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

Beam Parameters Analysis Interface for the Proton Irradiation Facility (IRRAD)

CERN’s proton irradiation facility IRRAD is a key infrastructure [1] for the High Energy Physics (HEP) community to perform radiation test studies. The usage ranges from radiation damage tests on semiconductor devices, electronics components, materials in operation around accelerators and experiments to degradation tests for components and systems. Obtaining a slow extracted beam from the Proton Synchrotron (PS) with momentum of 24 GeV/c allows exposing with a gaussian 12 × 12 mm2 beam to given particle fluence levels. The facility is located in the PS East Area at the T8 beamline. The facility’s upgrade in 2014 during the Long Shutdown 1 ensured adaption of the site to the challenging requirements for irradiation studies for the era of the High Luminosity LHC (HL-LHC). As the users rely on achieving the anticipated specifications, a regular monitoring of the Key Performance Indicators (KPI) on the part of the IRRAD operation team is crucial. With the beam spills being distributed to the various experiments regulated by the CERN Control Center (CCC), they also rely on feedback in order to improve their operation. Moreover, with regard to future accelerator projects demanding higher fluences, this analysis also contributes to improve the facilities performance for the future challenges. Therefore a software tool allowing for a quick and uncomplicated analysis of the KPIs on a weekly basis became indispensable

Felsenkeller 5 MV underground accelerator: Towards the Holy Grail of Nuclear Astrophysics 12C(α, γ)16O

Low-background experiments with stable ion beams are an important tool for putting the model of stellar hydrogen, helium, and carbon burning on a solid experimental foundation. The pioneering work in this regard has been done by the LUNA collaboration at Gran Sasso, using a 0.4 MV accelerator. The present contribution reviews the status of the project for a higher-energy underground accelerator in Felsenkeller, Germany. Results from γ-ray, neutron, and muon background measurements in the Felsenkeller underground site in Dresden, Germany, show that the background conditions are satisfactory. Two tunnels of the Felsenkeller site have recently been refurbished for the installation of a 5MV high-current Pelletron accelerator. Civil construction work has completed in March 2018. The accelerator will provide intense, 50 μA, beams of 1H+, 4He+, and 12C+ ions, enabling research on astrophysically relevant nuclear reactions with unprecedented sensitivity

Felsenkeller 5 MV underground accelerator: Towards the Holy Grail of Nuclear Astrophysics

Low-background experiments with stable ion beams are an important tool for putting the model of stellar hydrogen, helium, and carbon burning on a solid experimental foundation. The pioneering work in this regard has been done by the LUNA collaboration at Gran Sasso, using a 0.4 MV accelerator. The present contribution reviews the status of the project for a higher-energy underground accelerator in Felsenkeller, Germany. Results from γ-ray, neutron, and muon background measurements in the Felsenkeller underground site in Dresden, Germany, show that the background conditions are satisfactory. Two tunnels of the Felsenkeller site have recently been refurbished for the installation of a 5MV high-current Pelletron accelerator. Civil construction work has completed in March 2018. The accelerator will provide intense, 50 μA, beams of 1H+, 4He+, and 12C+ ions, enabling research on astrophysically relevant nuclear reactions with unprecedented sensitivity

Neutron Transmission Measurements at nELBE

Neutron total cross sections are an important source of experimental data in the evaluation of neutron induced cross sections. The sum of all neutron-induced reaction cross sections can be determined with a precision of a few percent in a relative measurement. The transmission is determined from the count rates of the neutron beam transmitted through a target sample relative to the count rate without sample and is independent of the neutron detection efficiency. The neutron spectrum of the photo neutron source nELBE extends in the fast region from about 100 keV to 10 MeV and has favourable conditions for transmission measurements due the low instantaneous flux of neutrons and low gamma-flash background. Several materials of interest (in part included in the CIELO evaluation or on the HPRL of OECD/NEA) have been investigated: 197Au, natFe, natW, 238U, natPt, 4He, natO, natNe, natXe. For gaseous targets high pressure gas cells have been built that hold up to 200 bar pressure. The experimental setup will be presented including results from several transmission experiments and the data analysis leading to the total cross sections will be discussed.JRC.G.2-Standards for Nuclear Safety, Security and Safeguard

Neutron transmission measurements at nELBE

Neutron total cross sections are an important source of experimental data in the evaluation of neutron-induced cross sections. The sum of all neutron-induced reaction cross sections can be determined with a precision of a few per cent in a relative measurement. The neutron spectrum of the photoneutron source nELBE extends in the fast region from about 100 keV to 10 MeV and has favourable conditions for transmission measurements due to the low instantaneous flux of neutrons and low gamma-flash background. Several materials of interest (in part included in the CIELO evaluation or on the HPRL of OECD/NEA) have been investigated: 197Au [1, 2], natFe [2], natW [2], 238U, natPt, 4He, natO, natNe, natXe. For gaseous targets high pressure gas cells with flat end-caps have been built that hold up to 200 bar pressure. The experimental setup will be presented including results from several transmission experiments and the data analysis leading to the total cross sections will be discussed

Annual Report 2023 and Phase-I Closeout

This report summarises the activities of the CERN strategic R&D programme on technologies for future experiments during the year 2023, and highlights the achievements of the programme during its first phase 2020-2023

Reduced Cancer Incidence in Huntington's Disease: Analysis in the Registry Study

Background: People with Huntington's disease (HD) have been observed to have lower rates of cancers. Objective: To investigate the relationship between age of onset of HD, CAG repeat length, and cancer diagnosis. Methods: Data were obtained from the European Huntington's disease network REGISTRY study for 6540 subjects. Population cancer incidence was ascertained from the GLOBOCAN database to obtain standardised incidence ratios of cancers in the REGISTRY subjects. Results: 173/6528 HD REGISTRY subjects had had a cancer diagnosis. The age-standardised incidence rate of all cancers in the REGISTRY HD population was 0.26 (CI 0.22-0.30). Individual cancers showed a lower age-standardised incidence rate compared with the control population with prostate and colorectal cancers showing the lowest rates. There was no effect of CAG length on the likelihood of cancer, but a cancer diagnosis within the last year was associated with a greatly increased rate of HD onset (Hazard Ratio 18.94, p < 0.001). Conclusions: Cancer is less common than expected in the HD population, confirming previous reports. However, this does not appear to be related to CAG length in HTT. A recent diagnosis of cancer increases the risk of HD onset at any age, likely due to increased investigation following a cancer diagnosis