GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment

Impact of infection on proteome-wide glycosylation revealed by distinct signatures for bacterial and viral pathogens

Mechanisms of infection and pathogenesis have predominantly been studied based on differential gene or protein expression. Less is known about posttranslational modifications, which are essential for protein functional diversity. We applied an innovative glycoproteomics method to study the systemic proteome-wide glycosylation in response to infection. The protein site-specific glycosylation was characterized in plasma derived from well-defined controls and patients. We found 3862 unique features, of which we identified 463 distinct intact glycopeptides, that could be mapped to more than 30 different proteins. Statistical analyses were used to derive a glycopeptide signature that enabled significant differentiation between patients with a bacterial or viral infection. Furthermore, supported by a machine learning algorithm, we demonstrated the ability to identify the causative pathogens based on the distinctive host blood plasma glycopeptide signatures. These results illustrate that glycoproteomics holds enormous potential as an innovative approach to improve the interpretation of relevant biological changes in response to infection

Relationship between molecular pathogen detection and clinical disease in febrile children across Europe: a multicentre, prospective observational study

BackgroundThe PERFORM study aimed to understand causes of febrile childhood illness by comparing molecular pathogen detection with current clinical practice.MethodsFebrile children and controls were recruited on presentation to hospital in 9 European countries 2016-2020. Each child was assigned a standardized diagnostic category based on retrospective review of local clinical and microbiological data. Subsequently, centralised molecular tests (CMTs) for 19 respiratory and 27 blood pathogens were performed.FindingsOf 4611 febrile children, 643 (14%) were classified as definite bacterial infection (DB), 491 (11%) as definite viral infection (DV), and 3477 (75%) had uncertain aetiology. 1061 controls without infection were recruited. CMTs detected blood bacteria more frequently in DB than DV cases for N. meningitidis (OR: 3.37, 95% CI: 1.92-5.99), S. pneumoniae (OR: 3.89, 95% CI: 2.07-7.59), Group A streptococcus (OR 2.73, 95% CI 1.13-6.09) and E. coli (OR 2.7, 95% CI 1.02-6.71). Respiratory viruses were more common in febrile children than controls, but only influenza A (OR 0.24, 95% CI 0.11-0.46), influenza B (OR 0.12, 95% CI 0.02-0.37) and RSV (OR 0.16, 95% CI: 0.06-0.36) were less common in DB than DV cases. Of 16 blood viruses, enterovirus (OR 0.43, 95% CI 0.23-0.72) and EBV (OR 0.71, 95% CI 0.56-0.90) were detected less often in DB than DV cases. Combined local diagnostics and CMTs respectively detected blood viruses and respiratory viruses in 360 (56%) and 161 (25%) of DB cases, and virus detection ruled-out bacterial infection poorly, with predictive values of 0.64 and 0.68 respectively.InterpretationMost febrile children cannot be conclusively defined as having bacterial or viral infection when molecular tests supplement conventional approaches. Viruses are detected in most patients with bacterial infections, and the clinical value of individual pathogen detection in determining treatment is low. New approaches are needed to help determine which febrile children require antibiotics.FundingEU Horizon 2020 grant 668303

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

A critical assessment of the applicability of the energy-limited approximation for estimating exoplanetary mass-loss rates

Context: The energy-limited (EL) atmospheric escape approach is used to estimate mass-loss rates for a broad range of planets that host hydrogen-dominated atmospheres as well as for performing atmospheric evolution calculations. Aims: We aim to study the applicability range of the EL approximation. Methods: We revise the EL formalism and its assumptions. We also compare its results with those of hydrodynamic simulations, employing a grid covering planets with masses, radii, and equilibrium temperatures ranging between 1 $M_{\oplus}$ and 39 $M_{\oplus}$, 1 $R_{\oplus}$ and 10 $R_{\oplus}$, and 300 and 2000 K, respectively. Results: Within the grid boundaries, we find that the EL approximation gives a correct order of magnitude estimate for mass-loss rates for about 76% of the planets, but there can be departures from hydrodynamic simulations by up to three orders of magnitude in individual cases. Furthermore, we find that planets for which the mass-loss rates are correctly estimated by the EL approximation to within one order of magnitude have intermediate gravitational potentials as well as low-to-intermediate equilibrium temperatures and irradiation fluxes of extreme ultraviolet and X-ray radiation. However, for planets with low or high gravitational potentials, or high equilibrium temperatures and irradiation fluxes, the approximation fails in most cases. Conclusions: The EL approximation should not be used for planetary evolution calculations that require computing mass-loss rates for planets that cover a broad parameter space. In this case, it is very likely that the EL approximation would at times return mass-loss rates of up to several orders of magnitude above or below those predicted by hydrodynamic simulations. For planetary atmospheric evolution calculations, interpolation routines or approximations based on grids of hydrodynamic models should be used instead.Comment: 12 pages, 7 figures, Published in A&A in June 2021; Revised on 9.11.2021 to correct typo in equation

L 363-38 b: A planet newly discovered with ESPRESSO orbiting a nearby M dwarf star

Context. Planets around stars in the solar neighbourhood will be prime targets for characterisation with upcoming large space- and ground-based facilities. Since large-scale exoplanet searches will not be feasible with such telescopes, it is crucial to use currently available data and instruments to find possible target planets before next-generation facilities come online. Aims. We aim to detect new extrasolar planets around stars in the solar neighbourhood via blind radial velocity (RV) searching with ESPRESSO. Our target sample consists of nearby stars (d < 11 pc) with few (<10) or no previous RV measurements. Methods. We used 31 radial velocity measurements obtained with ESPRESSO at the VLT between December 2020 and February 2022 of the nearby M dwarf star (M★ = 0.21 M⊙, d = 10.23 pc) L 363-38 to derive the orbital parameters of the newly discovered planet. In addition, we used TESS photometry and archival VLT/NaCo high-contrast imaging data to put further constraints on the orbit inclination and the possible planetary system architecture around L 363-38. Results. We present the detection of a new extrasolar planet orbiting the nearby M dwarf star L 363-38. L 363-38 b is a planet with a minimum mass of mp sin(i) = 4.67 ± 0.43 M⊕ orbiting its star with a period of P = 8.781 ± 0.007 days, corresponding to a semi-major axis of a = 0.048 ± 0.006 AU, which is smaller than the inner edge of the habitable zone. We further estimate a minimum radius of rp sin(i) ≈ 1.55–2.75 R⊕ and an equilibrium temperature of Teq ≈ 330 K. Conclusions. With this study, we further demonstrate the potential of the state-of-the-art spectrograph ESPRESSO in detecting and investigating planetary systems around nearby M dwarf stars, which were inaccessible to previous instruments such HARPS