Improving Genetic Prediction by Leveraging Genetic Correlations Among Human Diseases and Traits

Genomic prediction has the potential to contribute to precision medicine. However, to date, the utility of such predictors is limited due to low accuracy for most traits. Here theory and simulation study are used to demonstrate that widespread pleiotropy among phenotypes can be utilised to improve genomic risk prediction. We show how a genetic predictor can be created as a weighted index that combines published genome-wide association study (GWAS) summary statistics across many different traits. We apply this framework to predict risk of schizophrenia and bipolar disorder in the Psychiatric Genomics consortium data, finding substantial heterogeneity in prediction accuracy increases across cohorts. For six additional phenotypes in the UK Biobank data, we find increases in prediction accuracy ranging from 0.7 for height to 47 for type 2 diabetes, when using a multi-trait predictor that combines published summary statistics from multiple traits, as compared to a predictor based only on one trait. © 2018 The Author(s)

Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder

This paper is dedicated to the memory of Psychiatric Genomics Consortium (PGC) founding member and Bipolar disorder working group co-chair Pamela Sklar. We thank the participants who donated their time, experiences and DNA to this research, and to the clinical and scientific teams that worked with them. We are deeply indebted to the investigators who comprise the PGC. The views expressed are those of the authors and not necessarily those of any funding or regulatory body. Analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org ) hosted by SURFsara, and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu).Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P<1x10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (GWS, p < 5x10-8) in the discovery GWAS were not GWS in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis 30 loci were GWS including 20 novel loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene-sets including regulation of insulin secretion and endocannabinoid signaling. BDI is strongly genetically correlated with schizophrenia, driven by psychosis, whereas BDII is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for BD.This work was funded in part by the Brain and Behavior Research Foundation, Stanley Medical Research Institute, University of Michigan, Pritzker Neuropsychiatric Disorders Research Fund L.L.C., Marriot Foundation and the Mayo Clinic Center for Individualized Medicine, the NIMH Intramural Research Program; Canadian Institutes of Health Research; the UK Maudsley NHS Foundation Trust, NIHR, NRS, MRC, Wellcome Trust; European Research Council; German Ministry for Education and Research, German Research Foundation IZKF of Münster, Deutsche Forschungsgemeinschaft, ImmunoSensation, the Dr. Lisa-Oehler Foundation, University of Bonn; the Swiss National Science Foundation; French Foundation FondaMental and ANR; Spanish Ministerio de Economía, CIBERSAM, Industria y Competitividad, European Regional Development Fund (ERDF), Generalitat de Catalunya, EU Horizon 2020 Research and Innovation Programme; BBMRI-NL; South-East Norway Regional Health Authority and Mrs. Throne-Holst; Swedish Research Council, Stockholm County Council, Söderström Foundation; Lundbeck Foundation, Aarhus University; Australia NHMRC, NSW Ministry of Health, Janette M O'Neil and Betty C Lynch

Search for heavy resonances decaying into a Z or W boson and a Higgs boson in final states with leptons and b-jets in 139 fb−1 of pp collisions at s√ = 13 TeV with the ATLAS detector

This article presents a search for new resonances decaying into a Z or W boson and a 125 GeV Higgs boson h, and it targets the νν¯¯¯bb¯¯, ℓ+ℓ−bb¯¯, or ℓ±νbb¯¯ final states, where ℓ = e or μ, in proton-proton collisions at s√ = 13 TeV. The data used correspond to a total integrated luminosity of 139 fb−1 collected by the ATLAS detector during Run 2 of the LHC at CERN. The search is conducted by examining the reconstructed invariant or transverse mass distributions of Zh or Wh candidates for evidence of a localised excess in the mass range from 220 GeV to 5 TeV. No significant excess is observed and 95% confidence-level upper limits between 1.3 pb and 0.3 fb are placed on the production cross section times branching fraction of neutral and charged spin-1 resonances and CP-odd scalar bosons. These limits are converted into constraints on the parameter space of the Heavy Vector Triplet model and the two-Higgs-doublet model

