Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Association of Slight to Mild Hearing Loss With Behavioral Problems and School Performance in Children

Importance: Children with severe hearing loss are known to have more behavioral problems and may perform worse at school than children without. Few large-scale studies of slight to mild hearing loss are available. Objective: To examine the relevance of slight to mild hearing loss by studying its association with behavioral problems and school performance. Design, Setting, and Participants: This cross-sectional study was performed within an ongoing prospective birth cohort study in Rotterdam, the Netherlands. Participants were part of a population-based sample of children. Between ages 9 and 11 years, 5355 children underwent audiometric and behavioral evaluations. Children were excluded if they had missing data for either audiometry or both outcomes. Data were collected from April 2012 through October 2015. Data were analyzed from March to June 2018. Exposures: Audiometric evaluation included pure-tone audiometry tests and speech-in-noise testing. Main Outcomes and Measures: Child behavior was rated by the primary caregiver using the Child Behavior Checklist at ages 9 to 11 years (n = 4471). School performance was measured with a standardized test at age 12 years (n = 2399). Results: The final sample included 4779 participants who were a mean (SD) age of 9.8 (0.3) years. The sample had nearly equal distribution between boys (n = 2200; 49.2%) and girls (n = 2271; 50.8%). Associations of hearing thresholds with behavioral problems differed between boys and girls. Among boys, higher pure-tone hearing thresholds at low frequencies were associated with higher total problem, social problem, and attention problem scores (total problems for the better-hearing ear: β = 0.01; 95% CI, 0-0.02). Higher speech reception thresholds were associated with higher attention problem scores among girls (β = 0.04; 95% CI, 0-0.08). Higher speech reception thresholds were associated with poorer school performance scores for both boys and girls (β = -0.06; 95% CI, -0.10 to -0.02). Conclusions and Relevance: Higher hearing thresholds during pure-tone audiometric and speech-in-noise testing were associated with higher behavioral problem scores and poorer school performance. This supports the relevance of slight to mild hearing loss with these outcomes in school-aged children

Distress, Work Satisfaction, and Work Ability are Mediators of the Relation Between Psychosocial Working Conditions and Mental Health-Related Long-Term Sickness Absence

Purpose This study investigated the effects of psychosocial working conditions on mental health-related long-term sickness absence and whether distress, work satisfaction, burnout, engagement, and work ability mediated the associations between psychosocial working conditions and mental health-related long-term sickness absence. Methods This cohort study included 53,833 non-sick listed workers who participated in occupational health surveys between 2010 and 2013. The effects of the individual psychosocial working conditions on mental long-term sickness absence were analyzed using univariable and multivariable logistic regression analyses. Mediation analyses were performed to examine the mediating role of distress, burnout, work satisfaction, engagement, and work ability between psychosocial working conditions and mental long-term sickness absence. The mediation analyses were performed using structural equation modeling. Results Role clarity, cognitive demands, emotional demands, work variety, learning opportunities, and co-worker support were related to mental health-related long-term sickness absence after adjustment for other working conditions. The relationship between emotional demands and mental health-related long-term sickness absence was the strongest, OR 1.304 (p < 0.001, 95% CI 1.135 to 1.498). The relation between psychosocial working conditions and mental health-related long-term sickness absence was mediated by distress, burnout, work satisfaction, engagement, and work ability. Distress was the most important mediator between psychosocial working conditions and mental health-related long-term sickness absence. Conclusions Psychosocial working conditions are related to mental health-related long-term sickness absence. After correction for other working conditions, the association between emotional demands and mental health-related long-term sickness absence was the strongest. Psychosocial working conditions are indirectly related to mental health-related long-term sickness absence through mediation by distress, work satisfaction, and work ability

Determinants of COVID-19 Vaccine Uptake in The Netherlands: A Nationwide Registry-Based Study.

By September 2022, the uptake of at least one dose of COVID-19 vaccine in the Dutch adult population was 84%. Ecological studies have indicated a lower uptake in certain population groups. We aimed to investigate determinants of COVID-19 vaccine uptake in the Netherlands at individual level to evaluate and optimize implementation of the vaccination program and generate hypotheses for research on drivers of, and barriers to, vaccination. A retrospective database study was performed including the entire Dutch population ≥ 18. Vaccination data (5 January 2021–18 November 2021) were at individual levels linked to sociodemographic data. Random forest analyses ranked sociodemographic determinants of COVID-19 vaccine uptake. The most important determinant was age; uptake increased until the age of 80 (67% in 18–35 years, 92% in 67–79 years, and 88% in those > 80). Personal income and socioeconomic position ranked second and third, followed by migration status. Uptake was lower among individuals in the lowest income group (69%), those receiving social benefits (56%), and individuals with two parents born abroad (59%). Our finding that age is the most important determinant for uptake likely reflects the prioritisation of elderly in the programme and the general understanding of their increased vulnerability. However, our findings also reveal important other disparities in vaccine uptake. How to best address this inequity in future vaccination campaigns requires further research

Neighbourhood sociodemographic factors and COVID-19 vaccine uptake in the Netherlands: an ecological analysis.

Abstract Background While overall COVID-19 vaccine uptake is high in the Netherlands, it lags behind in certain subpopulations. Aim We aimed to explore the characteristics of groups with lower COVID-19 vaccine uptake at neighbourhood level to inform the strategy to improve uptake and guide research into barriers for vaccination. Methods We performed an ecological study using national vaccination register and socio-demographic data at neighbourhood level. Using univariate and multivariable generalized additive models we examined the (potentially non-linear) effect of each determinant on uptake. We focused on those aged 50 years and older, since they are at highest risk of severe disease. Results In those over 50 years of age, a higher proportion of individuals with a non-Western migration background and higher voting proportions for right-wing Christian and conservative political parties were at neighbourhood level univariately associated with lower COVID-19 vaccine uptake. In contrast, higher socioeconomic status and higher voting proportions for right-wing liberal, progressive liberal and Christian middle political parties were associated with higher uptake. Multivariable results differed from univariate results in that a higher voting proportion for progressive left-wing political parties was also associated with higher uptake. In addition, with regard to migration background only a Turkish background remained significant. Conclusion We identified determinants associated with COVID-19 vaccine uptake at neighbourhood level and observed heterogeneity in uptake between different subpopulations. Since the goal of vaccination is not only to reduce suffering and death by improving the average uptake, but also to reduce health inequity, it is important to focus on subpopulations with lower uptake