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1.
Circulation ; 2022 Apr 07.
Article in English | MEDLINE | ID: covidwho-1779500

ABSTRACT

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, enters human cells using the angiotensin-converting enzyme 2 (ACE2) protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart, respiratory and gastrointestinal tracts, playing important regulatory roles in the cardiovascular and other biologic systems. However, the genetic basis of the ACE2 protein levels is not well understood. Methods: We conduct so far the largest genome-wide association meta-analysis of plasma ACE2 levels in over 28,000 individuals of the SCALLOP Consortium. We summarize the cross-sectional epidemiologic correlates of circulating ACE2. Using the summary-statistics-based high-definition likelihood method, we estimate relevant genetic correlations with cardiometabolic phenotypes, COVID-19, and other human complex traits and diseases. We perform causal inference of soluble ACE2 on vascular disease outcomes and COVID-19 disease severity using Mendelian randomization. We also perform in silico functional analysis by integrating with other types of omics data. Results: We identified ten loci, including eight novel, capturing 30% of the protein's heritability. We detected that plasma ACE2 was genetically correlated with vascular diseases, severe COVID-19, and a wide range of human complex diseases and medications. An X-chromosome cis-pQTL-based Mendelian randomization analysis suggested a causal effect of elevated ACE2 levels on COVID-19 severity (odds ratio (OR), 1.63; 95% CI, 1.10 to 2.42; P = 0.01), hospitalization (OR, 1.52; 95% CI, 1.05 to 2.21; P = 0.03), and infection (OR, 1.60; 95% CI, 1.08 to 2.37; P = 0.02). Tissue- and cell-type-specific transcriptomic and epigenomic analysis revealed that the ACE2 regulatory variants were enriched for DNA methylation sites in blood immune cells. Conclusions: Human plasma ACE2 shares a genetic basis with cardiovascular disease, COVID-19, and other related diseases. The genetic architecture of the ACE2 protein is mapped, providing a useful resource for further biological and clinical studies on this coronavirus receptor.

2.
Science ; 374(6569): eabj1541, 2021 Nov 12.
Article in English | MEDLINE | ID: covidwho-1526448

ABSTRACT

Characterization of the genetic regulation of proteins is essential for understanding disease etiology and developing therapies. We identified 10,674 genetic associations for 3892 plasma proteins to create a cis-anchored gene-protein-disease map of 1859 connections that highlights strong cross-disease biological convergence. This proteo-genomic map provides a framework to connect etiologically related diseases, to provide biological context for new or emerging disorders, and to integrate different biological domains to establish mechanisms for known gene-disease links. Our results identify proteo-genomic connections within and between diseases and establish the value of cis-protein variants for annotation of likely causal disease genes at loci identified in genome-wide association studies, thereby addressing a major barrier to experimental validation and clinical translation of genetic discoveries.


Subject(s)
Blood Proteins/genetics , Disease/genetics , Genome, Human , Genomics , Proteins/genetics , Proteome , Aging , Alternative Splicing , Blood Proteins/metabolism , COVID-19/genetics , Connective Tissue Diseases/genetics , Disease/etiology , Drug Development , Female , Gallstones/genetics , Genetic Association Studies , Genetic Variation , Genome-Wide Association Study , Humans , Internet , Male , Phenotype , Proteins/metabolism , Quantitative Trait Loci , Sex Characteristics
4.
Nat Med ; 27(4): 668-676, 2021 04.
Article in English | MEDLINE | ID: covidwho-1174686

ABSTRACT

Drug repurposing provides a rapid approach to meet the urgent need for therapeutics to address COVID-19. To identify therapeutic targets relevant to COVID-19, we conducted Mendelian randomization analyses, deriving genetic instruments based on transcriptomic and proteomic data for 1,263 actionable proteins that are targeted by approved drugs or in clinical phase of drug development. Using summary statistics from the Host Genetics Initiative and the Million Veteran Program, we studied 7,554 patients hospitalized with COVID-19 and >1 million controls. We found significant Mendelian randomization results for three proteins (ACE2, P = 1.6 × 10-6; IFNAR2, P = 9.8 × 10-11 and IL-10RB, P = 2.3 × 10-14) using cis-expression quantitative trait loci genetic instruments that also had strong evidence for colocalization with COVID-19 hospitalization. To disentangle the shared expression quantitative trait loci signal for IL10RB and IFNAR2, we conducted phenome-wide association scans and pathway enrichment analysis, which suggested that IFNAR2 is more likely to play a role in COVID-19 hospitalization. Our findings prioritize trials of drugs targeting IFNAR2 and ACE2 for early management of COVID-19.


Subject(s)
COVID-19/genetics , Drug Repositioning , Mendelian Randomization Analysis/methods , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/physiology , COVID-19/drug therapy , Genome-Wide Association Study , Humans , Interleukin-10 Receptor beta Subunit/genetics , Interleukin-10 Receptor beta Subunit/physiology , Quantitative Trait Loci , Receptor, Interferon alpha-beta/genetics , Receptor, Interferon alpha-beta/physiology
5.
Nat Med ; 27(4): 659-667, 2021 04.
Article in English | MEDLINE | ID: covidwho-1104522

ABSTRACT

To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54, P = 7 × 10-8), hospitalization (OR = 0.61, P = 8 × 10-8) and susceptibility (OR = 0.78, P = 8 × 10-6). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case-control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development.


