Reassessment of candidate gene studies for idiopathic restless legs syndrome in a large genome-wide association study dataset of European ancestry

Study Objectives Several candidate gene studies have been published for idiopathic restless legs syndrome (RLS) in populations of European ancestry, but the reported associations have not been confirmed in independent samples. Our aim was to reassess these findings in a large case-control dataset in order to evaluate their validity. Methods We screened PubMed for RLS candidate gene studies. We used the genome-wide association study (GWAS) dataset of the International EU-RLS-GENE Consortium as our replication sample, which provided genome-wide single-variant association data based on at most 17 220 individuals of European ancestry. We performed additional gene-based tests using the software MAGMA and assessed the power of our study using the genpwr R package. Results We identified 14 studies conducted in European samples which assessed 45 variants in 27 genes of which 5 variants had been reported as significantly associated. None of these individual variants were replicated in our GWAS-based reassessment (nominal p > 0.05) and gene-based tests for the respective five genes ADH1B, GABRR3, HMOX1, MAOA, and VDR, were also nonsignificant (nominal p > 0.05). Our replication dataset was well powered to detect the reported effects, even when adjusting for effect size overestimation due to winner's curse. Power estimates were close to 100% for all variants. Conclusion In summary, none of the significant single-variant associations from candidate gene studies were confirmed in our GWAS dataset. Therefore, these associations were likely false positive. Our observations emphasize the need for large sample sizes and stringent significance thresholds in future association studies for RLS

HOPS-associated neurological disorders (HOPSANDs): linking endolysosomal dysfunction to the pathogenesis of dystonia

The homotypic fusion and protein sorting (HOPS) complex is the structural bridge necessary for the fusion of late endosomes and autophagosomes with lysosomes. Recent publications linked mutations in genes encoding HOPS complex proteins with the aetiopathogenesis of inherited dystonias (i.e. VPS16, VPS41, and VPS11). Functional and microstructural studies conducted on patient-derived fibroblasts carrying mutations of HOPS complex subunits displayed clear abnormalities of the lysosomal and autophagic compartments. We propose to name this group of diseases HOPS-associated neurological disorders (HOPSANDs), which are mainly characterized by dystonic presentations. The delineation of HOPSANDs further confirms the connection of lysosomal and autophagic dysfunction with the pathogenesis of dystonia, prompting researchers to find innovative therapies targeting this pathway

Personal protective equipment for healthcare workers during COVID-19: developing and applying a questionnaire and assessing associations between infection rates and shortages across 19 countries

This study aimed to assess the preparedness of European countries regarding personal protective equipment (PPE) for health and care workers (HCWs), the COVID-19 infection rates of HCWs compared to the general working age population, and the association between these. We developed a PPE-preparedness scale based on responses to a questionnaire from experts in the Health Systems and Policy Monitor network, with a response rate of 19 out of 31 countries. COVID-19 infection data were retrieved form the European center for Disease Prevention and Control. Shortages of PPE were found in most countries, in particular in home care and long-term care. HCW infection rates, compared to the general population, varied strongly between countries, influenced by different testing regimes. We found no relationships between HCW infection rates, PPE preparedness and shortages of PPE. Improved surveillance in the population as well as for HCWS are needed to be able to better assess these relationships

Restless Legs Syndrome-associated intronic common variant in Meis1 alters enhancer function in the developing telencephalon

This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported).-- et al.Genome-wide association studies (GWAS) identified the MEIS1 locus for Restless Legs Syndrome (RLS), but causal single nucleotide polymorphisms (SNPs) and their functional relevance remain unknown. This locus contains a large number of highly conserved noncoding regions (HCNRs) potentially functioning as cis-regulatory modules. We analyzed these HCNRs for allele-dependent enhancer activity in zebrafish and mice and found that the risk allele of the lead SNP rs12469063 reduces enhancer activity in the Meis1 expression domain of the murine embryonic ganglionic eminences (GE). CREB1 binds this enhancer and rs12469063 affects its binding in vitro. In addition, MEIS1 target genes suggest a role in the specification of neuronal progenitors in the GE, and heterozygous Meis1-deficient mice exhibit hyperactivity, resembling the RLS phenotype. Thus, in vivo and in vitro analysis of a common SNP with small effect size showed allele-dependent function in the prospective basal ganglia representing the first neurodevelopmental region implicated in RLS.The project was supported by Fritz-Thyssen-Stiftung, Cologne, Germany (10.09.2.146; 10.12.2.183), KKF-TUM (8766156), DAAD (0811963), and COST (“HOX and TALE homeoproteins in Development and Disease”). B.S. was partially supported by DFG grants (WI 1820/4-1; WI 1820/5-1) and a TUM-Excellence stipend. The KORA study was financed by the Helmholtz Zentrum München, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. KORA research was supported within the Munich Center of Health Sciences (MC Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. J.L.G.-S. and F.C. acknowledge funding of the Spanish and the Andalusian Governments and the Feder program for grants (BFU2010-14839, BFU2009-07044, CSD2007-00008, and Proyectos de Excelencia CVI-3488 and CVI 2658). This work was funded in part by a grant from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research (DZD), to the German Mouse Clinic (Infrafrontier: 01KX1012), to the German Center for Neurodegenerative Diseases (DZNE), Germany; by the Initiative and Networking Fund of the Helmholtz Association in the framework of the Helmholtz Alliance for Mental Research in an Ageing Society (HA-215); and the Munich Cluster for Systems Neurology (EXC 1010 SyNergy) and its Collaborative Research Center (CRC) 870/2 “Assembly and Function of Neuronal Circuits.”Peer Reviewe

