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1.
Alzheimers Dement ; 18(4): 790-809, 2022 04.
Article in English | MEDLINE | ID: covidwho-2172367

ABSTRACT

In tandem with the ever-increasing aging population in low and middle-income countries, the burden of dementia is rising on the African continent. Dementia prevalence varies from 2.3% to 20.0% and incidence rates are 13.3 per 1000 person-years with increasing mortality in parts of rapidly transforming Africa. Differences in nutrition, cardiovascular factors, comorbidities, infections, mortality, and detection likely contribute to lower incidence. Alzheimer's disease, vascular dementia, and human immunodeficiency virus/acquired immunodeficiency syndrome-associated neurocognitive disorders are the most common dementia subtypes. Comprehensive longitudinal studies with robust methodology and regional coverage would provide more reliable information. The apolipoprotein E (APOE) ε4 allele is most studied but has shown differential effects within African ancestry compared to Caucasian. More candidate gene and genome-wide association studies are needed to relate to dementia phenotypes. Validated culture-sensitive cognitive tools not influenced by education and language differences are critically needed for implementation across multidisciplinary groupings such as the proposed African Dementia Consortium.


Subject(s)
Alzheimer Disease , Dementia, Vascular , Dementia , Aged , Alzheimer Disease/genetics , Apolipoprotein E4/genetics , Dementia/epidemiology , Dementia/genetics , Dementia, Vascular/complications , Genome-Wide Association Study , Genotype , Humans
2.
Gigascience ; 10(6)2021 06 29.
Article in English | MEDLINE | ID: covidwho-2161022

ABSTRACT

BACKGROUND: Genome-wide association studies (GWAS) and phenome-wide association studies (PheWAS) involving 1 million GWAS samples from dozens of population-based biobanks present a considerable computational challenge and are carried out by large scientific groups under great expenditure of time and personnel. Automating these processes requires highly efficient and scalable methods and software, but so far there is no workflow solution to easily process 1 million GWAS samples. RESULTS: Here we present BIGwas, a portable, fully automated quality control and association testing pipeline for large-scale binary and quantitative trait GWAS data provided by biobank resources. By using Nextflow workflow and Singularity software container technology, BIGwas performs resource-efficient and reproducible analyses on a local computer or any high-performance compute (HPC) system with just 1 command, with no need to manually install a software execution environment or various software packages. For a single-command GWAS analysis with 974,818 individuals and 92 million genetic markers, BIGwas takes ∼16 days on a small HPC system with only 7 compute nodes to perform a complete GWAS QC and association analysis protocol. Our dynamic parallelization approach enables shorter runtimes for large HPCs. CONCLUSIONS: Researchers without extensive bioinformatics knowledge and with few computer resources can use BIGwas to perform multi-cohort GWAS with 1 million GWAS samples and, if desired, use it to build their own (genome-wide) PheWAS resource. BIGwas is freely available for download from http://github.com/ikmb/gwas-qc and http://github.com/ikmb/gwas-assoc.


Subject(s)
Biological Specimen Banks , Genome-Wide Association Study , Genome , Humans , Phenotype , Polymorphism, Single Nucleotide , Quality Control , Software
3.
Elife ; 112022 10 17.
Article in English | MEDLINE | ID: covidwho-2145045

ABSTRACT

Background: Epidemiological studies observed gender differences in COVID-19 outcomes, however, whether sex hormone plays a causal in COVID-19 risk remains unclear. This study aimed to examine associations of sex hormone, sex hormones-binding globulin (SHBG), insulin-like growth factor-1 (IGF-1), and COVID-19 risk. Methods: Two-sample Mendelian randomization (TSMR) study was performed to explore the causal associations between testosterone, estrogen, SHBG, IGF-1, and the risk of COVID-19 (susceptibility, hospitalization, and severity) using genome-wide association study (GWAS) summary level data from the COVID-19 Host Genetics Initiative (N=1,348,701). Random-effects inverse variance weighted (IVW) MR approach was used as the primary MR method and the weighted median, MR-Egger, and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test were conducted as sensitivity analyses. Results: Higher genetically predicted IGF-1 levels have nominally significant association with reduced risk of COVID-19 susceptibility and hospitalization. For one standard deviation increase in genetically predicted IGF-1 levels, the odds ratio was 0.77 (95% confidence interval [CI], 0.61-0.97, p=0.027) for COVID-19 susceptibility, 0.62 (95% CI: 0.25-0.51, p=0.018) for COVID-19 hospitalization, and 0.85 (95% CI: 0.52-1.38, p=0.513) for COVID-19 severity. There was no evidence that testosterone, estrogen, and SHBG are associated with the risk of COVID-19 susceptibility, hospitalization, and severity in either overall or sex-stratified TSMR analysis. Conclusions: Our study indicated that genetically predicted high IGF-1 levels were associated with decrease the risk of COVID-19 susceptibility and hospitalization, but these associations did not survive the Bonferroni correction of multiple testing. Further studies are needed to validate the findings and explore whether IGF-1 could be a potential intervention target to reduce COVID-19 risk. Funding: We acknowledge support from NSFC (LR22H260001), CRUK (C31250/A22804), SHLF (Hjärt-Lungfonden, 20210351), VR (Vetenskapsrådet, 2019-00977), and SCI (Cancerfonden).


