Genome-wide association study reveals a locus in ADARB2 for complete freedom from headache in Danish Blood Donors.

Headache disorders are the most common disorders of the nervous system. The lifetime prevalence of headache disorders show that some individuals never experience headache. The etiology of complete freedom from headache is not known. To assess genetic variants associated with complete freedom from headache, we performed a genome-wide association study of individuals who have never experienced a headache. We included 63,992 individuals (2,998 individuals with complete freedom from headache and 60,994 controls) from the Danish Blood Donor Study Genomic Cohort. Participants were included in two rounds, from 2015 to 2018 and in 2020. We discovered a genome-wide significant association, with the lead variant rs7904615[G] in ADARB2 (EAF = 27%, OR = 1.20 [1.13-1.27], p = 3.92 × 10-9). The genomic locus was replicated in a non-overlapping cohort of 13,032 individuals (539 individuals with complete freedom from headache and 12,493 controls) from the Danish Blood Donor Study Genomic Cohort (p < 0.05, two-sided). Participants for the replication were included from 2015 to 2020. In conclusion, we show that complete freedom from headache has a genetic component, and we suggest that ADARB2 is involved in complete freedom from headache. The genomic locus was specific for complete freedom from headache and was not associated with any primary headache disorders.

Stress-induced headache in the general working population is moderated by the NRCAM rs2300043 genotype.

OBJECTIVES: Earlier findings suggest that social stress such as abusive supervision may promote pain. In the present study we examine the possible moderating role of genetic variability in the NRCAM gene in this process. METHODS: The data were collected through a national survey drawn from the National Central Employee Register by Statistics Norway. A total of 1,205 individuals returned both the questionnaire and the saliva kit. Abusive supervision was scored by a 5-item version of the Tepper's 2,000 scale. Headache was measured on a four-category scale; 'not bothered,' 'a little bothered,' 'considerably bothered', 'seriously bothered'. Genotyping with regards to NRCAM rs2300043 was carried out using Taqman assay. Ordinal logistic regression was used to analyse the data. RESULTS: For males exposed to abusive supervision, those carrying the rs2300043 CC genotype reported the highest levels of headache. Women showed a trend towards the opposite pattern. Women with the rs2300043 CC genotype seem to have a weaker effect of abusive supervision regarding reported headache than their male counterparts with the CC genotype when exposed to abusive supervision. CONCLUSIONS: The present results indicated that the association between abusive supervision and headache in men with the NRCAM rs2300043 C allele was stronger than in other men. This suggests that the NRCAM genotype in men is important for the tolerance of social stress e.g., repeated negative acts from a superior. In contrast, a trend, though non-significant, towards the opposite pattern was observed in women. Our result suggests that the NRCAM genotype in men manifestly affects stress-induced pain such as headache.

Cross-Trait Genetic Analyses Indicate Pleiotropy and Complex Causal Relationships between Headache and Thyroid Function Traits.

Epidemiological studies have reported a comorbid relationship between headache and thyroid traits; however, little is known about the shared genetics and causality that contributes to this association. We investigated the genetic overlap and associations between headache and thyroid function traits using genome-wide association study (GWAS) data. We found a significant genetic correlation (rg) with headache and hypothyroidism (rg = 0.09, p = 2.00 × 10−4), free thyroxine (fT4) (rg = 0.08, p = 5.50 × 10−3), and hyperthyroidism (rg = −0.14, p = 1.80 × 10−3), a near significant genetic correlation with secondary hypothyroidism (rg = 0.20, p = 5.24 × 10−2), but not with thyroid stimulating hormone (TSH). Pairwise-GWAS analysis revealed six, 14, four and five shared (pleiotropic) loci with headache and hypothyroidism, hyperthyroidism, secondary hypothyroidism, and fT4, respectively. Cross-trait GWAS meta-analysis identified novel genome-wide significant loci for headache: five with hypothyroidism, three with secondary hypothyroidism, 12 with TSH, and nine with fT4. Of the genes at these loci, six (FAF1, TMX2-CTNND1, AARSD1, PLCD3, ZNF652, and C20orf203; headache-TSH) and six (HMGB1P45, RPL30P1, ZNF462, TMX2-CTNND1, ITPK1, SECISBP2L; headache-fT4) were significant in our gene-based analysis (pFisher's combined p-value < 2.09 × 10−6). Our causal analysis suggested a positive causal relationship between headache and secondary hypothyroidism (p = 3.64 × 10−4). The results also suggest a positive causal relationship between hypothyroidism and headache (p = 2.45 × 10−3) and a negative causal relationship between hyperthyroidism and headache (p = 1.16 × 10−13). These findings suggest a strong evidence base for a genetic correlation and complex causal relationships between headache and thyroid traits.

