset (AAO) of Parkinson disease (PD), which could be attributed to a lack of well-powered replication cohorts. The previous largest genome-wide association studies (GWAS) identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on the AAO of PD; these have not been independently replicated. This study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations., Methods: A meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium. This was followed by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson Disease Genomics Consortium (IPDGC)., Results: The COURAGE-PD Consortium included a cohort of 8,535 patients with PD (91.9%: Europeans and 9.1%: East Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD = 11.6), with an underrepresentation of females (40.2%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE = 0.057). None of the loci reached genome-wide significance ( p < 5 × 10 -8 ). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published TMEM175 variant as a genetic determinant of the AAO of PD with Bonferroni-corrected nominal levels of significance ( p < 0.025): (rs34311866: β(SE) COURAGE = 0.477(0.203), p COURAGE = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (N total = 25,950) led to the identification of 2 genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361: β(SE) COURAGE+IPDGC = 0.720(0.122), p COURAGE+IPDGC = 3.13 × 10 -9 ) and a novel BST1 locus (rs4698412: β(SE) COURAGE+IPDGC = -0.526(0.096), p COURAGE+IPDGC = 4.41 × 10 -8 )., Discussion: Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of BST1 as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding., Objective: The aim is to examine the association between genetically predicted dairy intake and PD using two-sample Mendelian randomization (MR)., Methods: We genotyped a well-established instrumental variable for dairy intake located in the lactase gene (rs4988235) within the Courage-PD consortium (23 studies; 9823 patients and 8376 controls of European ancestry)., Results: Based on a dominant model, there was an association between genetic predisposition toward higher dairy intake and PD (odds ratio [OR] per one serving per day = 1.70, 95% confidence interval = 1.12-2.60, P = 0.013) that was restricted to men (OR = 2.50 [1.37-4.56], P = 0.003; P-difference with women = 0.029)., Conclusions: Using MR, our findings provide further support for a causal relationship between dairy intake and higher PD risk, not biased by confounding or reverse causation. Further studies are needed to elucidate the underlying mechanisms. © 2022 International Parkinson and Movement Disorder Society., (© 2022 International Parkinson and Movement Disorder Society.)

Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology., (© 2022. The Author(s).)

Background: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation., Objective: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases., Methods: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017)., Results: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60-0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking., Conclusion: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.

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.

The trigeminal autonomic cephalalgia, cluster headache (CH), is one of the most painful disorders known to man. One of the disorder's most striking features is the reported diurnal rhythmicity of the attacks. For a majority of patients, the headache attacks occur at approximately the same time every day. Genetic variants of genes involved in the circadian rhythm such as Period Circadian Regulator 1, 2, and 3 ( PER1 , 2 and 3 ) are hypothesized to have an effect on the rhythmicity of the attacks. Six PER1 , 2 and 3 genetic markers; the indel rs57875989 and five single nucleotide polymorphisms (SNPs), rs2735611, rs2304672, rs934945, rs10462020, and rs228697, were genotyped, using TaqMan ® or regular polymerase chain reaction (PCR), in a Swedish CH case control material. Logistic regression showed no association between CH and any of the six genetic variants; rs57875989, p = 0.523; rs2735611, p = 0.416; rs2304672, p = 0.732; rs934945, p = 0.907; rs10462020, p = 0.726; and rs228697, p = 0.717. Furthermore, no difference in allele frequency was found for patients reporting diurnal rhythmicity of attacks, nor were any of the variants linked to diurnal preference. The results of this study indicate no involvement of these PER genetic variants in CH or diurnal phenotype in Sweden.