Subject(s)
COVID-19 , Genome-Wide Association Study , COVID-19/epidemiology , COVID-19/genetics , Estrogens , Gonadal Steroid Hormones , Hospitalization , Humans , Insulin-Like Growth Factor I/genetics , Polymorphism, Single Nucleotide , Testosterone
4.
Sci Rep ; 12(1): 20167, 2022 Nov 23.
Article in English | MEDLINE | ID: covidwho-2133629

ABSTRACT

To create a scientific resource of expression quantitative trail loci (eQTL), we conducted a genome-wide association study (GWAS) using genotypes obtained from whole genome sequencing (WGS) of DNA and gene expression levels from RNA sequencing (RNA-seq) of whole blood in 2622 participants in Framingham Heart Study. We identified 6,778,286 cis-eQTL variant-gene transcript (eGene) pairs at p < 5 × 10-8 (2,855,111 unique cis-eQTL variants and 15,982 unique eGenes) and 1,469,754 trans-eQTL variant-eGene pairs at p < 1e-12 (526,056 unique trans-eQTL variants and 7233 unique eGenes). In addition, 442,379 cis-eQTL variants were associated with expression of 1518 long non-protein coding RNAs (lncRNAs). Gene Ontology (GO) analyses revealed that the top GO terms for cis-eGenes are enriched for immune functions (FDR < 0.05). The cis-eQTL variants are enriched for SNPs reported to be associated with 815 traits in prior GWAS, including cardiovascular disease risk factors. As proof of concept, we used this eQTL resource in conjunction with genetic variants from public GWAS databases in causal inference testing (e.g., COVID-19 severity). After Bonferroni correction, Mendelian randomization analyses identified putative causal associations of 60 eGenes with systolic blood pressure, 13 genes with coronary artery disease, and seven genes with COVID-19 severity. This study created a comprehensive eQTL resource via BioData Catalyst that will be made available to the scientific community. This will advance understanding of the genetic architecture of gene expression underlying a wide range of diseases.


Subject(s)
Genetic Predisposition to Disease , Genome-Wide Association Study , Quantitative Trait Loci , Humans , DNA , Gene Expression , Quantitative Trait Loci/genetics , Sequence Analysis, RNA
5.
Nat Commun ; 13(1): 7255, 2022 Nov 25.
Article in English | MEDLINE | ID: covidwho-2133429

ABSTRACT

Severe COVID-19 causes profound immune perturbations, but pre-infection immune signatures contributing to severe COVID-19 remain unknown. Genome-wide association studies (GWAS) identified strong associations between severe disease and several chemokine receptors and molecules from the type I interferon pathway. Here, we define immune signatures associated with severe COVID-19 using high-dimensional flow cytometry. We measure the cells of the peripheral immune system from individuals who recovered from mild, moderate, severe or critical COVID-19 and focused only on those immune signatures returning to steady-state. Individuals that suffered from severe COVID-19 show reduced frequencies of T cell, mucosal-associated invariant T cell (MAIT) and dendritic cell (DC) subsets and altered chemokine receptor expression on several subsets, such as reduced levels of CCR1 and CCR2 on monocyte subsets. Furthermore, we find reduced frequencies of type I interferon-producing plasmacytoid DCs and altered IFNAR2 expression on several myeloid cells in individuals recovered from severe COVID-19. Thus, these data identify potential immune mechanisms contributing to severe COVID-19.


