GWAS meta-analysis reveals key risk loci in essential tremor pathogenesis.

Essential tremor (ET) is a prevalent neurological disorder with a largely unknown underlying biology. In this genome-wide association study meta-analysis, comprising 16,480 ET cases and 1,936,173 controls from seven datasets, we identify 12 sequence variants at 11 loci. Evaluating mRNA expression, splicing, plasma protein levels, and coding effects, we highlight seven putative causal genes at these loci, including CA3 and CPLX1. CA3 encodes Carbonic Anhydrase III and carbonic anhydrase inhibitors have been shown to decrease tremors. CPLX1, encoding Complexin-1, regulates neurotransmitter release. Through gene-set enrichment analysis, we identify a significant association with specific cell types, including dopaminergic and GABAergic neurons, as well as biological processes like Rho GTPase signaling. Genetic correlation analyses reveals a positive association between ET and Parkinson's disease, depression, and anxiety-related phenotypes. This research uncovers risk loci, enhancing our knowledge of the complex genetics of this common but poorly understood disorder, and highlights CA3 and CPLX1 as potential therapeutic targets.

Lifestyle and demographic associations with 47 inflammatory and vascular stress biomarkers in 9876 blood donors.

BACKGROUND: The emerging use of biomarkers in research and tailored care introduces a need for information about the association between biomarkers and basic demographics and lifestyle factors revealing expectable concentrations in healthy individuals while considering general demographic differences. METHODS: A selection of 47 biomarkers, including markers of inflammation and vascular stress, were measured in plasma samples from 9876 Danish Blood Donor Study participants. Using regression models, we examined the association between biomarkers and sex, age, Body Mass Index (BMI), and smoking. RESULTS: Here we show that concentrations of inflammation and vascular stress biomarkers generally increase with higher age, BMI, and smoking. Sex-specific effects are observed for multiple biomarkers. CONCLUSION: This study provides comprehensive information on concentrations of 47 plasma biomarkers in healthy individuals. The study emphasizes that knowledge about biomarker concentrations in healthy individuals is critical for improved understanding of disease pathology and for tailored care and decision support tools.

Blood-based biomarkers are circulating molecules that can help to indicate health or disease. Biomarker levels may vary depending on demographic and lifestyle factors such as age, sex, smoking status, and body mass index. Here, we examine the effects of these demographic and lifestyle factors on levels of biomarkers related to activation of the immune system and cardiovascular stress. Measurements of 47 different proteins were performed on blood samples from nearly 10,000 healthy Danish blood donors. Measurement data were linked with questionnaire data to assess effects of lifestyle. We found that immune activation and vascular stress generally increased with age, BMI, and smoking. As these measurements are from healthy blood donors they can serve as a reference for expectable effects and inflammation levels in healthy individuals. Knowledge about the healthy state is important for understanding disease progression and optimizing care.

A genome-wide association study of social trust in 33,882 Danish blood donors.

Social trust is a heritable trait that has been linked with physical health and longevity. In this study, we performed genome-wide association studies of self-reported social trust in n = 33,882 Danish blood donors. We observed genome-wide and local evidence of genetic similarity with other brain-related phenotypes and estimated the single nucleotide polymorphism-based heritability of trust to be 6% (95% confidence interval = (2.1, 9.9)). In our discovery cohort (n = 25,819), we identified one significantly associated locus (lead variant: rs12776883) in an intronic enhancer region of PLPP4, a gene highly expressed in brain, kidneys, and testes. However, we could not replicate the signal in an independent set of donors who were phenotyped a year later (n = 8063). In the subsequent meta-analysis, we found a second significantly associated variant (rs71543507) in an intergenic enhancer region. Overall, our work confirms that social trust is heritable, and provides an initial look into the genetic factors that influence it.

COVID-19 illness severity and 2-year prevalence of physical symptoms: an observational study in Iceland, Sweden, Norway and Denmark.

