New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Inclusive J/psi production in pp collisions at sqrt(s) = 2.76 TeV

The ALICE Collaboration has measured inclusive J/psi production in pp collisions at a center of mass energy sqrt(s)=2.76 TeV at the LHC. The results presented in this Letter refer to the rapidity ranges |y|<0.9 and 2.5<y<4 and have been obtained by measuring the electron and muon pair decay channels, respectively. The integrated luminosities for the two channels are L^e_int=1.1 nb^-1 and L^mu_int=19.9 nb^-1, and the corresponding signal statistics are N_J/psi^e+e-=59 +/- 14 and N_J/psi^mu+mu-=1364 +/- 53. We present dsigma_J/psi/dy for the two rapidity regions under study and, for the forward-y range, d^2sigma_J/psi/dydp_t in the transverse momentum domain 0<p_t<8 GeV/c. The results are compared with previously published results at sqrt(s)=7 TeV and with theoretical calculations.Comment: 7 figures, 3 tables, accepted for publication in Phys. Lett.

Neutral pion and η\eta meson production in proton-proton collisions at s=0.9\sqrt{s}=0.9 TeV and s=7\sqrt{s}=7 TeV

The first measurements of the invariant differential cross sections of inclusive $\pi^0$ and $\eta$ meson production at mid-rapidity in proton-proton collisions at $\sqrt{s}=0.9$ TeV and $\sqrt{s}=7$ TeV are reported. The $\pi^0$ measurement covers the ranges $0.4<p_T<7$ GeV/$c$ and $0.3<p_T<25$ GeV/$c$ for these two energies, respectively. The production of $\eta$ mesons was measured at $\sqrt{s}=7$ TeV in the range $0.4<p_T<15$ GeV/$c$. Next-to-Leading Order perturbative QCD calculations, which are consistent with the $\pi^0$ spectrum at $\sqrt{s}=0.9$ TeV, overestimate those of $\pi^0$ and $\eta$ mesons at $\sqrt{s}=7$ TeV, but agree with the measured $\eta/\pi^0$ ratio at $\sqrt{s}=7$ TeV.Comment: 17 pages, 5 captioned figures, 2 tables, authors from page 12, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/310

Ks0^0_sKs0^0_s correlations in pp collisions at s=7\sqrt{s}=7 TeV from the LHC ALICE experiment

Identical neutral kaon pair correlations are measured in $\sqrt{s}=7$ TeV pp collisions in the ALICE experiment. One-dimensional K$^0_s$K$^0_s$ correlation functions in terms of the invariant momentum difference of kaon pairs are formed in two multiplicity and two transverse momentum ranges. The femtoscopic parameters for the radius and correlation strength of the kaon source are extracted. The f${\rm i}$t includes quantum statistics and final-state interactions of the a$_0$/f$_0$ resonance. K$^0_s$K$^0_s$ correlations show an increase in radius for increasing multiplicity and a slight decrease in radius for increasing transverse mass, $m_{\rm T}$, as seen in $\pi\pi$ correlations in the pp system and in heavy-ion collisions. Transverse mass scaling is observed between the K$^0_s$K$^0_s$ and $\pi\pi$ radii. Also, the f${\rm i}$rst observation is made of the decay of the f$_2'$(1525) meson into the K$^0_s$K$^0_s$ channel in pp collisions.Comment: 17 pages, 7 captioned figures, 2 tables, authors from page 12, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/310

J/psi Production as a Function of Charged Particle Multiplicity in pp Collisions at sqrt{s} = 7 TeV

The ALICE collaboration reports the measurement of the inclusive J/psi yield as a function of charged particle pseudorapidity density dN_{ch}/deta in pp collisions at sqrt{s} = 7 TeV at the LHC. J/psi particles are detected for p_t > 0, in the rapidity interval |y| < 0.9 via decay into e+e-, and in the interval 2.5 < y < 4.0 via decay into mu+mu- pairs. An approximately linear increase of the J/psi yields normalized to their event average (dN_{J/psi}/dy)/ with (dN_{ch}/deta)/ is observed in both rapidity ranges, where dN_{ch}/deta is measured within |eta| < 1 and p_t > 0. In the highest multiplicity interval with = 24.1, corresponding to four times the minimum bias multiplicity density, an enhancement relative to the minimum bias J/psi yield by a factor of about 5 at 2.5 < y < 4 (8 at |y| < 0.9) is observed.Comment: Submitted to Phys. Lett.

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome

Parkinson’s disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson’s disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson’s disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson’s disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson’s disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson’s disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson’s disease drug development