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., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Cluster headache is characterized by activation of the autonomic-trigeminal reflex. Nitric oxide can trigger headaches in patients, and nitric oxide signaling is known to be affected in cluster headache. Based on the hypothesis of nitric oxide being involved in cluster headache pathophysiology we investigated nitric oxide synthases as potential candidate genes for cluster headache. We analyzed eight variants in the three forms of nitric oxide synthase ( NOS ) genes, inducible NOS ( iNOS ), endothelial NOS ( eNOS ) and neuronal NOS ( nNOS ), and tested for association with cluster headache. Swedish cluster headache patients ( n = 542) and controls ( n = 581) were genotyped using TaqMan ® assays on an Applied Biosystems 7500 qPCR cycler. This is the largest performed genetic study on NOS involvement in cluster headache so far. We found an association between cluster headache and one iNOS haplotype consisting of the minor alleles of rs2297518 and rs2779249 ( p = 0.022). In addition, one of the analyzed nNOS variants, rs2682826, was associated with reported triptan use ( p = 0.039). Our data suggest that genetic variants in NOS genes do not have a strong influence on cluster headache pathophysiology, but that certain combinations of genetic variants in NOS genes may influence the risk of developing the disorder or triptan use.

Objective: To determine the frequency of mutations known to cause autosomal dominant Parkinson disease (PD) in a series with more than 10% of Sweden's estimated number of PD patients., Methods: The Swedish Parkinson Disease Genetics Network was formed as a national multicenter consortium of clinical researchers who together have access to DNA from a total of 2,206 PD patients; 85.4% were from population-based studies. Samples were analyzed centrally for known pathogenic mutations in SNCA (duplications/triplications, p.Ala30Pro, p.Ala53Thr) and LRRK2 (p.Asn1437His, p.Arg1441His, p.Tyr1699Cys, p.Gly2019Ser, p.Ile2020Thr). We compared the frequency of these mutations in Swedish patients with published PD series and the gnomAD database., Results: A family history of PD in first- and/or second-degree relatives was reported by 21.6% of participants. Twelve patients (0.54%) carried LRRK2 p.(Gly2019Ser) mutations, one patient (0.045%) an SNCA duplication. The frequency of LRRK2 p.(Gly2019Ser) carriers was 0.11% in a matched Swedish control cohort and a similar 0.098% in total gnomAD, but there was a marked difference between ethnicities in gnomAD, with 42-fold higher frequency among Ashkenazi Jews than all others combined., Conclusions: In relative terms, the LRRK2 p.(Gly2019Ser) variant is the most frequent mutation among Swedish or international PD patients, and in gnomAD. SNCA duplications were the second most common of the mutations examined. In absolute terms, however, these known pathogenic variants in dominant PD genes are generally very rare and can only explain a minute fraction of familial aggregation of PD. Additional genetic and environmental mechanisms may explain the frequent co-occurrence of PD in close relatives., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cluster headache is a severe primary headache characterized by extremely painful attacks of unilateral headache. Verapamil is commonly used as a prophylactic treatment with good effect. In order to search for new pathways involved in the pathophysiology of cluster headache, we analyzed genetic variants that were previously linked to verapamil response in migraine in a Swedish cluster headache case-control sample. We used TaqMan qPCR for genetic screening and performed a gene expression analysis on associated genes in patient-derived fibroblasts, and further investigated which reference genes were suitable for analysis in fibroblasts from cluster headache patients. We discovered a significant association between anoctamin 3 , a gene encoding a calcium-activated ion channel, and cluster headache. The association was not dependent on verapamil treatment since the associated variant, rs1531394, was also overrepresented in patients not using verapamil. No difference was found in the anoctamin 3 gene expression between controls and patients. Also, we determined that TBP , IPO8 and PDHB were suitable reference genes in cluster headache fibroblasts. This finding is the first report of an association between a variant in a gene encoding an ion-channel and cluster headache, and the first significant genetic evidence of calcium involvement in cluster headache pathophysiology., Competing Interests: The authors declare no conflict of interest.

