Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 6 de 6
Filter
1.
EBioMedicine ; 74: 103695, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1596202

ABSTRACT

BACKGROUND: The heterogeneity in symptomatology and phenotypic profile attributable to COVID-19 is widely unknown. The objective of this manuscript is to conduct a trans-ancestry genome wide association study (GWAS) meta-analysis of COVID-19 severity to improve the understanding of potentially causal targets for SARS-CoV-2. METHODS: This cross-sectional study recruited 646 participants in the UAE that were divided into two phenotypic groups based on the severity of COVID-19 phenotypes, hospitalized (n=482) and non-hospitalized (n=164) participants. Hospitalized participants were COVID-19 patients that developed acute respiratory distress syndrome (ARDS), pneumonia or progression to respiratory failure that required supplemental oxygen therapy or mechanical ventilation support or had severe complications such as septic shock or multi-organ failure. We conducted a trans-ancestry meta-analysis GWAS of European (n=302), American (n=102), South Asian (n=99), and East Asian (n=107) ancestry populations. We also carried out comprehensive post-GWAS analysis, including enrichment of SNP associations in tissues and cell-types, expression quantitative trait loci and differential expression analysis. FINDINGS: Eight genes demonstrated a strong association signal: VWA8 gene in locus 13p14·11 (SNP rs10507497; p=9·54 x10-7), PDE8B gene in locus 5q13·3 (SNP rs7715119; p=2·19 x10-6), CTSC gene in locus 11q14·2 (rs72953026; p=2·38 x10-6), THSD7B gene in locus 2q22·1 (rs7605851; p=3·07x10-6), STK39 gene in locus 2q24·3 (rs7595310; p=4·55 x10-6), FBXO34 gene in locus 14q22·3 (rs10140801; p=8·26 x10-6), RPL6P27 gene in locus 18p11·31 (rs11659676; p=8·88 x10-6), and METTL21C gene in locus 13q33·1 (rs599976; p=8·95 x10-6). The genes are expressed in the lung, associated to tumour progression, emphysema, airway obstruction, and surface tension within the lung, as well as an association to T-cell-mediated inflammation and the production of inflammatory cytokines. INTERPRETATION: We have discovered eight highly plausible genetic association with hospitalized cases in COVID-19. Further studies must be conducted on worldwide population genetics to facilitate the development of population specific therapeutics to mitigate this worldwide challenge. FUNDING: This review was commissioned as part of a project to study the host cell receptors of coronaviruses funded by Khalifa University's CPRA grant (Reference number 2020-004).


Subject(s)
Genetic Predisposition to Disease/genetics , Quantitative Trait Loci/genetics , Quantitative Trait, Heritable , Respiratory Distress Syndrome/genetics , Severity of Illness Index , Adolescent , Adult , Aged , COVID-19/mortality , COVID-19/pathology , Cross-Sectional Studies , Female , Genome-Wide Association Study , Hospitalization/statistics & numerical data , Humans , Inflammation/genetics , Lung/pathology , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Population Groups/genetics , Respiratory Distress Syndrome/pathology , SARS-CoV-2 , T-Lymphocytes/immunology , Treatment Outcome , United Arab Emirates , Young Adult
2.
Cell Rep ; 37(7): 110020, 2021 11 16.
Article in English | MEDLINE | ID: covidwho-1509641

ABSTRACT

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.


Subject(s)
COVID-19/genetics , SARS-CoV-2/genetics , Chromosome Mapping/methods , Computational Biology/methods , Databases, Genetic , Gene Expression/genetics , Gene Expression Profiling/methods , Genetic Predisposition to Disease/genetics , Genetic Variation/genetics , Genome-Wide Association Study/methods , Humans , Organ Specificity/genetics , Polymorphism, Single Nucleotide/genetics , Quantitative Trait Loci/genetics , SARS-CoV-2/pathogenicity , Severity of Illness Index , Transcriptome/genetics
3.
Cell ; 184(20): 5247-5260.e19, 2021 09 30.
Article in English | MEDLINE | ID: covidwho-1415259

ABSTRACT

3' untranslated region (3'UTR) variants are strongly associated with human traits and diseases, yet few have been causally identified. We developed the massively parallel reporter assay for 3'UTRs (MPRAu) to sensitively assay 12,173 3'UTR variants. We applied MPRAu to six human cell lines, focusing on genetic variants associated with genome-wide association studies (GWAS) and human evolutionary adaptation. MPRAu expands our understanding of 3'UTR function, suggesting that simple sequences predominately explain 3'UTR regulatory activity. We adapt MPRAu to uncover diverse molecular mechanisms at base pair resolution, including an adenylate-uridylate (AU)-rich element of LEPR linked to potential metabolic evolutionary adaptations in East Asians. We nominate hundreds of 3'UTR causal variants with genetically fine-mapped phenotype associations. Using endogenous allelic replacements, we characterize one variant that disrupts a miRNA site regulating the viral defense gene TRIM14 and one that alters PILRB abundance, nominating a causal variant underlying transcriptional changes in age-related macular degeneration.