Identification and Clinical Validation of Key Extracellular Proteins as the Potential Biomarkers in Relapsing-Remitting Multiple Sclerosis.

Background: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) mediated by autoimmunity. No objective clinical indicators are available for the diagnosis and prognosis of MS. Extracellular proteins are most glycosylated and likely to enter into the body fluid to serve as potential biomarkers. Our work will contribute to the in-depth study of the functions of extracellular proteins and the discovery of disease biomarkers. Methods: MS expression profiling data of the human brain was downloaded from the Gene Expression Omnibus (GEO). Extracellular protein-differentially expressed genes (EP-DEGs) were screened by protein annotation databases. GO and KEGG were used to analyze the function and pathway of EP-DEGs. STRING, Cytoscape, MCODE and Cytohubba were used to construct a protein-protein interaction (PPI) network and screen key EP-DEGs. Key EP-DEGs levels were detected in the CSF of MS patients. ROC curve and survival analysis were used to evaluate the diagnostic and prognostic ability of key EP-DEGs. Results: We screened 133 EP-DEGs from DEGs. EP-DEGs were enriched in the collagen-containing extracellular matrix, signaling receptor activator activity, immune-related pathways, and PI3K-Akt signaling pathway. The PPI network of EP-DEGs had 85 nodes and 185 edges. We identified 4 key extracellular proteins IL17A, IL2, CD44, IGF1, and 16 extracellular proteins that interacted with IL17A. We clinically verified that IL17A levels decreased, but Del-1 and resolvinD1 levels increased. The diagnostic accuracy of Del-1 (AUC: 0.947) was superior to that of IgG (AUC: 0.740) with a sensitivity of 82.4% and a specificity of 100%. High Del-1 levels were significantly associated with better relapse-free and progression-free survival. Conclusion: IL17A, IL2, CD44, and IGF1 may be key extracellular proteins in the pathogenesis of MS. IL17A, Del-1, and resolvinD1 may co-regulate the development of MS and Del-1 is a potential biomarker of MS. We used bioinformatics methods to explore the biomarkers of MS and validated the results in clinical samples. The study provides a theoretical and experimental basis for revealing the pathogenesis of MS and improving the diagnosis and prognosis of MS.

Epigenetic changes in headache.

INTRODUCTION: Multiple factors, including both genetic and environmental mechanisms, appear to play a role in the aetiology of headache. An interesting area of study is the possible involvement of epigenetic mechanisms in headache development and the transformation to chronic headache, and the potential role of these factors as a therapeutic target. METHODS: We performed a literature review of the involvement of different epigenetic mechanisms in headache, mainly using the Medline/PubMed database. To this end, we used the following English search terms: headache, migraine, epigenetics, DNA methylation, histones, non-coding RNA, and miRNA. RESULTS: A total of 15 English-language publications related to the above terms were obtained. CONCLUSION: There is limited but consistent evidence of the relationship between epigenetics and headache; it is therefore essential to continue research of epigenetic changes in headache. This may help to understand the pathophysiology of headache and even to identify candidate biomarkers and new, more effective, therapeutic targets.

Headache in people with epilepsy.

Epidemiological estimates indicate that individuals with epilepsy are more likely to experience headaches, including migraine, than individuals without epilepsy. Headaches can be temporally unrelated to seizures, or can occur before, during or after an episode; seizures and migraine attacks are mostly not temporally linked. The pathophysiological links between headaches (including migraine) and epilepsy are complex and have not yet been fully elucidated. Correct diagnoses and appropriate treatment of headaches in individuals with epilepsy is essential, as headaches can contribute substantially to disease burden. Here, we review the insights that have been made into the associations between headache and epilepsy over the past 5 years, including information on the pathophysiological mechanisms and genetic variants that link the two disorders. We also discuss the current best practice for the management of headaches co-occurring with epilepsy and highlight future challenges for this area of research.