Subject(s)
COVID-19 , Interferon Type I , Humans , Genome-Wide Association Study , Dendritic Cells , Receptors, Chemokine , Phenotype , Interferon Type I/genetics
6.
Clin Microbiol Infect ; 28(11): 1417-1421, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2130458

ABSTRACT

BACKGROUND: During the past 2 years, studies on patients with SARS-CoV-2 infection have revealed rare inborn errors of immunity (IEIs) in type interferon (IFN) pathways underlying critical COVID-19 pneumonia. This has provided insights into pathophysiological mechanisms and immune signaling circuits regulating antiviral responses to SARS-CoV-2 and governing the susceptibility to and outcome of SARS-CoV-2 infection in humans. OBJECTIVES: In this review, the current knowledge on IEIs underlying critical COVID-19 is presented, and the clinical implications of these findings for individualized prophylaxis and treatment are outlined. SOURCES: The review is based on a broad literature search, including primarily studies on whole-exome sequencing, and to a lesser extent genome-wide association studies, of patients with critical COVID-19, as well as retrospective descriptive studies of the SARS-CoV-2 disease course in individuals with known IEIs. CONTENT: The review describes the discovery of monogenic IEI in 9 genetic loci related to the production or responses to type I IFN in patients with critical COVID-19 pneumonia and the surprising finding of phenocopies of these, represented by neutralizing autoantibodies to type IFN in a significant proportion of patients with critical pneumonia, particularly in elderly men, and further enriched in patients with lethal disease course. Moreover insights gained from studies on SARS-CoV-2 infection, disease course, and outcome in patients with known IEI is presented. Finally, some hypotheses for a possible genetic basis of autoimmune, inflammatory, and long-term complications of SARS-CoV-2 infection are presented and discussed. IMPLICATIONS: Uncovering IEIs underlying critical COVID-19 or other severe SARS-CoV-2 disease manifestations provides valuable insights into the basic principles of antiviral immune responses and pathophysiology related to SARS-CoV-2 infection. Such knowledge has important clinical implications for identification of susceptible individuals and for diagnosis, prophylaxis, and treatment of patients to reduce disease burden and improve preparedness against viral pandemics with known or emerging viruses in the future.


Subject(s)
COVID-19 , Male , Humans , Aged , COVID-19/genetics , SARS-CoV-2/genetics , Genome-Wide Association Study , Retrospective Studies , Antiviral Agents/therapeutic use , Interferons , Autoantibodies , Human Genetics
7.
Front Endocrinol (Lausanne) ; 13: 961717, 2022.
Article in English | MEDLINE | ID: covidwho-2121935

ABSTRACT

Background: Observational studies have reported an association between coronavirus disease 2019 (COVID-19) risk and thyroid dysfunction, but without a clear causal relationship. We attempted to evaluate the association between thyroid function and COVID-19 risk using a bidirectional two-sample Mendelian randomization (MR) analysis. Methods: Summary statistics on the characteristics of thyroid dysfunction (hypothyroidism and hyperthyroidism) were obtained from the ThyroidOmics Consortium. Genome-wide association study statistics for COVID-19 susceptibility and its severity were obtained from the COVID-19 Host Genetics Initiative, and severity phenotypes included hospitalization and very severe disease in COVID-19 participants. The inverse variance-weighted (IVW) method was used as the primary analysis method, supplemented by the weighted-median (WM), MR-Egger, and MR-PRESSO methods. Results were adjusted for Bonferroni correction thresholds. Results: The forward MR estimates show no effect of thyroid dysfunction on COVID-19 susceptibility and severity. The reverse MR found that COVID-19 susceptibility was the suggestive risk factor for hypothyroidism (IVW: OR = 1.577, 95% CI = 1.065-2.333, P = 0.022; WM: OR = 1.527, 95% CI = 1.042-2.240, P = 0.029), and there was lightly association between COVID-19 hospitalized and hypothyroidism (IVW: OR = 1.151, 95% CI = 1.004-1.319, P = 0.042; WM: OR = 1.197, 95% CI = 1.023-1.401, P = 0.023). There was no evidence supporting the association between any phenotype of COVID-19 and hyperthyroidism. Conclusion: Our results identified that COVID-19 might be the potential risk factor for hypothyroidism. Therefore, patients infected with SARS-CoV-2 should strengthen the monitoring of thyroid function.