Subject(s)
2',5'-Oligoadenylate Synthetase/physiology , COVID-19/etiology , Genetic Predisposition to Disease , SARS-CoV-2 , 2',5'-Oligoadenylate Synthetase/genetics , Aged , Aged, 80 and over , Animals , COVID-19/genetics , Case-Control Studies , Female , Humans , Interleukin-10 Receptor beta Subunit/genetics , Male , Mendelian Randomization Analysis , Middle Aged , Neanderthals , Protein Isoforms/physiology , Quantitative Trait Loci , Severity of Illness Index
6.
Nat Commun ; 11(1): 6397, 2020 12 16.
Article in English | MEDLINE | ID: covidwho-1023894

ABSTRACT

Understanding the genetic architecture of host proteins interacting with SARS-CoV-2 or mediating the maladaptive host response to COVID-19 can help to identify new or repurpose existing drugs targeting those proteins. We present a genetic discovery study of 179 such host proteins among 10,708 individuals using an aptamer-based technique. We identify 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links and evidence that putative viral interaction partners such as MARK3 affect immune response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and detailed interrogation of results is facilitated through an interactive webserver ( https://omicscience.org/apps/covidpgwas/ ).


Subject(s)
COVID-19/genetics , COVID-19/virology , Host-Pathogen Interactions/genetics , Proteins/genetics , SARS-CoV-2/physiology , ABO Blood-Group System/metabolism , Aptamers, Peptide/blood , Aptamers, Peptide/metabolism , Blood Coagulation , Drug Delivery Systems , Female , Gene Expression Regulation , Host-Derived Cellular Factors/metabolism , Humans , Internet , Male , Middle Aged , Quantitative Trait Loci/genetics
7.
SSRN; 2020.
Preprint | SSRN | ID: ppcovidwho-734

ABSTRACT

Background: Few paediatric cases of COVID-19 have been reported and we know little about the epidemiology in children. We have synthesised what is known globall

8.
bioRxiv ; 2020 Jul 01.
Article in English | MEDLINE | ID: covidwho-636928

ABSTRACT

Strategies to develop therapeutics for SARS-CoV-2 infection may be informed by experimental identification of viral-host protein interactions in cellular assays and measurement of host response proteins in COVID-19 patients. Identification of genetic variants that influence the level or activity of these proteins in the host could enable rapid 'in silico' assessment in human genetic studies of their causal relevance as molecular targets for new or repurposed drugs to treat COVID-19. We integrated large-scale genomic and aptamer-based plasma proteomic data from 10,708 individuals to characterize the genetic architecture of 179 host proteins reported to interact with SARS-CoV-2 proteins or to participate in the host response to COVID-19. We identified 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links, evidence that putative viral interaction partners such as MARK3 affect immune response, and establish the first link between a recently reported variant for respiratory failure of COVID-19 patients at the ABO locus and hypercoagulation, i.e. maladaptive host response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and dynamic and detailed interrogation of results is facilitated through an interactive webserver ( https://omicscience.org/apps/covidpgwas/ ).

9.
Cell Syst ; 11(1): 11-24.e4, 2020 07 22.
Article in English | MEDLINE | ID: covidwho-459007

ABSTRACT

The COVID-19 pandemic is an unprecedented global challenge, and point-of-care diagnostic classifiers are urgently required. Here, we present a platform for ultra-high-throughput serum and plasma proteomics that builds on ISO13485 standardization to facilitate simple implementation in regulated clinical laboratories. Our low-cost workflow handles up to 180 samples per day, enables high precision quantification, and reduces batch effects for large-scale and longitudinal studies. We use our platform on samples collected from a cohort of early hospitalized cases of the SARS-CoV-2 pandemic and identify 27 potential biomarkers that are differentially expressed depending on the WHO severity grade of COVID-19. They include complement factors, the coagulation system, inflammation modulators, and pro-inflammatory factors upstream and downstream of interleukin 6. All protocols and software for implementing our approach are freely available. In total, this work supports the development of routine proteomic assays to aid clinical decision making and generate hypotheses about potential COVID-19 therapeutic targets.