Val66Met polymorphism is associated with decreased likelihood for pediatric headache and migraine.

Background: Migraine is a complex multifactorial disorder and its pathogenesis still remains unclear. Evidence suggests the involvement of the activated trigeminovascular pathway, in which BDNF seems to play an important role. Therefore, BDNF polymorphisms are promising candidate susceptibility factors.Aim: BDNF rs6265 functional polymorphism was analyzed in order to determine its possible association with pediatric headache and migraine risk.Methods: The research included 120 consecutive pediatric patients who were diagnosed with headache and 120 healthy controls. The diagnosis was in compliance with the International Classification of Headache Disorders. Blood samples were collected from all participants and genotyped for rs6265.Results: BDNF rs6265 was significantly associated with decreased headache risk, particularly in the dominant model [Odds Ratio, OR (95% confidence interval, C.I.): 0.47 (0.26-0.85), p = 0.011] and the log-additive model [OR (95% C.I.): 0.48 (0.28-0.82), p = 0.0053]. During the sensitivity analysis, the associations were also maintained among patients with migraine.Conclusions: This is the first study to reveal a significant association of this BDNF variant with headache risk. Additionally, Val66Met was also for the first time related to decreased childhood migraine risk.

Evaluation of Posttraumatic Headache Phenotype and Recovery Time After Youth Concussion.

Importance: The Four Corners Youth Consortium was created to fill the gap in our understanding of youth concussion. This study is the first analysis of posttraumatic headache (PTH) phenotype and prognosis in this cohort of concussed youth. Objective: To describe the characteristics of youth with PTH and determine whether the PTH phenotype is associated with outcome. Design, Setting, and Participants: This cohort study examined outcomes from patients in a multi-institutional registry of traumatic brain injury (TBI) clinics from December 2017 to June 2019. Inclusion criteria included being between ages 5 and 18 years at enrollment and presentation within 8 weeks of a mild TBI. Data were analyzed between February 2019 and January 2021. Exposure: Mild TBI with standard care. Main Outcomes and Measures: Time to recovery and headache 3 months after injury; measurement device is the Postconcussion Symptom Inventory (PCSI). PTH with migraine phenotype was defined as moderate-severe headache that is new or significantly worse compared with baseline and associated with nausea and/or photophobia and phonophobia. Results: A total of 612 patients with 625 concussions were enrolled, of whom 387 patients with 395 concussions consented to participate in this study. One hundred nine concussions were excluded (concussions, rather than patients, were the unit of analysis), leaving 281 participants with 286 concussions (168 [58.7%] girls; 195 [75.6%] White; 238 [83.2%] aged 13-18 years). At the initial visit, 133 concussions (46.5%) were from patients experiencing PTH with a migraine phenotype, 57 (20%) were from patients experiencing PTH with a nonmigraine phenotype, and 96 (34%) were from patients with no PTH. Patients with any PTH after concussion were more likely to have prolonged recovery than those without PTH (median [interquartile range], 89 [48-165] days vs 44 [26-96] days; log-rank P < .001). Patients with PTH and a migraine phenotype took significantly longer to recover than those with nonmigraine phenotype (median [interquartile range], 95 [54-195] days vs 70 [46-119] days; log-rank P = .01). Within each phenotype, there was no significant difference between sexes in recovery or PTH at 3 months. Conclusions and Relevance: PTH with a migraine phenotype is associated with persistent symptoms following concussion compared with nonmigraine PTH or no PTH. Given that female sex is associated with higher rates of migraine and migraine PTH, our finding may be one explanation for findings in prior studies that girls are at higher risk for persistent postconcussion symptoms than boys.

Leadership Style, Headache, and Neck Pain: The Moderating Role of the Catechol-O-Methyltransferase (COMT) Genotype.

