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

Clinical and genetic characteristics of late-onset Huntington's disease

Background: The frequency of late-onset Huntington's disease (>59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. Objective: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database. Methods: Participants with late- and common-onset (30–50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded. Results: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P <.001). Overall motor and cognitive performance (P <.001) were worse, however only disease motor progression was slower (coefficient, −0.58; SE 0.16; P <.001) compared to the common-onset group. Repeat size was significantly lower in the late-onset (n = 40.8; SD 1.6) compared to common-onset (n = 44.4; SD 2.8) (P <.001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P <.001). Conclusions: Late-onset patients present more frequently with gait and balance problems as first symptom, and disease progression is not milder compared to common-onset HD patients apart from motor progression. The family history is likely to be negative, which might make diagnosing HD more difficult in this population. However, the balance and gait problems might be helpful in diagnosing HD in elderly patients

Elliptic flow of electrons from heavy-flavour hadron decays at mid-rapidity in Pb–Pb collisions at √sNN = 2.76 TeV

The elliptic flow of electrons from heavy-flavour hadron decays at mid-rapidity (|y| < 0.7) is measured in Pb-Pb collisions at sNN−−−√=2.76 TeV with ALICE at the LHC. The particle azimuthal distribution with respect to the reaction plane can be parametrized with a Fourier expansion, where the second coefficient (v2) represents the elliptic flow. The v2 coefficient of inclusive electrons is measured in three centrality classes (0-10%, 10-20% and 20-40%) with the event plane and the scalar product methods in the transverse momentum (pT) intervals 0.5-13 GeV/c and 0.5-8 GeV/c, respectively. After subtracting the background, mainly from photon conversions and Dalitz decays of neutral mesons, a positive v2 of electrons from heavy-flavour hadron decays is observed in all centrality classes, with a maximum significance of 5.9σ in the interval 2< pT < 2.5 GeV/c in semi-central collisions (20-40%). The value of v2 decreases towards more central collisions at low and intermediate pT (0.5 < pT < 3 GeV/c). The v2 of electrons from heavy-flavour hadron decays at mid-rapidity is found to be similar to the one of muons from heavy-flavour hadron decays at forward rapidity (2.5 < y < 4). The results are described within uncertainties by model calculations including substantial elastic interactions of heavy quarks with an expanding strongly-interacting medium

Production of Σ(1385)± and Ξ(1530)0 in p–Pb collisions at √sNN = 5.02 TeV

The transverse momentum distributions of the strange and double-strange hyperon resonances (Σ(1385)±, Ξ(1530)0) produced in p-Pb collisions at sNN−−−√=5.02 TeV were measured in the rapidity range −0.5<yCMS<0 for event classes corresponding to different charged-particle multiplicity densities, ⟨dNch/dηlab⟩. The mean transverse momentum values are presented as a function of ⟨dNch/dηlab⟩, as well as a function of the particle masses and compared with previous results on hyperon production. The integrated yield ratios of excited to ground-state hyperons are constant as a function of ⟨dNch/dηlab⟩. The equivalent ratios to pions exhibit an increase with ⟨dNch/dηlab⟩, depending on their strangeness content

Inclusive J/ψ\psi production at midrapidity in pp collisions at s = 13\sqrt{s}~=~13 TeV

We report on the inclusive J/$\psi$ production cross section measured at the CERN Large Hadron Collider in proton-proton collisions at a centre-of-mass energy $\sqrt{s}~=~13$ TeV. The J/$\psi$ mesons are reconstructed in the $\rm e^{+} e^{-}$ decay channel and the measurements are performed at midrapidity ($|y|<0.9$) in the transverse-momentum interval $0< p_{\rm T} <40$ GeV/$c$, using a minimum bias data sample corresponding to an integrated luminosity $L_{\text{int}} = 32.2~\text{nb}^{-1}$ and an Electromagnetic Calorimeter triggered data sample with $L_{\text{int}} = 8.3~\mathrm{pb}^{-1}$. The $p_{\rm T}$-integrated J/$\psi$ production cross section at midrapidity, computed using the minimum bias data sample, is $\text{d}\sigma/\text{d}y|_{y=0} = 8.97\pm0.24~(\text{stat})\pm0.48~(\text{syst})\pm0.15~(\text{lumi})~\mu\text{b}$. An approximate logarithmic dependence with the collision energy is suggested by these results and available world data, in agreement with model predictions. The integrated and $p_{\rm T}$-differential measurements are compared with measurements in pp collisions at lower energies and with several recent phenomenological calculations based on the non-relativistic QCD and Color Evaporation models

Measurement of electrons from beauty-hadron decays in p–Pb collisions at √sNN = 5.02 TeV and Pb–Pb collisions at √sNN = 2.76 TeV

The production of beauty hadrons was measured via semi-leptonic decays at mid-rapidity with the ALICE detector at the LHC in the transverse momentum interval 1<pT<8 GeV/c in minimum-bias p-Pb collisions at sNN−−−√=5.02 TeV and in 1.3<pT<8 GeV/c in the 20% most central Pb-Pb collisions at sNN−−−√=2.76 TeV. The pp reference spectra at s√=5.02 TeV and s√=2.76 TeV, needed for the calculation of the nuclear modification factors RpPb and RPbPb, were obtained by a pQCD-driven scaling of the cross section of electrons from beauty-hadron decays measured at s√=7 TeV. In the pT interval 3<pT<8 GeV/c a suppression of the yield of electrons from beauty-hadron decays is observed in Pb-Pb compared to pp collisions. Towards lower pT, the RPbPb values increase with large systematic uncertainties. The RpPb is consistent with unity within systematic uncertainties and is well described by theoretical calculations that include cold nuclear matter effects in p-Pb collisions. The measured RpPb and these calculations indicate that cold nuclear matter effects are small at high transverse momentum also in Pb-Pb collisions. Therefore, the observed reduction of RPbPb below unity at high pT may be ascribed to an effect of the hot and dense medium formed in Pb-Pb collisions

Measurement of charged jet cross section in pp collisions at √s = 5.02 TeV

The cross section of jets reconstructed from charged particles is measured in the transverse momentum range of 5<pT<100 GeV/c in pp collisions at the center-of-mass energy of s√=5.02 TeV with the ALICE detector. The jets are reconstructed using the anti-kT algorithm with resolution parameters R=0.2, 0.3, 0.4, and 0.6 in the pseudorapidity range |η|<0.9−R. The charged jet cross sections are compared with the leading order (LO) and to next-to-leading order (NLO) perturbative Quantum ChromoDynamics (pQCD) calculations. It was found that the NLO calculations agree better with the measurements. The cross section ratios for different resolution parameters were also measured. These ratios increase from low pT to high pT and saturate at high pT, indicating that jet collimation is larger at high pT than at low pT. These results provide a precision test of pQCD predictions and serve as a baseline for the measurement in Pb−Pb collisions at the same energy to quantify the effects of the hot and dense medium created in heavy-ion collisions at the LHC