Search for light long-lived neutral particles that decay to collimated pairs of leptons or light hadrons in pp collisions at s√ = 13 TeV with the ATLAS detector

A search for light long-lived neutral particles with masses in the O(MeV–GeV) range is presented. The analysis targets the production of long-lived dark photons in the decay of a Higgs boson produced via gluon–gluon fusion or in association with a W boson. Events that contain displaced collimated Standard Model fermions reconstructed in the calorimeter or muon spectrometer are selected in 139 fb−1 of s√ = 13 TeV pp collision data collected by the ATLAS detector at the LHC. Background estimates for contributions from Standard Model processes and instrumental effects are extracted from data. The observed event yields are consistent with the expected background. Exclusion limits are reported on the production cross-section times branching fraction as a function of the mean proper decay length cτ of the dark photon, or as a function of the dark-photon mass and kinetic mixing parameter that quantifies the coupling between the Standard Model and potential hidden (dark) sectors. A Higgs boson branching fraction above 1% is excluded at 95% CL for a Higgs boson decaying into two dark photons for dark-photon mean proper decay lengths between 10 mm and 250 mm and dark photons with masses between 0.4 GeV and 2 GeV

Inclusive-photon production and its dependence on photon isolation in pp collisions at s√ = 13 TeV using 139 fb−1 of ATLAS data

Measurements of differential cross sections are presented for inclusive isolated-photon production in pp collisions at a centre-of-mass energy of 13 TeV provided by the LHC and using 139 fb−1 of data recorded by the ATLAS experiment. The cross sections are measured as functions of the photon transverse energy in different regions of photon pseudorapidity. The photons are required to be isolated by means of a fixed-cone method with two different cone radii. The dependence of the inclusive-photon production on the photon isolation is investigated by measuring the fiducial cross sections as functions of the isolation-cone radius and the ratios of the differential cross sections with different radii in different regions of photon pseudorapidity. The results presented in this paper constitute an improvement with respect to those published by ATLAS earlier: the measurements are provided for different isolation radii and with a more granular segmentation in photon pseudorapidity that can be exploited in improving the determination of the proton parton distribution functions. These improvements provide a more in-depth test of the theoretical predictions. Next-to-leading-order QCD predictions from JETPHOX and SHERPA and next-to-next-to-leading-order QCD predictions from NNLOJET are compared to the measurements, using several parameterisations of the proton parton distribution functions. The measured cross sections are well described by the fixed-order QCD predictions within the experimental and theoretical uncertainties in most of the investigated phase-space region

Measurements of Zγ+jets differential cross sections in pp collisions at s√ = 13 TeV with the ATLAS detector

Differential cross-section measurements of Zγ production in association with hadronic jets are presented, using the full 139 fb−1 dataset of s√ = 13 TeV proton–proton collisions collected by the ATLAS detector during Run 2 of the LHC. Distributions are measured using events in which the Z boson decays leptonically and the photon is usually radiated from an initial-state quark. Measurements are made in both one and two observables, including those sensitive to the hard scattering in the event and others which probe additional soft and collinear radiation. Different Standard Model predictions, from both parton-shower Monte Carlo simulation and fixed-order QCD calculations, are compared with the measurements. In general, good agreement is observed between data and predictions from MATRIX and MiNNLOPS, as well as next-to-leading-order predictions from MADGRAPH5_AMC@NLO and SHERPA

Measurement of electroweak Z(νν) γjj production and limits on anomalous quartic gauge couplings in pp collisions at s√ = 13 TeV with the ATLAS detector