OBJECTIVE: Leadership styles can influence subordinates' health. We investigated how the gene encoding the Catechol-O-Methyltransferase (COMT) enzyme (ie, COMT rs4680 Val158Met) influenced effects of abusive supervision and transformational leadership on subordinates' headache and neck pain. METHODS: Multiple group structural equation modeling (SEM) was employed to test associations of leadership with subordinates' pain 6 months after in a representative sample of the Norwegian working population (n = 996). Genotyping was performed by TaqMan technology. RESULTS: Abusive supervision was associated with increased risk, and transformational leadership with decreased risk, of headache and neck pain. Both leadership styles exhibited more pronounced effects in individuals with the Met/Met genotype. CONCLUSION: Met/Met employees were relatively vulnerable to adversity, but also relatively responsive to constructive leadership. Many workers may benefit more from constructive leadership than population-averaged associations might suggest.

Down syndrome with co-occurring Marfan syndrome.

Down syndrome (DS) and Marfan syndrome (MFS) are two unique genetic disorders that share limited phenotypic overlap. There are very few reported cases in the existing literature on overlapping DS and MFS. Although these two disorders are phenotypically unique, features present in these cases are variable, resulting in mixed and dominant expressions of particular features. We present the first adolescent case of trisomy 21 associated DS and fibrillin-1 gene associated MFS in the literature who had a height at 90th percentile for an 11-year old boy and discuss the implications of this case in terms of future medical care when these two genetic syndromes are present in the same individual. Understanding of certain features of the 'non-dominating' syndrome is crucial for clinicians to recognise when DS co-occurs with MFS. Close monitoring of the cardiovascular, ophthalmologic and musculoskeletal systems is recommended if both syndromes are diagnosed given that both can be independently associated with disorders in these organ systems.

Neurological manifestations of COVID-19: available evidences and a new paradigm.

The recent pandemic outbreak of coronavirus is pathogenic and a highly transmittable viral infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2). In this time of ongoing pandemic, many emerging reports suggested that the SARS-CoV-2 has inimical effects on neurological functions, and even causes serious neurological damage. The neurological symptoms associated with COVID-19 include headache, dizziness, depression, anosmia, encephalitis, stroke, epileptic seizures, and Guillain-Barre syndrome along with many others. The involvement of the CNS may be related with poor prognosis and disease worsening. Here, we review the evidence of nervous system involvement and currently known neurological manifestations in COVID-19 infections caused by SARS-CoV-2. We prioritize the 332 human targets of SARS-CoV-2 according to their association with brain-related disease and identified 73 candidate genes. We prioritize these 73 genes according to their spatio-temporal expression in the different regions of brain and also through evolutionary intolerance analysis. The prioritized genes could be considered potential indicators of COVID-19-associated neurological symptoms and thus act as a possible therapeutic target for the prevention and treatment of CNS manifestations associated with COVID-19 patients.

Serum Protein Profiling Reveals a Landscape of Inflammation and Immune Signaling in Early-stage COVID-19 Infection.

Coronavirus disease 2019 (COVID-19) is a highly contagious infection and threating the human lives in the world. The elevation of cytokines in blood is crucial to induce cytokine storm and immunosuppression in the transition of severity in COVID-19 patients. However, the comprehensive changes of serum proteins in COVID-19 patients throughout the SARS-CoV-2 infection is unknown. In this work, we developed a high-density antibody microarray and performed an in-depth proteomics analysis of serum samples collected from early COVID-19 (n = 15) and influenza (n = 13) patients. We identified a large set of differentially expressed proteins (n = 132) that participate in a landscape of inflammation and immune signaling related to the SARS-CoV-2 infection. Furthermore, the significant correlations of neutrophil and lymphocyte with the CCL2 and CXCL10 mediated cytokine signaling pathways was identified. These information are valuable for the understanding of COVID-19 pathogenesis, identification of biomarkers and development of the optimal anti-inflammation therapy.

Neurological phenotypes in patients with NLRP3-, MEFV-, and TNFRSF1A low-penetrance variants.