Objective: The purpose of this study was to investigate the HCRTR2 gene variants rs3122156, rs2653342, and rs2653349 in a large homogenous Swedish case-control cohort in order to further evaluate the possible contribution of HCRTR2 to cluster headache., Background: Cluster headache is a severe neurovascular disorder and the pathophysiology is not yet fully understood. Due to striking circadian and circannual patterns of this disease, the hypothalamus has been a research focus in cluster headache. Several studies with many different cohorts from Europe have investigated the hypocretin receptor 2 (HCRTR2) gene, which is expressed in the hypothalamus. In particular, one HCRTR2 single nucleotide polymorphism, rs2653349, has been subject to a number of genetic association studies on cluster headache, with conflicting results. Two other HCRTR2 gene variants, rs2653342 and rs2653349, have been reported to be linked to cluster headache in an Italian study., Methods: We genotyped a total of 517 patients diagnosed with cluster headache and 581 controls, representing a general Swedish population, for rs3122156, rs2653342, and rs2653349 using quantitative real-time PCR. Statistical analyses of genotype, allele, and haplotype frequencies for the 3 gene variants were performed comparing patients and controls., Results: For rs3122156, the minor allele frequency in patients was 25.9% compared to 29.9% in controls (P = .0421). However, this significance did not hold after correction for multiple testing. The minor allele frequencies for rs2653342 (14.7% vs 14.7%) and rs2653349 (19.5% vs 18.8%) were similar for patients and controls. Furthermore, we found one haplotype that was significantly less common in patients than controls (P = .0264). This haplotype included the minor allele for rs3122156 and the major alleles for rs2653342 and rs2653349. Significance did not hold after applying a permutation test., Conclusions: Our data show a trend for association between cluster headache and the HCRTR2 polymorphism rs3122156, where the minor allele seems to be a protective factor. However, the other 2 HCRTR2 gene variants, including the previously reported rs2653349, were not associated with cluster headache in our Swedish material. A comparison with previous studies points to variance in genotype and allele frequencies among the different populations, which most likely contributes to the opposing results regarding rs2653349. Although the results from this study do not strongly support an association, HCRTR2 remains an interesting candidate gene for involvement in the pathophysiology of cluster headache., (© 2019 The Authors Headache: The Journal of Head and Face Pain published by Wiley Periodicals, Inc. on behalf of American Headache Society.)

Background: Cluster headache is a severe headache disorder with unknown aetiology. The pathophysiology and symptoms present certain common features with migraine. Specifically, activation of the trigeminal vascular system seems to be involved in both disorders, which is hypothesized to result in neurogenic inflammation and vasodilation of the cerebral vessels. In addition, genetic factors have been implicated in both migraine and cluster headache., Objective: In order to determine whether or not migraine and cluster headache share genetic risk factors, we screened two genetic variants known to increase the risk of migraine in Sweden in a Swedish cluster headache case-control study population., Methods: In all, 541 patients and 581 control subjects were genotyped for rs1835740 in close proximity to MTDH (metadherin) and rs2651899 in the PRDM16 (PR/SET domain 16) gene, using TaqMan® real-time PCR and pyrosequencing. In addition, we analyzed MTDH gene expression in a subset of the material, using reverse transcription real-time PCR to determine relative mRNA levels in primary fibroblast cell lines from patients and controls., Results: We found a trend for association between rs1835740, which is reported to affect MTDH mRNA levels, and cluster headache in our Swedish case-control material (p = 0.043, Χ 2  = 4.102). This association was stronger in a subgroup of patients suffering from both cluster headache and migraine (p = 0.031, Χ 2  = 6.964). We could further confirm that rs1835740 has an effect on the transcriptional activity of MTDH. In this Swedish cluster headache cohort we did not find an association with the rs2651899 variant., Conclusions: We conclude that rs1835740 is a potential risk factor for cluster headache in Sweden. Our data indicates that rs1835740 and MTDH might be involved in neurovascular headaches in general whilst rs2651899 is specifically related to migraine.