The electroweak production of Z(νν¯¯¯)γ in association with two jets is studied in a regime with a photon of high transverse momentum above 150 GeV using proton–proton collisions at a centre-of-mass energy of 13 TeV at the Large Hadron Collider. The analysis uses a data sample with an integrated luminosity of 139 fb−1 collected by the ATLAS detector during the 2015–2018 LHC data-taking period. This process is an important probe of the electroweak symmetry breaking mechanism in the Standard Model and is sensitive to quartic gauge boson couplings via vector-boson scattering. The fiducial Z(νν¯¯¯)γjj cross section for electroweak production is measured to be 0.77+0.34−0.30 fb and is consistent with the Standard Model prediction. Evidence of electroweak Z(νν¯¯¯)γjj production is found with an observed significance of 3.2σ for the background-only hypothesis, compared with an expected significance of 3.7σ. The combination of this result with the previously published ATLAS observation of electroweak Z(νν¯¯¯)γjj production yields an observed (expected) signal significance of 6.3σ (6.6σ). Limits on anomalous quartic gauge boson couplings are obtained in the framework of effective field theory with dimension-8 operators

Search for a new scalar resonance in flavour-changing neutral-current top-quark decays t → qX (q = u, c), with X → bb¯¯, in proton-proton collisions at s√ = 13 TeV with the ATLAS detector

A search for flavour-changing neutral-current decays of a top quark into an up-type quark (either up or charm) and a light scalar particle X decaying into a bottom anti-bottom quark pair is presented. The search focuses on top-quark pair production where one top quark decays to qX, with X → bb¯¯, and the other top quark decays according to the Standard Model, with the W boson decaying leptonically. The final state is thus characterised by an isolated electron or muon and at least four jets. Events are categorised according to the multiplicity of jets and jets tagged as originating from b-quarks, and a neural network is used to discriminate between signal and background processes. The data analysed correspond to 139 fb−1 of proton–proton collisions at a centre-of-mass energy of 13 TeV, recorded with the ATLAS detector at the LHC. The 95% confidence-level upper limits between 0.019% and 0.062% are derived for the branching fraction B(t → uX) and between 0.018% and 0.078% for the branching fraction B(t → cX), for masses of the scalar particle X between 20 and 160 GeV

Search for the Zγ decay mode of new high-mass resonances in pp collisions at √s = 13 TeV with the ATLAS detector

This letter presents a search for narrow, high-mass resonances in the Zγ final state with the Z boson decaying into a pair of electrons or muons. The √s = 13 TeV pp collision data were recorded by the ATLAS detector at the CERN Large Hadron Collider and have an integrated luminosity of 140 fb−1. The data are found to be in agreement with the Standard Model background expectation. Upper limits are set on the resonance production cross section times the decay branching ratio into Zγ. For spin-0 resonances produced via gluon–gluon fusion, the observed limits at 95% confidence level vary between 65.5 fb and 0.6 fb, while for spin-2 resonances produced via gluon–gluon fusion (or quark–antiquark initial states) limits vary between 77.4 (76.1) fb and 0.6 (0.5) fb, for the mass range from 220 GeV to 3400 GeV

Search for boosted diphoton resonances in the 10 to 70 GeV mass range using 138 fb−1 of 13 TeV pp collisions with the ATLAS detector

A search for diphoton resonances in the mass range between 10 and 70 GeV with the ATLAS experiment at the Large Hadron Collider (LHC) is presented. The analysis is based on pp collision data corresponding to an integrated luminosity of 138 fb−1 at a centre-of-mass energy of 13 TeV recorded from 2015 to 2018. Previous searches for diphoton resonances at the LHC have explored masses down to 65 GeV, finding no evidence of new particles. This search exploits the particular kinematics of events with pairs of closely spaced photons reconstructed in the detector, allowing examination of invariant masses down to 10 GeV. The presented strategy covers a region previously unexplored at hadron colliders because of the experimental challenges of recording low-energy photons and estimating the backgrounds. No significant excess is observed and the reported limits provide the strongest bound on promptly decaying axion-like particles coupling to gluons and photons for masses between 10 and 70 GeV