Background: Although the persistence of physical symptoms after SARS-CoV-2 infection is a major public health concern, evidence from large observational studies beyond one year post diagnosis remain scarce. We aimed to assess the prevalence of physical symptoms in relation to acute illness severity up to more than 2-years after diagnosis of COVID-19. Methods: This multinational study included 64,880 adult participants from Iceland, Sweden, Denmark, and Norway with self-reported data on COVID-19 and physical symptoms from April 2020 to August 2022. We compared the prevalence of 15 physical symptoms, measured by the Patient Health Questionnaire (PHQ-15), among individuals with or without a confirmed COVID-19 diagnosis, by acute illness severity, and by time since diagnosis. We additionally assessed the change in symptoms in a subset of Swedish adults with repeated measures, before and after COVID-19 diagnosis. Findings: During up to 27 months of follow-up, 34.5% participants (22,382/64,880) were diagnosed with COVID-19. Individuals who were diagnosed with COVID-19, compared to those not diagnosed, had an overall 37% higher prevalence of severe physical symptom burden (PHQ-15 score ≥15, adjusted prevalence ratio [PR] 1.37 [95% confidence interval [CI] 1.23-1.52]). The prevalence was associated with acute COVID-19 severity: individuals bedridden for seven days or longer presented with the highest prevalence (PR 2.25 [1.85-2.74]), while individuals never bedridden presented with similar prevalence as individuals not diagnosed with COVID-19 (PR 0.92 [0.68-1.24]). The prevalence was statistically significantly elevated among individuals diagnosed with COVID-19 for eight of the fifteen measured symptoms: shortness of breath, chest pain, dizziness, heart racing, headaches, low energy/fatigue, trouble sleeping, and back pain. The analysis of repeated measurements rendered similar results as the main analysis. Interpretation: These data suggest an elevated prevalence of some, but not all, physical symptoms during up to more than 2 years after diagnosis of COVID-19, particularly among individuals suffering a severe acute illness, highlighting the importance of continued monitoring and alleviation of these targeted core symptoms. Funding: This work was mainly supported by grants from NordForsk (COVIDMENT, grant number 105668 and 138929) and Horizon 2020 (CoMorMent, 847776). See Acknowledgements for further details on funding.

Genetic prediction of 33 blood group phenotypes using an existing genotype dataset.

BACKGROUND: Accurate blood type data are essential for blood bank management, but due to costs, few of 43 blood group systems are routinely determined in Danish blood banks. However, a more comprehensive dataset of blood types is useful in scenarios such as rare blood type allocation. We aimed to investigate the viability and accuracy of predicting blood types by leveraging an existing dataset of imputed genotypes for two cohorts of approximately 90,000 each (Danish Blood Donor Study and Copenhagen Biobank) and present a more comprehensive overview of blood types for our Danish donor cohort. STUDY DESIGN AND METHODS: Blood types were predicted from genome array data using known variant determinants. Prediction accuracy was confirmed by comparing with preexisting serological blood types. The Vel blood group was used to test the viability of using genetic prediction to narrow down the list of candidate donors with rare blood types. RESULTS: Predicted phenotypes showed a high balanced accuracy >99.5% in most cases: A, B, C/c, Coa /Cob , Doa /Dob , E/e, Jka /Jkb , Kna /Knb , Kpa /Kpb , M/N, S/s, Sda , Se, and Yta /Ytb , while some performed slightly worse: Fya /Fyb , K/k, Lua /Lub , and Vel ~99%-98% and CW and P1 ~96%. Genetic prediction identified 70 potential Vel negatives in our cohort, 64 of whom were confirmed correct using polymerase chain reaction (negative predictive value: 91.5%). DISCUSSION: High genetic prediction accuracy in most blood groups demonstrated the viability of generating blood types using preexisting genotype data at no cost and successfully narrowed the pool of potential individuals with the rare Vel-negative phenotype from 180,000 to 70.

Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura.