Migraine and major depressive disorder (MDD) are common brain disorders that frequently co-occur. Despite epidemiological evidence that migraine and MDD share a genetic basis, their overlap at the molecular genetic level has not been thoroughly investigated. Using single-nucleotide polymorphism (SNP) and gene-based analysis of genome-wide association study (GWAS) genotype data, we found significant genetic overlap across the two disorders. LD Score regression revealed a significant SNP-based heritability for both migraine (h 2  = 12%) and MDD (h 2  = 19%), and a significant cross-disorder genetic correlation (r G  = 0.25; P = 0.04). Meta-analysis of results for 8,045,569 SNPs from a migraine GWAS (comprising 30,465 migraine cases and 143,147 control samples) and the top 10,000 SNPs from a MDD GWAS (comprising 75,607 MDD cases and 231,747 healthy controls), implicated three SNPs (rs146377178, rs672931, and rs11858956) with novel genome-wide significant association (P SNP  ≤ 5 × 10 -8 ) to migraine and MDD. Moreover, gene-based association analyses revealed significant enrichment of genes nominally associated (P gene-based  ≤ 0.05) with both migraine and MDD (P binomial-test  = 0.001). Combining results across migraine and MDD, two genes, ANKDD1B and KCNK5, produced Fisher's combined gene-based P values that surpassed the genome-wide significance threshold (P Fisher's-combined  ≤ 3.6 × 10 -6 ). Pathway analysis of genes with P Fisher's-combined  ≤ 1 × 10 -3 suggested several pathways, foremost neural-related pathways of signalling and ion channel regulation, to be involved in migraine and MDD aetiology. In conclusion, our study provides strong molecular genetic support for shared genetically determined biological mechanisms underlying migraine and MDD.

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background The aim of this study was to investigate clinical features of a cluster headache cohort in Sweden and to construct and test a new scale for grading severity. Methods Subjects were identified by screening medical records for the ICD 10 code G44.0, that is, cluster headache. Five hundred participating research subjects filled in a questionnaire including personal, demographic and medical aspects. We constructed a novel scale for grading cluster headache in this cohort: The Cluster Headache Severity Scale, which included number of attacks per day, attack and period duration. The lowest total score was three and the highest 12, and we used the Cluster Headache Severity Scale to grade subjects suffering from cluster headache. We further implemented the scale by defining a cluster headache maximum severity subgroup with a high Cluster Headache Severity Scale score ≥ 9. Results A majority (66.7%) of the patients reported that attacks appear at certain time intervals. In addition, cluster headache patients who were current tobacco users or had a history of tobacco consumption had a later age of disease onset (31.7 years) compared to non-tobacco users (28.5 years). The Cluster Headache Severity Scale score was higher in the patient group reporting sporadic or no alcohol intake than in the groups reporting an alcohol consumption of three to four standard units per week or more. Maximum severity cluster headache patients were characterised by higher age at disease onset, greater use of prophylactic medication, reduced hours of sleep, and lower alcohol consumption compared to the non-cluster headache maximum severity group. Conclusion There was a wide variation of severity grade among cluster headache patients, with a very marked impact on daily living for the most profoundly affected.

Background Cluster headache is characterized by recurrent unilateral headache attacks of severe intensity. One of the main features in a majority of patients is a striking rhythmicity of attacks. The CLOCK ( Circadian Locomotor Output Cycles Kaput) gene encodes a transcription factor that serves as a basic driving force for circadian rhythm in humans and is therefore particularly interesting as a candidate gene for cluster headache. Methods We performed an association study on a large Swedish cluster headache case-control sample (449 patients and 677 controls) screening for three single nucleotide polymorphisms (SNPs) in the CLOCK gene implicated in diurnal preference (rs1801260) or sleep duration (rs11932595 and rs12649507), respectively. We further wanted to investigate the effect of identified associated SNPs on CLOCK gene expression. Results We found a significant association with rs12649507 and cluster headache ( p = 0.0069) and this data was strengthened when stratifying for reported diurnal rhythmicity of attacks ( p = 0.0009). We investigated the effect of rs12649507 on CLOCK gene expression in human primary fibroblast cultures and identified a significant increase in CLOCK mRNA expression ( p = 0.0232). Conclusions Our results strengthen the hypothesis of the involvement of circadian rhythm in cluster headache.

