Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes

Carriers of single pathogenic variants of the CFTR (cystic fibrosis transmembrane conductance regulator) gene have a higher risk of severe COVID-19 and 14-day death. The machine learning post-Mendelian model pinpointed CFTR as a bidirectional modulator of COVID-19 outcomes. Here, we demonstrate that the rare complex allele [G576V;R668C] is associated with a milder disease via a gain-of-function mechanism. Conversely, CFTR ultra-rare alleles with reduced function are associated with disease severity either alone (dominant disorder) or with another hypomorphic allele in the second chromosome (recessive disorder) with a global residual CFTR activity between 50 to 91%. Furthermore, we characterized novel CFTR complex alleles, including [A238V;F508del], [R74W;D1270N;V201M], [I1027T;F508del], [I506V;D1168G], and simple alleles, including R347C, F1052V, Y625N, I328V, K68E, A309D, A252T, G542*, V562I, R1066H, I506V, I807M, which lead to a reduced CFTR function and thus, to more severe COVID-19. In conclusion, CFTR genetic analysis is an important tool in identifying patients at risk of severe COVID-19

An explainable model of host genetic interactions linked to COVID-19 severity

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as "Respiratory or thoracic disease", supporting their link with COVID-19 severity outcome.A multifaceted computational strategy identifies 16 genetic variants contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing dataset of a cohort of Italian patients

Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19

Thrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, frequently triggered by infections. Carriers are reported to be asymptomatic. Exome analysis of about 3000 SARS-CoV-2 infected subjects of different severities, belonging to the GEN-COVID cohort, revealed the specific role of vWF cleaving enzyme ADAMTS13 (A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13). We report here that ultra-rare variants in a heterozygous state lead to a rare form of COVID-19 characterized by hyper-inflammation signs, which segregates in families as an autosomal dominant disorder conditioned by SARS-CoV-2 infection, sex, and age. This has clinical relevance due to the availability of drugs such as Caplacizumab, which inhibits vWF-platelet interaction, and Crizanlizumab, which, by inhibiting P-selectin binding to its ligands, prevents leukocyte recruitment and platelet aggregation at the site of vascular damage

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

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

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Thermal Behavior of Unusual Local-Scale Features on Vesta

On Vesta, the thermal behavior of areas of unusual albedo seen at the local scale can be related to physical properties that can provide information about the origin of those materials. Dawn's Visible and Infrared Mapping Spectrometer (VIR) hyperspectral cubes are used to retrieve surface temperatures and emissivities, with high accuracy as long as temperatures are greater than ~180 K. Data acquired in the Survey phase (23 July through 29 August 2011) show several unusual surface features: 1) high-albedo (bright) and low-albedo (dark) material deposits, 2) spectrally distinct ejecta and pitted materials, 3) regions suggesting finer-grained materials. Some of the unusual dark and bright features were re-observed by VIR in the subsequent High-Altitude Mapping Orbit (HAMO) and Low-Altitude Mapping Orbit (LAMO) phases at increased pixel resolution. In particular, bright and dark surface materials on Vesta, and pitted materials, are currently being investigated by the Dawn team. In this work we present temperature maps and emissivities of several local-scale features that were observed by Dawn under different illumination conditions and different local solar times. To calculate surface temperatures, we applied a Bayesian approach to nonlinear inversion based on the Kirchhoff law and the Planck function, and whose results were compared with those provided by the application of alternative methods. Data from the IR channel of VIR show that bright regions generally correspond to regions with lower thermal emission, i.e. lower temperature, while dark regions correspond to areas with higher thermal emission, i.e. higher temperature. This behavior confirms that many of the dark appearances in the VIS mainly reflect albedo variations, and not, for example, shadowing. During maximum daily insolation, dark features in the equatorial region may rise to temperatures greater than 270 K, while brightest features stop at roughly 258 K for similar local solar times. However, pitted materials, showing relatively low reflectance, have significantly lower temperatures, as a result of differences in composition and/or structure (e.g, average grain size of the surface regolith, porosity, etc.). To complement this work, we provide preliminary values of thermal inertia for some bright and dark features

Postpartum depression screening in mothers and fathers at well-child visits: a feasibility study within the NASCITA cohort

Objective To assess the feasibility of the family paediatrician’s (FP) role in identifying the signs of postpartum depression in parents in time to guarantee child well-being.Design, setting and participants Data for this observational prospective study were collected within the NASCITA (NAscere e creSCere in ITAlia) cohort. During the first visit, paediatricians collected sociodemographic data regarding the parents and information about their health status, the pregnancy and the delivery. Whooley questions were administered during the first and second visits (scheduled 60–90 days after childbirth). Moreover, on the third visit (5–7 months after childbirth) the FP was asked to answer ‘yes’ or ‘no’ to a question on the parental postpartum depression, based on his knowledge and on the acquired information.Results In 2203 couples who completed the assessment, 529 mothers (19.9%), 141 fathers (6.3%) and 110 (5%) couples reported any depressive symptomatology. Of these, 141 mothers (5.3% of the total sample) and 18 fathers (0.8% of the total sample) were classified as ‘likely depressed’. An association was found between maternal postnatal depressive symptoms and having a diagnosed psychiatric disorder during pregnancy (OR 9.49, 95% CI: 3.20 to 28.17), not exclusively breastfeeding at hospital discharge (OR 1.76, 95% CI: 1.19 to 2.61) and the presence of child sleeping disorders at 3 (OR 2.46, 95% CI: 1.41 to 4.28) and 6 months (OR 2.18, 95% CI: 1.37 to 3.47). Another significant predictor of postpartum depression was being primiparous (OR 1.99, 95% CI: 1.31 to 3.02). Concerning the fathers, a significant association was reported only between likely depressed fathers and child sleeping disorders at 3 months (OR 7.64, 95% CI: 2.92 to 19.97). Moreover, having a likely depressed partner was strongly associated with depressive symptoms in fathers (OR 85.53, 95% CI 26.83 to 272.69).Conclusions The findings of this study support the feasibility of an active screening programme for parental postnatal depression during well-child visits as an integral part of postpartum care.Trial registration number NCT03894566; Pre-results

Author response: Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study

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