Migraine is a complex neurovascular disease with a range of severity and symptoms, yet mostly studied as one phenotype in genome-wide association studies (GWAS). Here we combine large GWAS datasets from six European populations to study the main migraine subtypes, migraine with aura (MA) and migraine without aura (MO). We identified four new MA-associated variants (in PRRT2, PALMD, ABO and LRRK2) and classified 13 MO-associated variants. Rare variants with large effects highlight three genes. A rare frameshift variant in brain-expressed PRRT2 confers large risk of MA and epilepsy, but not MO. A burden test of rare loss-of-function variants in SCN11A, encoding a neuron-expressed sodium channel with a key role in pain sensation, shows strong protection against migraine. Finally, a rare variant with cis-regulatory effects on KCNK5 confers large protection against migraine and brain aneurysms. Our findings offer new insights with therapeutic potential into the complex biology of migraine and its subtypes.

Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality.

Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.

Two Novel Human Leukocyte Antigen Alleles Are Associated with Decreased Risk of Onychomycosis in a Large Cohort of Danish Blood Donors.

Introduction: Antigen presentation and antimicrobial immune responses involve the human leukocyte antigen (HLA) system. Onychomycosis is primarily caused by dermatophytes and affects around 5.5% of the population worldwide. Yet, only limited data exist on the associations between the HLA system and onychomycosis. Thus, the objective of the study was to investigate if there is an association between HLA alleles and onychomycosis. Methods: Participants in the Danish Blood Donor Study were defined as cases of onychomycosis and controls based on antifungal prescriptions in the national prescription registry. Associations were investigated using logistic regressions adjusted for confounders and were Bonferroni corrected for multiple tests. Results: A total of 3,665 participants were considered onychomycosis cases, and 24,144 participants were considered controls. We found two protective HLA alleles of onychomycosis: DQB1*06:04, odds ratios (OR) 0.80 (95% confidence interval (CI) 0.71-0.90), and DRB1*13:02, OR 0.79 (95% CI: 0.71-0.89). Conclusion: The finding of two novel protective alleles of onychomycosis indicates that certain HLA alleles have certain antigen presentation properties affecting the risk of fungal infection. These findings may provide the basis for future research identifying immunologically relevant antigens of fungi causing onychomycosis, which could ultimately lead to targets of new drugs with antifungal effects.

Population-Based Characterization of Menstrual Migraine and Proposed Diagnostic Criteria.

Importance: There is a need for better recognition and more extensive research into menstrual migraine (MM) in the general population, and a revision of the diagnostic criteria for MM is warranted to move the field forward. Increased understanding of MM is crucial for improving clinical care, diagnosis, and therapy for MM. Objectives: To assess the clinical characteristics of MM, including severity and treatment response, and to propose new diagnostic criteria for pure MM and menstrually related migraine. Design, Setting, and Participants: This is a case-control study of Danish individuals with migraine. All individuals completed a 105-item validated diagnostic migraine questionnaire, sent via the Danish electronic mailing system (e-Boks) between May and August 2020, allowing diagnosis of pure MM and menstrually related migraine by the International Classification of Headache Disorders, Third Edition (ICHD-3). Data analysis was performed from September 2021 to November 2022. Exposure: Diagnosis of migraine. Main Outcomes and Measures: Clinical characteristics of women with MM and women with nonmenstrual migraine (non-MM) were compared using the ICHD-3 diagnostic criteria. A simulation of the risk of randomly misclassifying MM was based on number of migraine attacks during 3 menstrual cycles (3 × 28 days), and simulation analyses were performed using 100 000 permutations of random migraine attacks in migraine patients. Results: A total of 12 618 individuals, including 9184 women, with migraine participated in the study. Among the women with migraine, the prevalence of MM was 16.6% (1532 women), and the prevalence of non-MM was 45.9% (4216 women). The mean (SD) age was 38.7 (8.7) years for women with MM and 37.0 (9.2) years for women with non-MM. Of the 1532 women with MM, 410 (26.8%) fulfilled ICHD-3 diagnostic criteria for pure MM, 1037 (67.7%) fulfilled ICHD-3 diagnostic criteria for menstrually related migraine, and 152 (9.9%) fulfilled proposed diagnostic criteria for rare pure MM. MM was associated with a higher frequency of migraine-accompanying symptoms (odds ratio [OR], 1.98; 95% CI, 1.71-2.29), more frequent (OR, 7.21; 95% CI, 5.77-9.03) and more severe (OR, 1.17; 95% CI, 1.13-1.21) migraine attacks, lower frequency of nonmigraine headache (OR, 0.31; 95% CI, 0.18-0.49), an overall greater response to treatment with triptans (OR, 1.66; 95% CI, 1.24-2.24), better improvement of migraine attacks during late pregnancy (OR, 5.10; 95% CI, 2.17-14.00), and faster reappearance of migraine attacks post partum (OR, 3.19; 95% CI, 2.40-4.25). Hormonal contraceptive-related MM was associated with a higher prevalence of migraine without aura than migraine related to spontaneous menstruation (OR, 1.82; 95% CI, 1.62-2.06). Otherwise, no differences between hormonal and spontaneous MM were observed. The risk of random diagnostic misclassification of ICHD-3 menstrually related migraine in women with high frequency episodic migraine was 43%. This risk was reduced to 3% when applying the proposed criteria for menstrually related migraine. Conclusions and Relevance: In this case-control study, MM in the general population had clinical characteristics that were quantitively different from those of non-MM. Detailed descriptive data and suggested improved diagnostic criteria for pure MM and menstrually related migraine were provided.