BACKGROUND: Neurological manifestations and the co-occurrence of multiple sclerosis (MS) have been reported in patients with autoinflammatory diseases (AID) and variants of the NLRP3-, MEFV-, or TNFRSF1A gene. However, type and frequency of neurological involvement are widely undetermined. METHODS: We assessed clinical characteristics of 151 (108 with MS) patients carrying NLRP3-, MEFV- and TNFRSF1A low-penetrance variants  from the Institute of Clinical Neuroimmunology. We evaluated demographic, genetic, and clinical features with a focus on central nervous system (CNS) involvement including magnetic resonance imaging (MRI) results and cerebrospinal fluid (CSF) data. The disease course of AID patients with MS was compared to a matched MS control group without mutations. RESULTS: The genetic distribution comprised 36 patients (23%) with NLRP3- and 66 patients (43%) with TNFRSF1A low-penetrance variants as well as 53 (34%) patients carrying pathogenic mutations or low-penetrance variants in the MEFV gene. MS patients displayed most frequently the R92Q TNFRSF1A variant (n = 51; 46%) followed by the Q703K NLRP3 variant (n = 15; 14%) and the E148Q substitution (n = 9; 8%) in the MEFV gene. The disease course of MS was not influenced by the genetic variants and did not differ from MS patients (n = 51) without mutations. AID patients without MS most frequently harbored MEFV mutations (n = 19, 43%) followed by NLRP3- (n = 17, 39%) and TNFRSF1A (n = 8, 18%) low-penetrance variants. Sixteen (36%) of them suffered from severe CNS involvement predominantly recurrent aseptic meningoencephalitis and optic neuritis accompanied by abnormal MRI and CSF results. Severe CNS inflammation was associated with the Q703K allele. Headache was a highly prevalent neurological symptom (up to 74%), irrespective of the underlying genetic variation. The NLRP3 cohort without MS more frequently exhibited affections of the cranial nerves (CN) (p = 0.0228) and motor symptoms (p = 0.0455). Elevated acute-phase reactants were detected in all patients, and fever episodes were present in up to 50%. Arthralgias were the most frequently identified constitutional symptom among all subgroups. CONCLUSIONS: Our data highlight the high prevalence of neurological manifestations, including concomitant MS, among NLRP3-, MEFV-, and TNFRSF1A low-penetrance variants. In particular, patients carrying the Q703K NLRP3 variant are at risk for severe CNS inflammation and CN affection.

The first Japanese case of primary familial brain calcification caused by an MYORG variant.

Primary familial brain calcification (PFBC) is a hereditary neurological disorder characterized by idiopathic calcification of the bilateral basal ganglia and other areas of the brain. MYORG has been identified as the first causative gene of autosomal recessive PFBC in Chinese families. There have been several reports of PFBC associated with MYORG (MYORG-PFBC) in individuals of Middle Eastern, European, and Latin American ancestry but to date, there have been no reported Japanese cases. We report the first Japanese case of MYORG-PFBC. The patient was a 43-year-old Japanese woman who experienced mild headaches and cerebellar ataxia including dysarthria. Computed tomography showed calcification in the cerebral white matter, basal ganglia, cerebellum, and brainstem. Using exome sequencing, we identified a homozygous variant in the MYORG gene (NM_020702.4: c.794C>T,p.Thr265Met). Our patient presented dysarthria and extensive calcification affecting the pons, which are specific features of MYORG-PFBC. We report clinical symptoms and imaging findings of a case with p.Thr265Met variant.

Association of EPAS1 and PPARA Gene Polymorphisms with High-Altitude Headache in Chinese Han Population.

BACKGROUND: High-altitude headache (HAH) is the most common complication after high-altitude exposure. Hypoxia-inducible factor- (HIF-) related genes have been confirmed to contribute to high-altitude acclimatization. We aim to investigate a possible association between HIF-related genes and HAH in the Chinese Han population. METHODS: In total, 580 healthy Chinese Han volunteers were recruited in Chengdu (500 m) and carried to Lhasa (3700 m) by plane in 2 hours. HAH scores and basic physiological parameters were collected within 18-24 hours after the arrival. Thirty-five single nucleotide polymorphisms (SNPs) in HIF-related genes were genotyped, and linkage disequilibrium (LD) was evaluated by Haploview software. The functions of SNPs/haplotypes for HAH were developed by using logistic regression analysis. RESULTS: In comparison with wild types, the rs4953354 "G" allele (P=0.013), rs6756667 "A" allele (P=0.013), rs6756667 "A" allele (EPAS1, and rs6520015 "C" allele in PPARA (P=0.013), rs6756667 "A" allele (PPARA (P=0.013), rs6756667 "A" allele (EPAS1, and rs6520015 "C" allele in PPARA (P=0.013), rs6756667 "A" allele (. CONCLUSIONS: EPAS1 and PPARA polymorphisms were associated with HAH in the Chinese Han population. Our findings pointed out potentially predictive gene markers, provided new insights into understanding pathogenesis, and may further provide prophylaxis and treatment strategies for HAH.EPAS1, and rs6520015 "C" allele in PPARA (.