Subject(s)
3' Untranslated Regions/genetics , Biological Evolution , Disease/genetics , Genome-Wide Association Study , Algorithms , Alleles , Gene Expression Regulation , Genes, Reporter , Genetic Variation , Humans , Phenotype , Polymorphism, Single Nucleotide/genetics , Polyribosomes/metabolism , Quantitative Trait Loci/genetics , RNA/genetics
4.
Eur J Hum Genet ; 29(6): 1019-1026, 2021 06.
Article in English | MEDLINE | ID: covidwho-1111983

ABSTRACT

Germline variants in genes involved in SARS-CoV-2 cell entry and in host innate immune responses to viruses may influence the susceptibility to infection. This study used whole-genome analyses of lung tissue to identify polymorphisms acting as expression quantitative trait loci (eQTLs) for 60 genes of relevance to SARS-CoV-2 infection susceptibility. The expression of genes with confirmed or possible roles in viral entry-replication and in host antiviral responses was studied in the non-diseased lung tissue of 408 lung adenocarcinoma patients. No gene was differently expressed by sex, but APOBEC3H levels were higher and PARP12 levels lower in older individuals. A total of 125 cis-eQTLs (false discovery rate < 0.05) was found to modulate mRNA expression of 15 genes (ABO, ANPEP, AP2A2, APOBEC3D, APOBEC3G, BSG, CLEC4G, DDX58, DPP4, FURIN, FYCO1, RAB14, SERINC3, TRIM5, ZCRB1). eQTLs regulating ABO and FYCO1 were found in COVID-19 susceptibility loci. No trans-eQTLs were identified. Genetic control of the expression of these 15 genes, which encode putative virus receptors, proteins required for vesicle trafficking, enzymes that interfere with viral replication, and other restriction factors, may underlie interindividual differences in risk or severity of infection with SARS-CoV-2 or other viruses.


Subject(s)
ABO Blood-Group System/genetics , COVID-19/genetics , Galactosyltransferases/genetics , Genetic Predisposition to Disease , Microtubule-Associated Proteins/genetics , COVID-19/virology , Gene Expression Regulation/genetics , Humans , Immunity, Innate/genetics , Lung/metabolism , Lung/pathology , Polymorphism, Genetic , Quantitative Trait Loci/genetics , Receptors, Virus/genetics , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity
5.
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
6.
Biochem Biophys Res Commun ; 529(2): 263-269, 2020 08 20.
Article in English | MEDLINE | ID: covidwho-617705

ABSTRACT

The World Health Organization recently announced that pandemic status has been achieved for coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Exponential increases in patient numbers have been reported around the world, along with proportional increases in the number of COVID-19-related deaths. The SARS-CoV-2 infection rate in a population is expected to be influenced by social practices, availability of vaccines or prophylactics, and the prevalence of susceptibility genes in the population. Previous work revealed that cellular uptake of SARS-CoV-2 requires Angiotensin Converting Enzyme 2 (ACE-2) and a cellular protease. The spike (S) protein on SARS-CoV-2 binds ACE-2, which functions as an entry receptor. Following receptor binding, transmembrane protease serine 2 (encoded by TMPRSS2) primes the S protein to allow cellular uptake. Therefore, individual expression of TMPRSS2 may be a crucial determinant of SARS-CoV-2 infection susceptibility. Here, we utilized multiple large genome databases, including the GTEx portal, SNP nexus, and Ensembl genome project, to identify gene expression profiles for TMPRSS2 and its important expression quantitative trait loci. Our results show that four variants (rs464397, rs469390, rs2070788 and rs383510) affect expression of TMPRSS2 in lung tissue. The allele frequency of each variant was then assessed in regional populations, including African, American, European, and three Asian cohorts (China, Japan and Taiwan). Interestingly, our data shows that TMPRSS2-upregulating variants are at higher frequencies in European and American populations than in the Asian populations, which implies that these populations might be relatively susceptible to SARS-CoV-2 infection.


Subject(s)
Betacoronavirus/metabolism , Gene Expression Regulation/genetics , Internationality , Lung/metabolism , Receptors, Virus/genetics , Serine Endopeptidases/genetics , Asia/ethnology , Cohort Studies , Europe/ethnology , Gene Frequency , Genetics, Population , Geographic Mapping , Humans , Organ Specificity/genetics , Polymorphism, Single Nucleotide , Quantitative Trait Loci/genetics , SARS-CoV-2 , United States/ethnology , Up-Regulation/genetics
SELECTION OF CITATIONS
SEARCH DETAIL