Experience of loneliness during the COVID-19 pandemic: a cross-sectional study of 50 968 adult Danes.

OBJECTIVES: To examine the level of loneliness experienced during the COVID-19 pandemic in Denmark and to identify associated behavioural patterns and demographic factors. DESIGN: Cross-sectional cohort study. SETTING: Includes Danish active and former blood donors. PARTICIPANTS: A questionnaire was sent to 124 307 active and former blood donors, of these a total of 50 968 participants completed the study questionnaire (response rate=41%). PRIMARY AND SECONDARY OUTCOME MEASURES: Subjective experience of loneliness was measured using the 3-item University of California, Los Angeles Loneliness Scale (UCLA-3). Besides the UCLA-3, the respondents answered items on sociodemographic and economic characteristics, items on precautionary measures taken to avoid COVID-19 infection as well as on COVID-19 anxiety. RESULTS: The participants indicated their experienced level of loneliness both before and during the pandemic. Comparing the two reports yielded a mean increase in loneliness scores of 14.1% (p<0.001). Exploratory factor analysis identified the factor well-being, which comprised three questionnaire items related to emotional heath, physical health and happiness. A high score on the factor well-being was associated with reduced levels of loneliness (coefficient=-0.47, 95% CI -0.49 to -0.46)). Furthermore, women were more likely than men to have experienced increased levels of loneliness during the pandemic (coefficient=0.27, 95% CI 0.25 to 0.29). Furthermore, a negative correlation between higher age and change in loneliness score was observed. CONCLUSIONS: The findings document an increase in the level of experienced loneliness during the COVID-19 pandemic, particularly affecting individuals with low well-being, women and younger individuals.

Symptoms of attention deficit hyperactivity disorder are associated with Hidradenitis suppurativa in Danish blood donors.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease associated with psychiatric comorbidity. Attention deficit hyperactivity disorder (ADHD) is a mental disorder associated with systemic and skin inflammation such as psoriasis and atopic dermatitis. Whether HS symptoms are associated with ADHD symptoms remains unexplored. Thus, the aim of this study was to explore the possible association between HS and ADHD. Participants in the Danish Blood Donor Study (DBDS) were included in this cross-sectional study during 2015-2017. The participants provided questionnaire data on screening items of HS, ADHD symptoms (ASRS-score), and depressive symptoms, smoking and body mass index (BMI). A logistic regression with HS symptoms as a binary outcome predicted by ADHD adjusted for age, sex, smoking, BMI, and depression was conducted to investigate the association between HS and ADHD. A total of 52,909 Danish blood donors were included in the study. Of these were 1004/52,909 (1.9%) considered participants with HS. Of the participants with HS, 74/996 (7.4%) screened positive of ADHD symptoms, while only 1786/51,129 (3.5%) of the participants without HS screened positive of ADHD. Adjusted for confounders, ADHD was positively associated with HS, odds ratio 1.85 (95% confidence interval: 1.43-2.37). Psychiatric comorbidity of HS is not limited to depression and anxiety. This study shows a positive association between HS and ADHD. Further research on the biological mechanisms behind this association is warranted.