Is an "Epigenetic Diet" for Migraines Justified? The Case of Folate and DNA Methylation.

Migraines are a common disease with limited treatment options and some dietary factors are recognized to trigger headaches. Although migraine pathogenesis is not completely known, aberrant DNA methylation has been reported to be associated with its occurrence. Folate, an essential micronutrient involved in one-carbon metabolism and DNA methylation, was shown to have beneficial effects on migraines. Moreover, the variability of the methylenetetrahydrofolate reductase gene, important in both folate metabolism and migraine pathogenesis, modulates the beneficial effects of folate for migraines. Therefore, migraine could be targeted by a folate-rich, DNA methylation-directed diet, but there are no data showing that beneficial effects of folate consumption result from its epigenetic action. Furthermore, contrary to epigenetic drugs, epigenetic diets contain many compounds, some yet unidentified, with poorly known or completely unknown potential to interfere with the epigenetic action of the main dietary components. The application of epigenetic diets for migraines and other diseases requires its personalization to the epigenetic profile of a patient, which is largely unknown. Results obtained so far do not warrant the recommendation of any epigenetic diet as effective in migraine prevention and therapy. Further studies including a folate-rich diet fortified with valproic acid, another modifier of epigenetic profile effective in migraine prophylaxis, may help to clarify this issue.

A Midbrain Circuit that Mediates Headache Aversiveness in Rats.

Migraines are a major health burden, but treatment is limited because of inadequate understanding of neural mechanisms underlying headache. Imaging studies of migraine patients demonstrate changes in both pain-modulatory circuits and reward-processing regions, but whether these changes contribute to the experience of headache is unknown. Here, we demonstrate a direct connection between the ventrolateral periaqueductal gray (vlPAG) and the ventral tegmental area (VTA) that contributes to headache aversiveness in rats. Many VTA neurons receive monosynaptic input from the vlPAG, and cranial nociceptive input increases Fos expression in VTA-projecting vlPAG neurons. Activation of PAG inputs to the VTA induces avoidance behavior, while inactivation of these projections induces a place preference only in animals with headache. This work identifies a distinct pathway that mediates cranial nociceptive aversiveness.

Blau syndrome with a rare mutation in exon 9 of NOD2 gene.

Blau syndrome is an autosomal dominant rare disease caused by mutations in NOD2 gene. Less than 200 patients published with Blau Syndrome Worldwide. We reported a 41-year old female Turkish patient diagnosed as Blau syndrome. Granulomatous dermatitis and severe headache, as well as recurrent chest and pelvic pain have been present since she was 8 years old. Arthritis started when she was teenage, hypertension diagnosed when she was 20 and other symptoms also occurred during the lifetime (severe preeclampsia, ischemic stroke, recurrent hemiparesis, recurrent-transient-vision-loss and renal-artery-stenosis). Genomic DNA was isolated from peripheral blood and 12 genes sequenced in Autoinflammatory panel on IonTorrent-S5-NGS platform with Parseq-VariFind™AIPassay. NGS analysis showed 107 variants in in the index case, mainly benign with no strong association with Blau syndrome. Additionally, we identified one very rare missense mutation in NOD2 gene (c2803G>A, p.Val935Met) and in silico assessment of the mutation indicated possible pathogenic significance and strong association with Blau syndrome. In addition, we analyzed family members of the index case and identified the same mutation in NOD2 gene. The segregation analysis shows the presence of the same mutant allele in NOD2 gene in the index case affected sister, as well as in her son with arthralgia, while in her non affecter brother we didn't detect the Val935Met mutation in NOD2 gene. Blau Syndrome is known as a very rare disease, mainly caused by mutations in NOD2 gene. Missense mutation diagnosed in our case could be responsible for the phenotype of the index case. Our results indicate the importance of NGS testing and its major role in the detection of rare mutations that may responsible for the onset of autoinflammatory disorders.