Subject(s)
COVID-19 , Hyperthyroidism , Hypothyroidism , COVID-19/complications , COVID-19/epidemiology , COVID-19/genetics , Genome-Wide Association Study , Humans , Hyperthyroidism/complications , Hyperthyroidism/epidemiology , Hyperthyroidism/genetics , Hypothyroidism/complications , Hypothyroidism/epidemiology , Hypothyroidism/genetics , Mendelian Randomization Analysis/methods , Polymorphism, Single Nucleotide , SARS-CoV-2
8.
Sci Rep ; 12(1): 19564, 2022 Nov 15.
Article in English | MEDLINE | ID: covidwho-2119334

ABSTRACT

DNA methylation commonly occurs at cytosine-phosphate-guanine sites (CpGs) that can serve as biomarkers for many diseases. We analyzed whole genome sequencing data to identify DNA methylation quantitative trait loci (mQTLs) in 4126 Framingham Heart Study participants. Our mQTL mapping identified 94,362,817 cis-mQTLvariant-CpG pairs (for 210,156 unique autosomal CpGs) at P < 1e-7 and 33,572,145 trans-mQTL variant-CpG pairs (for 213,606 unique autosomal CpGs) at P < 1e-14. Using cis-mQTL variants for 1258 CpGs associated with seven cardiovascular disease (CVD) risk factors, we found 104 unique CpGs that colocalized with at least one CVD trait. For example, cg11554650 (PPP1R18) colocalized with type 2 diabetes, and was driven by a single nucleotide polymorphism (rs2516396). We performed Mendelian randomization (MR) analysis and demonstrated 58 putatively causal relations of CVD risk factor-associated CpGs to one or more risk factors (e.g., cg05337441 [APOB] with LDL; MR P = 1.2e-99, and 17 causal associations with coronary artery disease (e.g. cg08129017 [SREBF1] with coronary artery disease; MR P = 5e-13). We also showed that three CpGs, e.g., cg14893161 (PM20D1), are putatively causally associated with COVID-19 severity. To assist in future analyses of the role of DNA methylation in disease pathogenesis, we have posted a comprehensive summary data set in the National Heart, Lung, and Blood Institute's BioData Catalyst.


Subject(s)
COVID-19 , Coronary Artery Disease , Diabetes Mellitus, Type 2 , Humans , DNA Methylation , Diabetes Mellitus, Type 2/genetics , Coronary Artery Disease/genetics , Quantitative Trait Loci , Polymorphism, Single Nucleotide , Cytosine , CpG Islands/genetics , Genome-Wide Association Study
9.
Int J Mol Sci ; 23(22)2022 Nov 17.
Article in English | MEDLINE | ID: covidwho-2115936

ABSTRACT

Vitamin D (VD) is a fat-soluble vitamin, and pivotal for maintaining health. Several genetic markers have been related to a deficient VD status; these markers could confer an increased risk to develop osteoporosis and other chronic diseases. A VD deficiency could also be a determinant of a severe COVID-19 disease. This study aimed to interrogate genetic/biological databases on the biological implications of a VD deficiency and its association with diseases, to further explore its link with COVID-19. The genetic variants of both a VD deficiency and COVID-19 were identified in the genome-wide association studies (GWAS) catalog and other sources. We conducted enrichment analyses (considering corrected p-values < 0.05 as statistically significant) of the pathways, and gene-disease associations using tools, such as FUMA, REVIGO, DAVID and DisGeNET, and databases, such as the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO). There were 26 and 46 genes associated with a VD deficiency and COVID-19, respectively. However, there were no genes shared between the two. Genes related to a VD deficiency were involved in the metabolism of carbohydrates, retinol, drugs and xenobiotics, and were associated with the metabolic syndrome and related factors (obesity, hypertension and diabetes mellitus), as well as with neoplasms. There were few enriched pathways and disease connections for the COVID-19-related genes, among which some of the aforementioned comorbidities were also present. In conclusion, genetic factors that influence the VD levels in the body are most prominently associated with nutritional and metabolic diseases. A VD deficiency in high-risk populations could be therefore relevant in a severe COVID-19, underlining the need to examine whether a VD supplementation could reduce the severity of this disease.


Subject(s)
COVID-19 , Vitamin D Deficiency , Humans , COVID-19/genetics , Genome-Wide Association Study , Vitamin D Deficiency/complications , Vitamin D Deficiency/epidemiology , Vitamin D Deficiency/genetics , Vitamin D/genetics , Vitamin D/metabolism , Vitamins
10.
Front Public Health ; 10: 1023935, 2022.
Article in English | MEDLINE | ID: covidwho-2109887