A large cohort study of the effects of Lewis, ABO, 13 other blood groups, and secretor status on COVID-19 susceptibility, severity, and long COVID-19.

BACKGROUND: Previous studies have reported Blood type O to confer a lower risk of SARS-CoV-2 infection, while secretor status and other blood groups have been suspected to have a similar effect as well. STUDY DESIGN AND METHODS: To determine whether any other blood groups influence testing positive for SARS-CoV-2, COVID-19 severity, or prolonged COVID-19, we used a large cohort of 650,156 Danish blood donors with varying available data for secretor status and blood groups ABO, Rh, Colton, Duffy, Diego, Dombrock, Kell, Kidd, Knops, Lewis, Lutheran, MNS, P1PK, Vel, and Yt. Of these, 36,068 tested positive for SARS-CoV-2 whereas 614,088 tested negative between 2020-02-17 and 2021-08-04. Associations between infection and blood groups were assessed using logistic regression models with sex and age as covariates. RESULTS: The Lewis blood group antigen Lea displayed strongly reduced SARS-CoV-2 susceptibility OR 0.85 CI[0.79-0.93] p < .001. Compared to blood type O, the blood types B, A, and AB were found more susceptible toward infection with ORs 1.1 CI[1.06-1.14] p < .001, 1.17 CI[1.14-1.2] p < .001, and 1.2 CI[1.14-1.26] p < .001, respectively. No susceptibility associations were found for the other 13 blood groups investigated. There was no association between any blood groups and COVID-19 hospitalization or long COVID-19. No secretor status associations were found. DISCUSSION: This study uncovers a new association to reduced SARS-CoV-2 susceptibility for Lewis type Lea and confirms the previous link to blood group O. The new association to Lea could be explained by a link between mucosal microbiome and SARS-CoV-2.

Prevalence of major depressive disorder in 51,658 otherwise healthy adult Danes: Sex differences in symptomatology and prediction of future anti-depressive medication.

Major Depressive Disorder (MDD) is a heterogeneous disease, which displays sex differences in symptomatology. This study aimed to assess point prevalence of MDD in undiagnosed, healthy adults as well as sex differences in symptomatology and clarify if specific symptoms increased the later need for anti-depressive medication. The study included 51,658 blood donors. Depressive symptoms were assessed according to ICD-10 using the Major Depression Inventory. Demographics, previous MDD, anti-depressive medication were collected from questionnaires and population registers. Descriptive, Logistic and Cox regression analyses were conducted. In total, 1.15% participants met the criteria for MDD. Women were significantly more likely to experience "increased appetite" and less likely to experience "a feeling of life not worth living", compared to men. MDD significantly associated with an increased hazard of later receiving a prescription for anti-depressive medication. The risk increased proportionally with increasing MDD severity. The two symptoms, "feeling that life is not worth living" and "trouble sleeping" were the strongest individual predictive symptoms of future anti-depressive medication in women and men, respectively. The results confirm findings in MDD patient groups. The diagnostic and prognostic value should be investigated further to address their potential as part of the clinical assessment.

The health-related quality of life in hyperhidrosis and co-morbidities.

