Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Search for a right-handed W boson and a heavy neutrino in proton-proton collisions at s \sqrt{s} = 13 TeV

A search is presented for a right-handed W boson (WR) and a heavy neutrino (N), in a final state consisting of two same-flavor leptons (ee or μμ) and two quarks. The search is performed with the CMS experiment at the CERN LHC using a data sample of proton-proton collisions at a center-of-mass energy of 13 TeV corresponding to an integrated luminosity of 138 fb−1. The search covers two regions of phase space, one where the decay products of the heavy neutrino are merged into a single large-area jet, and one where the decay products are well separated. The expected signal is characterized by an excess in the invariant mass distribution of the final-state objects. No significant excess over the standard model background expectations is observed. The observations are interpreted as upper limits on the product of WR production cross sections and branching fractions assuming that couplings are identical to those of the standard model W boson. For N masses mN equal to half the WR mass mWR (mN = 0.2 TeV), mWR is excluded at 95% confidence level up to 4.7 (4.8) and 5.0 (5.4) TeV for the electron and muon channels, respectively. This analysis provides the most stringent limits on the WR mass to date

Search for flavor-changing neutral current interactions of the top quark and the Higgs boson decaying to a bottom quark-antiquark pair at s√ = 13 TeV

A search for flavor-changing neutral current interactions of the top quark (t) and the Higgs boson (H) is presented. The search is based on a data sample corresponding to an integrated luminosity of 137 fb−1 recorded by the CMS experiment at the LHC in proton-proton collisions at s√ = 13 TeV. Events containing exactly one lepton (muon or electron) and at least three jets, among which at least two are identified as originating from the hadronization of a bottom quark, are analyzed. A set of deep neural networks is used for kinematic event reconstruction, while boosted decision trees distinguish the signal from the background events. No significant excess over the background predictions is observed, and upper limits on the signal production cross sections are extracted. These limits are interpreted in terms of top quark decay branching fractions (B ) to the Higgs boson and an up (u) or a charm quark (c). Assuming one nonvanishing extra coupling at a time, the observed (expected) upper limits at 95% confidence level are B (t → Hu) < 0.079 (0.11)% and B (t → Hc) < 0.094 (0.086)%

Measurement of the production cross section for Z + b jets in proton-proton collisions at s\sqrt{s} = 13 TeV

The measurement of the cross section for the production of a Z boson, decaying to dielectrons or dimuons, in association with at least one bottom quark jet is performed with proton-proton collision data at √s=13  TeV. The data sample corresponds to an integrated luminosity of 137  fb$^{-1}$, collected by the CMS experiment at the LHC during 2016–2018. The integrated cross sections for Z+≥1 b jet and Z+≥2 b jets are reported for the electron, muon, and combined channels. The fiducial cross sections in the combined channel are 6.52±0.04(stat)±0.40(syst)±0.14(theo)  pb for Z+≥1 b jet and 0.65±0.03(stat)±0.07(syst)±0.02(theo)  pb for Z+≥2 b jets. The differential cross section distributions are measured as functions of various kinematic observables that are useful for precision tests of perturbative quantum chromodynamics predictions. The ratios of integrated and differential cross sections for Z+≥2b  jets and Z+≥1 b jet processes are also determined. The value of the integrated cross section ratio measured in the combined channel is 0.100±0.005(stat)±0.007(syst)±0.003(theo). All measurements are compared with predictions from various event generators

Search for heavy resonances decaying to ZZ or ZW and axion-like particles mediating nonresonant ZZ or ZH production at S\sqrt{S} = 13 TeV

A search has been performed for heavy resonances decaying to ZZ or ZW and for axion-like particles (ALPs) mediating nonresonant ZZ or ZH production, in final states with two charged leptons (ℓ = e, μ) produced by the decay of a Z boson, and two quarks produced by the decay of a Z, W, or Higgs boson H. The analysis is sensitive to resonances with masses in the range 450 to 2000 GeV. Two categories are defined corresponding to the merged or resolved reconstruction of the hadronically decaying boson. The search is based on data collected during 2016–2018 by the CMS experiment at the LHC in proton-proton collisions at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 138 fb−1. No significant excess is observed in the data above the standard model background expectation. Upper limits on the production cross section of heavy, narrow spin-2 and spin-1 resonances are derived as functions of the resonance mass, and exclusion limits on the production of bulk graviton particles and W′ bosons are calculated in the framework of the warped extra dimensions and heavy vector triplet models, respectively. In addition, upper limits on the ALP-mediated diboson production cross section and ALP couplings to standard model particles are obtained in the framework of linear and chiral effective field theories. These are the first limits on nonresonant ALP-mediated ZZ and ZH production obtained by the LHC experiments

Inclusive nonresonant multilepton probes of new phenomena at s\sqrt{s}= 13 TeV

An inclusive search for nonresonant signatures of beyond the standard model (SM) phenomena in events with three or more charged leptons, including hadronically decaying τ leptons, is presented. The analysis is based on a data sample corresponding to an integrated luminosity of 138 fb$^{-1}$ of proton-proton collisions at $\sqrt{s}$= 13 TeV collected by the CMS experiment at the LHC in 2016–2018. Events are categorized based on the lepton and b-tagged jet multiplicities and various kinematic variables. Three scenarios of physics beyond the SM are probed, and signal-specific boosted decision trees are used for enhancing sensitivity. No significant deviations from the background expectations are observed. Lower limits are set at 95% confidence level on the mass of type-III seesaw heavy fermions in the range 845–1065 GeV for various decay branching fraction combinations to SM leptons. Doublet and singlet vectorlike τ lepton extensions of the SM are excluded for masses below 1045 GeV and in the mass range 125–150 GeV, respectively. Scalar leptoquarks decaying exclusively to a top quark and a lepton are excluded below 1.12–1.42 TeV, depending on the lepton flavor. For the type-III seesaw as well as the vectorlike doublet model, these constraints are the most stringent to date. For the vectorlike singlet model, these are the first constraints from the LHC experiments. Detailed results are also presented to facilitate alternative theoretical interpretations