ABSTRACT

Background: Coronavirus Disease 2019 (COVID-19) has rapidly evolved as a global pandemic. Observational studies found that visceral adipose tissue (VAT) increased the likelihood of worse clinical outcomes in COVID-19 patients. Whereas, whether VAT is causally associated with the susceptibility, hospitalization, or severity of COVID-19 remains unconfirmed. We aimed to investigate the causal associations between VAT and susceptibility, hospitalization, and severity of COVID-19. Methods: We applied a two-sample Mendelian randomization (MR) study to infer causal associations between VAT and COVID-19 outcomes. Single-nucleotide polymorphisms significantly associated with VAT were derived from a large-scale genome-wide association study. The random-effects inverse-variance weighted method was used as the main MR approach, complemented by three other MR methods. Additional sensitivity analyses were also performed. Results: Genetically predicted higher VAT mass was causally associated with higher risks of COVID-19 susceptibility [odds ratios (ORs) = 1.13; 95% confidence interval (CI), 1.09-1.17; P = 4.37 × 10-12], hospitalization (OR = 1.51; 95% CI = 1.38-1.65; P = 4.14 × 10-20), and severity (OR = 1.58; 95% CI = 1.38-1.82; P = 7.34 × 10-11). Conclusion: This study provided genetic evidence that higher VAT mass was causally associated with higher risks of susceptibility, hospitalization, and severity of COVID-19. VAT can be a useful tool for risk assessment in the general population and COVID-19 patients, as well as an important prevention target.


Subject(s)
COVID-19 , Humans , COVID-19/epidemiology , Intra-Abdominal Fat , Mendelian Randomization Analysis , Genome-Wide Association Study , Hospitalization
11.
PLoS Genet ; 18(11): e1010367, 2022 11.
Article in English | MEDLINE | ID: covidwho-2098659

ABSTRACT

Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.


Subject(s)
COVID-19 , Exome , Humans , Exome/genetics , Genome-Wide Association Study , COVID-19/genetics , Genetic Predisposition to Disease , Toll-Like Receptor 7/genetics , SARS-CoV-2/genetics
12.
PLoS Genet ; 18(11): e1010253, 2022 11.
Article in English | MEDLINE | ID: covidwho-2098658

ABSTRACT

Genome wide association studies show there is a genetic component to severe COVID-19. We find evidence that the genome-wide genetic association signal with severe COVID-19 is correlated with that of systemic lupus erythematosus (SLE), having formally tested this using genetic correlation analysis by LD score regression. To identify the shared associated loci and gain insight into the shared genetic effects, using summary level data we performed meta-analyses, a local genetic correlation analysis and fine-mapping using stepwise regression and functional annotation. This identified multiple loci shared between the two traits, some of which exert opposing effects. The locus with most evidence of shared association is TYK2, a gene critical to the type I interferon pathway, where the local genetic correlation is negative. Another shared locus is CLEC1A, where the direction of effects is aligned, that encodes a lectin involved in cell signaling, and the anti-fungal immune response. Our analyses suggest that several loci with reciprocal effects between the two traits have a role in the defense response pathway, adding to the evidence that SLE risk alleles are protective against infection.


Subject(s)
Autoimmune Diseases , COVID-19 , Lupus Erythematosus, Systemic , Humans , Genome-Wide Association Study , Genetic Predisposition to Disease , COVID-19/genetics , Lupus Erythematosus, Systemic/genetics , Autoimmune Diseases/genetics , Polymorphism, Single Nucleotide
13.
Cell Rep ; 41(8): 111708, 2022 Nov 22.
Article in English | MEDLINE | ID: covidwho-2095146

ABSTRACT

Genome-wide association studies (GWASs) show that genetic factors contribute to the risk of severe coronavirus disease 2019 (COVID-19) and blood analyte levels. Here, we utilize GWAS summary statistics to study the shared genetic influences (pleiotropy) between severe COVID-19 and 344 blood analytes at the genome, gene, and single-nucleotide polymorphism (SNP) levels. Our pleiotropy analyses genetically link blood levels of 71 analytes to severe COVID-19 in at least one of the three levels of investigation-suggesting shared biological mechanisms or causal relationships. Six analytes (alanine aminotransferase, alkaline phosphatase, apolipoprotein B, C-reactive protein, triglycerides, and urate) display evidence of pleiotropy with severe COVID-19 at all three levels. Causality analyses indicate that higher triglycerides levels causally increase the risk of severe COVID-19, thereby providing important support for the use of lipid-lowering drugs such as statins and fibrates to prevent severe COVID-19.