PURPOSE: Hyperhidrosis has been associated with a reduced health-related quality of life (HRQoL). The role of common confounding factors of this association such as stress and socioeconomic status, however, remain largely unexplored, and may affect the management strategy for hyperhidrosis. Therefore, the study objective was to compare the HRQoL in individuals with and without hyperhidrosis while adjusting for confounders. METHODS: In this retrospective cohort study, data on the HRQoL measured by the short-form-12 questionnaire and self-reported hyperhidrosis were collected from the Danish Blood Donor Study-cohort. Data on international classification of disease-10 codes and redeemed prescriptions were collected from nationwide registries. Linear regression investigated the association between hyperhidrosis and HRQoL. RESULTS: Total 2794 (9.1%) of 30,808 blood donors had self-reported hyperhidrosis and 284 (0.2%) of 122,225 had hospital diagnosed hyperhidrosis. Self-reported hyperhidrosis was associated with a reduced mental HRQoL (adjusted beta coefficient - 1.10; 95% confidence interval - 1.37, - 0.82; p < 0.001) and physical HRQoL (adjusted beta coefficient - 0.90; 95% confidence interval - 1.09, - 0.70; p < 0.001). Hospital diagnosed hyperhidrosis was associated with a reduced mental HRQoL (adjusted beta coefficient - 0.91; 95% confidence interval - 1.82, - 0.04; p = 0.049). CONCLUSION: Hyperhidrosis is associated with a reduced HRQoL, independently of confounders or mode of diagnosis. This supports an approach primarily targeting hyperhidrosis.

Chronic inflammation markers and cytokine-specific autoantibodies in Danish blood donors with restless legs syndrome.

Restless Legs Syndrome (RLS) is a neurological sensorimotor disorder negatively impacting sufferers' quality of sleep and health-related quality of life. The pathophysiology of RLS is poorly understood and research focusing on the link between RLS and inflammation has been limited. Our study aimed to investigate whether chronic inflammation markers C-reactive protein (CRP) and soluble urokinase-type plasminogen activator receptor (suPAR), as well plasma levels of five different cytokine-specific autoantibodies (c-aAb), i.e. modulators of inflammation, associate with RLS in otherwise healthy individuals. CRP, suPAR and c-aAb were measured in plasma samples of participants from the Danish Blood Donor Study in 2010. Returning donors between 2015 and 2018 completed the validated Cambridge-Hopkins RLS-questionnaire for RLS assessment, resulting in datasets with RLS assessment and values for CRP (N = 3564), suPAR (N = 2546) and c-aAb (N = 1478). We performed logistic regression models using the CRP, suPAR or c-aAb as the independent variable and RLS status as the dependent variable, adjusted for appropriate covariates. Our study indicates that a high concentration of CRP is associated with RLS, while an increased probability of experiencing frequent RLS symptoms in those with an elevated plasma suPAR level appears to be mediated through lifestyle factors. We additionally report that a high titer of autoantibodies specific against the cytokine interferon-alpha was associated with RLS. Our results support the existence of links between systemic inflammation and RLS, though further RLS studies on CRP, suPAR and c-aAb in larger cohorts are warranted to confirm our findings and further reveal the hitherto underexplored links between RLS and inflammation.

Hyperhidrosis and the risk of being treated for skin infections.

BACKGROUND: A few studies have described an increased prevalence of skin infections in individuals with hyperhidrosis compared to others. However, it remains uncertain whether hyperhidrosis is an independent risk factor for skin infections. OBJECTIVE: To compare the risk of skin infections in individuals with and without hyperhidrosis. METHODS: In this retrospective cohort study, data on hyperhidrosis were collected from the Danish Blood Donor Study. Blood donors included in 2010-2019 were followed from inclusion until December 2019. Data on redeemed prescriptions against skin infections were collected from the National Prescription Register. The intensity of prescription-use by hyperhidrosis status was assessed in Andersen-Gill models. RESULTS: Overall, 4,176 (9.6%) of 43,477 blood donors had self-reported hyperhidrosis and 437 (0.34%) of 127,823 blood donors had hospital diagnosed hyperhidrosis. Self-reported hyperhidrosis was associated with the use of antibiotic prescriptions (adjusted hazard ratio = 1.21; 95% confidence interval 1.00-1.45, p = 0.047). Hospital diagnosed hyperhidrosis was associated with the use of antibiotic (adjusted hazard ratio = 1.33; 95% confidence interval 1.03-1.68, p = 0.028) and topical antifungal prescriptions (adjusted hazard ratio = 1.43; 95% confidence interval 1.04-1.97, p = 0.027). CONCLUSIONS: Hyperhidrosis is associated with the use of prescriptions for antibiotics and topical antifungals. This suggests a clinically relevant association between hyperhidrosis and skin infections.