CMView: Interactive contact map visualization and analysis

Summary: Contact maps are a valuable visualization tool in structural biology. They are a convenient way to display proteins in two dimensions and to quickly identify structural features such as domain architecture, secondary structure and contact clusters. We developed a tool called CMView which integrates rich contact map analysis with 3D visualization using PyMol. Our tool provides functions for contact map calculation from structure, basic editing, visualization in contact map and 3D space and structural comparison with different built-in alignment methods. A unique feature is the interactive refinement of structural alignments based on user selected substructures. Availability: CMView is freely available for Linux, Windows and MacOS. The software and a comprehensive manual can be downloaded from http://www.bioinformatics.org/cmview/. The source code is licensed under the GNU General Public License. Contact: [email protected], [email protected]

Intronic elements associated with insomnia and restless legs syndrome exhibit cell-type-specific epigenetic features contributing to MEIS1 regulation

A highly evolutionarily conserved myeloid ecotropic viral integration site 1 (MEIS1) intronic region is strongly associated with restless legs syndrome (RLS) and insomnia. To understand its regulatory function, we dissected the region by analyzing chromatin accessibility, enhancer-promoter contacts, DNA methylation and expression quantitative trait locus (eQTLs) in different human neural cell types and tissues. We observed specific activity with respect to cell type and developmental maturation, indicating a prominent role for distinct highly conserved intronic elements in forebrain inhibitory neuron differentiation. Two elements were hypomethylated in neural cells with higher MEIS1 expression, suggesting a role of enhancer demethylation in gene regulation. MEIS1 eQTLs showed a striking modular chromosomal distribution, with forebrain eQTLs clustering in intron 8/9. Clustered regularly interspersed short palindromic repeats interference targeting of individual elements in this region attenuated MEIS1 expression, revealing a complex regulatory interplay of distinct elements. In summary, we found that MEIS1 regulation is organized in a modular pattern. Disease-associated intronic regulatory elements control MEIS1 expression with cell type and maturation stage specificity, particularly in the inhibitory neuron lineage. The precise spatiotemporal activity of these elements likely contributes to the pathogenesis of insomnia and RLS

Perspective: lessons from COVID-19 of countries in the European region in light of findings from the health system response monitor

Introduction: Decision-makers initially had limited data to inform their policy responses to the COVID-19 pandemic. The research community developed several online databases to track cases, deaths, and hospitalizations; however, a major deficiency was the lack of detailed information on how health systems were responding to the pandemic and how they would need to be transformed going forward. Approach: In an eort to fill this information gap, in March 2020, the European Observatory on Health Systems and Policies, the WHO European Regional Oce and the European Commission created the COVID-19 Health System Response Monitor (HSRM) to collect and organise up-to-date information on how health systems, mainly in the WHO European Region, were responding to the COVID-19 pandemic. Findings: The HSRM analysis and broader Observatory work on COVID-19 shone light on a range of health system challenges and weaknesses and catalogued policy options countries put in place during the pandemic to address these. Countries prioritised policies on investing in public health, supporting the workforce, maintaining financial stability, and strengthening governance in their response to COVID-19. Outlook: COVID-19 is likely to continue to impact health systems for the foreseeable future; the ability to cope with this pressure, and other shocks, depends on having good information on what other countries have done so that health systems develop adequate policy options. In support of this, the country information on the COVID-19 HSRM will remain available as a repository to inform decision makers on options for actions and possible measures against COVID-19 and other public health emergencies. Building on its previous work on health systems resilience, the European Observatory on Health Systems and Policies will sustain its focus on analysing key issues relate to the recovery from the pandemic and making health systems more resilient. This includes policy knowledge transfer between countries and systematic resilience testing, aiming at contributing to an improved understanding of health system response, recovery, and preparedness. Contribution to the literature in non-technical language: The COVID-19 Health System Response Monitor (HSRM) was the first database in the WHO European Region to collect and organise up-to-date information on how health systems were responding to the COVID-19 pandemic. The HSRM provides a repository of policies which can be used to inform decision makers in health and other policy domains on options for action and possible measures against COVID-19 and other public health emergencies. This initiative proved particularly valuable, especially during the early phases of the pandemic, when there was limited information for countries to draw on as they formulated their own policy response to the pandemic. Our perspectives paper highlights some key challenges within health systems that the HSRM was able to identify during the pandemic and considers policy options countries put in place in response. Our research contributes to literature on emergency responses and recovery, health systems performance assessment, particularly health system resilience, and showcases the Observatory experience on how to design such a data collection tool, as well as how to leverage its findings to support cross-country learning