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

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

peer reviewe

Direct ACE2- Spike RBD Binding Disruption with Small Molecules: A Strategy for COVID-19 Treatment

ACE2 is a key receptor for SARS-CoV-2 cell entry. Binding of SARS-Cov-2 to ACE2 involves the viral Spike protein. The molecular interaction between ACE2 and Spike has been resolved. Interfering with this interaction might be used in treating patients with COVID-19. Inhibition of this interaction can be attained via multiple routes: here we focus on identifying small molecules that would prevent the interaction. Specifically we focus on small molecules and peptides that have the capacity to effectively bind the ACE2: RBD contact domain to prevent and reduce SARS-CoV-2 entry into the cell. We aim to identify molecules that prevent the docking of viral spike protein (mediated by RBD) onto cells expressing ACE2, without inhibiting the activity of ACE2. We utilize the most recent ACE2-RBD crystallography resolved model (PDB-ID:6LZG). Based on animal susceptibility data we narrowed down our interest to the location of amino acid 34 (Histidine) located on ACE2. We performed an in silico screen of a chemical library of compounds with several thousand small molecules including FDA approved compounds. All compounds were tested for binding to the proximal binding site located close to histidine 34 on ACE2. We report a list of four potential small molecules that potentially have the capacity to bind target residue: AY-NH2, a selective PAR4 receptor agonist peptide (CAS number: 352017-71-1), NAD+ (CAS number: 53-84-9), Reproterol, a short-acting β2 adrenoreceptor agonist used in the treatment of asthma (CAS number: 54063-54-6), and Thymopentin, a synthetic immune-stimulant which enhances production of thymic T cells (CAS number: 69558-55-0). The focus is on a High Throughput Screen Assay (HTSA), or in silico screen, delineating small molecules that are selectively binding/masking the crucial interface residue on ACE2 at His34. Consequently, inhibiting SARS-CoV-2 binding to host ACE2 and viral entry is a potent strategy to reduce cellular entry of the virus. We suggest that this anti-viral nature of this interaction is a viable strategy for COVID19 whereas the small molecules including peptides warrant further in vitro screens

Direct ACE2- Spike RBD Binding Disruption with Small Molecules: A Strategy for COVID-19 Treatment

ACE2 is a key receptor for SARS-CoV-2 cell entry. Binding of SARS-Cov-2 to ACE2 involves the viral Spike protein. The molecular interaction between ACE2 and Spike has been resolved. Interfering with this interaction might be used in treating patients with COVID-19. Inhibition of this interaction can be attained via multiple routes: here we focus on identifying small molecules that would prevent the interaction. Specifically we focus on small molecules and peptides that have the capacity to effectively bind the ACE2: RBD contact domain to prevent and reduce SARS-CoV-2 entry into the cell. We aim to identify molecules that prevent the docking of viral spike protein (mediated by RBD) onto cells expressing ACE2, without inhibiting the activity of ACE2. We utilize the most recent ACE2-RBD crystallography resolved model (PDB-ID:6LZG). Based on animal susceptibility data we narrowed down our interest to the location of amino acid 34 (Histidine) located on ACE2. We performed an in silico screen of a chemical library of compounds with several thousand small molecules including FDA approved compounds. All compounds were tested for binding to the proximal binding site located close to histidine 34 on ACE2. We report a list of four potential small molecules that potentially have the capacity to bind target residue: AY-NH2, a selective PAR4 receptor agonist peptide (CAS number: 352017-71-1), NAD+ (CAS number: 53-84-9), Reproterol, a short-acting β2 adrenoreceptor agonist used in the treatment of asthma (CAS number: 54063-54-6), and Thymopentin, a synthetic immune-stimulant which enhances production of thymic T cells (CAS number: 69558-55-0). The focus is on a High Throughput Screen Assay (HTSA), or in silico screen, delineating small molecules that are selectively binding/masking the crucial interface residue on ACE2 at His34. Consequently, inhibiting SARS-CoV-2 binding to host ACE2 and viral entry is a potent strategy to reduce cellular entry of the virus. We suggest that this anti-viral nature of this interaction is a viable strategy for COVID19 whereas the small molecules including peptides warrant further in vitro screens.</jats:p

A Potential Role of Coenzyme Q10 Deficiency in Severe SARS-CoV2 Infection

There is a dramatic need for extensive research into the predictors of severe infection with SARS-CoV2 and therapeutic options for infected people. People who suffer from severe illness and higher mortality display a pattern of having specific co-morbidities (diabetes, obesity, hypertension) and are of higher age. Recent research has described methods of viral entry via receptors (ACE2, TMPRSS2) and the hyper-inflammatory state often associated with severe illness (increase in interleukins, increase in TNF-alpha). These discoveries have led to the research of currently available and developing therapies, that are helpful to patients. Deficiencies of specific vitamins and other endogenous molecules of the body should be examined to understand if a pattern exists among the people most severely affected. Coenzyme Q10 (CoQ10) is a fat-soluble substance ubiquitously expressed throughout the body that is important for the generation of ATP and mediation of inflammatory disease. CoQ10 faces a decline with increasing age, genetic predispositions, and ingestion of exogenous compounds that could reduce the level of CoQ10. Deficiencies and subsequent supplementation with CoQ10 recently has displayed encouraging results for the improvement of a wide variety of diseases. This manuscript is significant as it points to a potential relationship of CoQ10 and the population suffering from severe illness of COVID-19, and further encourages the need for research into measuring the levels of CoQ10 and vitamins to understand if levels predict severe illness and mortality. This could offer new avenues into research in combating this pandemic and potentially future therapeutic options.</jats:p

Role of FYVE and Coiled-Coil Domain Autophagy Adaptor 1 in severity of COVID-19 infection

AbstractCoronaviruses remodel intracellular membranes to form specialized viral replication compartments, such as double-membrane vesicles where viral RNA genome replication takes place. Understanding the factors affecting host response is instrumental to design of therapeutics to prevent or ameliorate the course of infection.As part of explorative tests in hospitalized patients with confirmed COVID-19 infection participating in ODYSSEY trial, we obtained samples for whole genome sequencing analysis as well as for viral genome sequencing. Based on our data, we confirm one of the strongest severity susceptibility locus thus far reported in association with severe COVID-19: 3p21.31 locus with lead variant rs73064425. We further examine the associated region. Interestingly based on LD analysis we report 3 coding mutations within one gene in the region of FYVE and Coiled-Coil Domain Autophagy Adaptor 1 (FYCO1). We specifically focus on the role of FYCO1 modifiers and gain-of-function variants. We report the associations between the region and clinical characteristics in this severe set of COVID-19 patients.We next analyzed expression profiles of FYCO1 across all 466 compounds tested. We selected only those results that showed a significant reduction of expression of FYCO1. The most significant candidate was indomethacin – an anti-inflammatory that could potentially downregulate FYCO1. We hypothesize that via its direct effects on efficiency of viral egress, it may serve as a potent therapeutic decreasing the replication and infectivity of the virus. Clinical studies will be needed to examine the therapeutic utility of indomethacin and other compounds downregulating FYCO1 in COVID-19 infection and other strains of betacoronaviruses.</jats:p