Background: We have genotyped a Swedish cluster headache case-control population for three genetic variants representing the most significant markers identified in a recently published genome wide association study on cluster headache. The genetic variants were two common polymorphisms; rs12668955 in ADCYAP1R1 (adenylate cyclase activating polypeptide 1 receptor type 1), rs1006417, an intergenic variant on chromosome 14q21 and one rare mutation, rs147564881, in MME (membrane metalloendopeptidase)., Results: We screened 542 cluster headache patients and 581 controls using TaqMan real-time PCR on a 7500 fast cycler, and pyrosequencing on a PSQ 96 System. Statistical analysis for genotype and allele association showed that neither of the two common variants, rs12668955 and rs1006417 were associated with cluster headache. The MME mutation was investigated with pyrosequencing in patients, of whom all were wild type., Conclusion: In conclusion rs12668955 and rs1006417 do not impact the risk of developing cluster headache in the Swedish population. Also, rs147564881 does not seem to be enriched within the Swedish cluster headache patient group.

Nuclear factor erythroid 2-like 2 (NRF2) encodes a transcription factor regulating mechanisms of cellular protection and is activated by oxidative stress. NRF2 has therefore been hypothesized to confer protection against Parkinson's disease and so far an NRF2 haplotype has been reported to decrease the risk of developing disease and delay disease onset. Also NRF2 adopts a nuclear localization in Parkinson's disease, which is indicative of increased NRF2 activity. We have investigated the association between NRF2 and Parkinson's disease in a Swedish case-control material and whether NRF2 expression levels correlate with NRF2 genetic variants, disease, or disease onset. Using pyrosequencing, we genotyped one intronic and three promoter variants in 504 patients and 509 control subjects from Stockholm. Further, we quantified NRF2 mRNA expression in EBV transfected human lymphocytes from patients and controls using quantitative real-time reverse transcription PCR. We found that one of the promoter variants, rs35652124, was associated with age of disease onset (Χ 2 = 14.19, p value = 0.0067). NRF2 mRNA expression levels however did not correlate with the rs35652124 genotype, Parkinson's disease, or age of onset in our material. More detailed studies on NRF2 are needed in order to elucidate how this gene affects pathophysiology of Parkinson's disease.

The suprachiasmatic nuclei (SCN) contain the major circadian clock responsible for generation of circadian rhythms in mammals. The time measured by the molecular circadian clock must eventually be translated into a neuronal firing rate pattern to transmit a meaningful signal to other tissues and organs in the animal. Previous observations suggest that circadian modulation of ryanodine receptors (RyR) is a key element of the output pathway from the molecular circadian clock. To directly test this hypothesis, we studied the effects of RyR activation and inhibition on real time expression of PERIOD2::LUCIFERASE, intracellular calcium levels and spontaneous firing frequency in mouse SCN neurons. Furthermore, we determined whether the RyR-2 mRNA is expressed with a daily variation in SCN neurons. We provide evidence that pharmacological manipulation of RyR in mice SCN neurons alters the free [Ca 2+ ] i in the cytoplasm and the spontaneous firing without affecting the molecular clock mechanism. Our data also show a daily variation in RyR-2 mRNA from single mouse SCN neurons with highest levels during the day. Together, these results confirm the hypothesis that RyR-2 is a key element of the circadian clock output from SCN neurons., (© 2016 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Several genetic studies have demonstrated an association between mutations in glucocerebrosidase (GBA), originally implicated in Gaucher's disease, and an increased risk of Parkinson's disease (PD). We have investigated the possible involvement of genetic GBA variations in PD in the Swedish population. Three GBA variants, E326K, N370S, and L444P were screened in the largest Swedish Parkinson cohort reported to date; 1625 cases and 2025 control individuals. We found a significant association with high effect size of the rare variant L444P with PD (odds ratio 8.17; 95% confidence interval: 2.51-26.23; p-value = 0.0020) and a significant association of the common variant E326K (odds ratio 1.60; 95% confidence interval: 1.16-2.22; p-value = 0.026). The rare variant N370S showed a trend for association. Most L444P carriers (68%) were found to reside in northern Sweden, which is consistent with a higher prevalence of Gaucher's disease in this part of the country. Our findings support the role of GBA mutations as risk factors for PD and point to lysosomal dysfunction as a mechanism contributing to PD etiology., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10(-8)) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.