Subject(s)
Blood Proteins/metabolism , Coronavirus Infections/blood , Pneumonia, Viral/blood , Proteomics/methods , Adult , Aged , Aged, 80 and over , Betacoronavirus/isolation & purification , Biomarkers/blood , Blood Proteins/analysis , COVID-19 , Coronavirus Infections/classification , Coronavirus Infections/pathology , Coronavirus Infections/virology , Female , Humans , Male , Middle Aged , Pandemics/classification , Pneumonia, Viral/classification , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2 , Young Adult
10.
Lancet ; 395(10238): 1715-1725, 2020 05 30.
Article in English | MEDLINE | ID: covidwho-245277

ABSTRACT

BACKGROUND: The medical, societal, and economic impact of the coronavirus disease 2019 (COVID-19) pandemic has unknown effects on overall population mortality. Previous models of population mortality are based on death over days among infected people, nearly all of whom thus far have underlying conditions. Models have not incorporated information on high-risk conditions or their longer-term baseline (pre-COVID-19) mortality. We estimated the excess number of deaths over 1 year under different COVID-19 incidence scenarios based on varying levels of transmission suppression and differing mortality impacts based on different relative risks for the disease. METHODS: In this population-based cohort study, we used linked primary and secondary care electronic health records from England (Health Data Research UK-CALIBER). We report prevalence of underlying conditions defined by Public Health England guidelines (from March 16, 2020) in individuals aged 30 years or older registered with a practice between 1997 and 2017, using validated, openly available phenotypes for each condition. We estimated 1-year mortality in each condition, developing simple models (and a tool for calculation) of excess COVID-19-related deaths, assuming relative impact (as relative risks [RRs]) of the COVID-19 pandemic (compared with background mortality) of 1·5, 2·0, and 3·0 at differing infection rate scenarios, including full suppression (0·001%), partial suppression (1%), mitigation (10%), and do nothing (80%). We also developed an online, public, prototype risk calculator for excess death estimation. FINDINGS: We included 3 862 012 individuals (1 957 935 [50·7%] women and 1 904 077 [49·3%] men). We estimated that more than 20% of the study population are in the high-risk category, of whom 13·7% were older than 70 years and 6·3% were aged 70 years or younger with at least one underlying condition. 1-year mortality in the high-risk population was estimated to be 4·46% (95% CI 4·41-4·51). Age and underlying conditions combined to influence background risk, varying markedly across conditions. In a full suppression scenario in the UK population, we estimated that there would be two excess deaths (vs baseline deaths) with an RR of 1·5, four with an RR of 2·0, and seven with an RR of 3·0. In a mitigation scenario, we estimated 18 374 excess deaths with an RR of 1·5, 36 749 with an RR of 2·0, and 73 498 with an RR of 3·0. In a do nothing scenario, we estimated 146 996 excess deaths with an RR of 1·5, 293 991 with an RR of 2·0, and 587 982 with an RR of 3·0. INTERPRETATION: We provide policy makers, researchers, and the public a simple model and an online tool for understanding excess mortality over 1 year from the COVID-19 pandemic, based on age, sex, and underlying condition-specific estimates. These results signal the need for sustained stringent suppression measures as well as sustained efforts to target those at highest risk because of underlying conditions with a range of preventive interventions. Countries should assess the overall (direct and indirect) effects of the pandemic on excess mortality. FUNDING: National Institute for Health Research University College London Hospitals Biomedical Research Centre, Health Data Research UK.


Subject(s)
Coronavirus Infections/epidemiology , Mortality/trends , Pneumonia, Viral/epidemiology , Adult , Aged , Aged, 80 and over , COVID-19 , Cohort Studies , Coronavirus Infections/complications , Female , Humans , Male , Middle Aged , Models, Statistical , Multimorbidity , Pandemics , Pneumonia, Viral/complications , Risk Factors , United Kingdom/epidemiology
11.
Clin Infect Dis ; 71(9): 2469-2479, 2020 12 03.
Article in English | MEDLINE | ID: covidwho-232507

ABSTRACT

BACKGROUND: Few pediatric cases of coronavirus disease 2019 (COVID-19) have been reported and we know little about the epidemiology in children, although more is known about other coronaviruses. We aimed to understand the infection rate, clinical presentation, clinical outcomes, and transmission dynamics for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in order to inform clinical and public health measures. METHODS: We undertook a rapid systematic review and narrative synthesis of all literature relating to SARS-CoV-2 in pediatric populations. The search terms also included SARS-CoV and MERS-CoV. We searched 3 databases and the COVID-19 resource centers of 11 major journals and publishers. English abstracts of Chinese-language papers were included. Data were extracted and narrative syntheses conducted. RESULTS: Twenty-four studies relating to COVID-19 were included in the review. Children appear to be less affected by COVID-19 than adults by observed rate of cases in large epidemiological studies. Limited data on attack rate indicate that children are just as susceptible to infection. Data on clinical outcomes are scarce but include several reports of asymptomatic infection and a milder course of disease in young children, although radiological abnormalities are noted. Severe cases are not reported in detail and there are few data relating to transmission. CONCLUSIONS: Children appear to have a low observed case rate of COVID-19 but may have rates similar to adults of infection with SARS-CoV-2. This discrepancy may be because children are asymptomatic or too mildly infected to draw medical attention and be tested and counted in observed cases of COVID-19.


Subject(s)
COVID-19/epidemiology , SARS-CoV-2 , Adolescent , Asymptomatic Infections/epidemiology , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Pediatrics/statistics & numerical data
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