Background: Integrin alpha 8 (ITGA8) encodes the alpha 8 subunit of the integrin alpha8beta1 protein and has recently been suggested as a new candidate gene for Parkinson's disease, an age related neurodegenerative disease with unknown etiology. ITGA8 is a transmembrane protein involved in several cellular processes, such as cell adhesion, migration and cytoskeletal rearrangement., Objective: Screen a Swedish case control material for rs7077361, a genetic variant in ITGA8, in order to investigate its possible implication in Parkinson's disease in Sweden., Method: Rs7077361 was genotyped using TaqMan quantitative Real-time PCR and tested for association using appropriate statistical methods., Results: We have screened 502 Swedish Parkinson patients and 599 healthy control individuals for rs7077361 in ITGA8. This genetic variant was in Hardy Weinberg equilibrium in the Swedish population. Allele and genotype frequencies were highly similar between the patients and controls and statistical testing showed that this genetic maker did not associate with Parkinson's disease (p=0.67)., Conclusion: Our results do not support the hypothesis of ITGA8 as a candidate gene for Parkinson's disease in Sweden.

Studies of complex genetic diseases have revealed many risk factors of small effect, but the combined amount of heritability explained is still low. Genome-wide association studies are often underpowered to identify true effects because of the very large number of parallel tests. There is, therefore, a great need to generate data sets that are enriched for those markers that have an increased a priori chance of being functional, such as markers in genomic regions involved in gene regulation. ReMo-SNPs is a computational program developed to aid researchers in the process of selecting functional SNPs for association analyses in user-specified regions and/or motifs genome-wide. The useful feature of automatic selection of genotyped markers in the user-provided material makes the output data ready to be used in a following association study. In this article we describe the program and its functions. We also validate the program by including an example study on three different transcription factors and results from an association study on two psychiatric phenotypes. The flexibility of the ReMo-SNPs program enables the user to study any region or sequence of interest, without limitation to transcription factor binding regions and motifs. The program is freely available at: http://www.neuro.ki.se/ReMo-SNPs/.

Background: Migraine is a common neurovascular disorder with symptoms including headache of moderate to severe intensity and recurring attacks. There is no cure for migraine today and the pathology is poorly understood. Common forms of migraine have a complex genetic background and heritability has been estimated to be around 50%. Recent genome-wide association studies (GWAS) on European and American migraine cohorts have led to the identification of new genetic risk factors for migraine., Methods: We performed an association study in a Swedish population based cohort, investigating the frequency of eight single nucleotide polymorphisms (SNPs) recently identified as genetic risk factors for migraine in three GWAS, using available array data (Illumina Omni Express chip). The eight SNPs were rs2651899, rs3790455, rs10166942, rs7640543, rs9349379, rs1835740, rs6478241 and rs11172113. Because information on rs3790455, rs10166942 and rs7640543 was not directly available, we selected SNPs in high Linkage Disequilibrium (LD) with these three SNPs, and replaced them with rs2274316, rs1003540 and rs4075749, respectively., Results: We were able to replicate the association with rs2651899 and found a trend for association with rs1835740 in our Swedish cohort., Conclusions: This is the first reported genetic association study of a Swedish migraine case control material. We have thus replicated findings of susceptibility loci for migraine in an independent genetic material, thereby increasing knowledge about genetic risk factors for this common neurological disorder.