Subject(s)
COVID-19 , Humans , COVID-19/blood , COVID-19/genetics , Genome-Wide Association Study , Polymorphism, Single Nucleotide , Triglycerides/blood , Risk Factors
14.
Brief Funct Genomics ; 21(6): 423-432, 2022 Nov 17.
Article in English | MEDLINE | ID: covidwho-2087742

ABSTRACT

The elevated levels of inflammatory cytokines have attracted much attention during the treatment of COVID-19 patients. The conclusions of current observational studies are often controversial in terms of the causal effects of COVID-19 on various cytokines because of the confounding factors involving underlying diseases. To resolve this problem, we conducted a Mendelian randomization analysis by integrating the GWAS data of COVID-19 and 41 cytokines. As a result, the levels of 2 cytokines were identified to be promoted by COVID-19 and had unsignificant pleiotropy. In comparison, the levels of 10 cytokines were found to be inhibited and had unsignificant pleiotropy. Among down-regulated cytokines, CCL2, CCL3 and CCL7 were members of CC chemokine family. We then explored the potential molecular mechanism for a significant causal association at a single cell resolution based on single-cell RNA data, and discovered the suppression of CCL3 and the inhibition of CCL3-CCR1 interaction in classical monocytes (CMs) of COVID-19 patients. Our findings may indicate that the capability of COVID-19 in decreasing the chemotaxis of lymphocytes by inhibiting the CCL3-CCR1 interaction in CMs.


Subject(s)
COVID-19 , Cytokines , Humans , Mendelian Randomization Analysis , COVID-19/genetics , Sequence Analysis, RNA , Genome-Wide Association Study , Polymorphism, Single Nucleotide/genetics
15.
Commun Biol ; 5(1): 1133, 2022 Oct 26.
Article in English | MEDLINE | ID: covidwho-2087324

ABSTRACT

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.


Subject(s)
COVID-19 , Humans , COVID-19/genetics , Genome-Wide Association Study , Genetic Predisposition to Disease , Whole Exome Sequencing , Phenotype
16.
Sci Rep ; 12(1): 17703, 2022 Oct 21.
Article in English | MEDLINE | ID: covidwho-2087305

ABSTRACT

Autoimmune diseases and coronavirus disease 2019 (COVID-19) share many similarities. Concerns have arisen that autoimmune diseases may increase the susceptibility and severity of COVID-19. We used Mendelian randomization to investigate whether liability to autoimmune diseases is related to COVID-19 susceptibility and severity. Genetic instruments for 8 autoimmune diseases, including type 1 diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, multiple sclerosis, primary sclerosing cholangitis, primary biliary cirrhosis and juvenile idiopathic arthritis, were obtained from published genome-wide association studies. Two-sample Mendelian randomization analyses of the associations of liability to each autoimmune disease with COVID-19 infection, hospitalized COVID-19, and very severe COVID-19 were performed using the latest publicly available genome-wide association study for COVID-19. Genetic liability to each of the autoimmune diseases was largely not associated with COVID-19 infection, hospitalized COVID-19, or very severe COVID-19 after accounting for multiple comparison. Sensitivity analysis excluding genetic variants in the human leukocyte antigen gene, which has an important role in the immune response, showed similar results. The autoimmune diseases examined were largely not genetically associated with the susceptibility or severity of COVID-19. Further investigations are warranted.


Subject(s)
Arthritis, Juvenile , Autoimmune Diseases , COVID-19 , Humans , Genetic Predisposition to Disease , COVID-19/epidemiology , COVID-19/genetics , Genome-Wide Association Study , Mendelian Randomization Analysis , Autoimmune Diseases/epidemiology , Autoimmune Diseases/genetics , Arthritis, Juvenile/genetics , HLA Antigens , Polymorphism, Single Nucleotide
17.
Nat Commun ; 13(1): 6336, 2022 Oct 25.
Article in English | MEDLINE | ID: covidwho-2087204

ABSTRACT

Genes with moderate to low expression heritability may explain a large proportion of complex trait etiology, but such genes cannot be sufficiently captured in conventional transcriptome-wide association studies (TWASs), partly due to the relatively small available reference datasets for developing expression genetic prediction models to capture the moderate to low genetically regulated components of gene expression. Here, we introduce a method, the Summary-level Unified Method for Modeling Integrated Transcriptome (SUMMIT), to improve the expression prediction model accuracy and the power of TWAS by using a large expression quantitative trait loci (eQTL) summary-level dataset. We apply SUMMIT to the eQTL summary-level data provided by the eQTLGen consortium. Through simulation studies and analyses of genome-wide association study summary statistics for 24 complex traits, we show that SUMMIT improves the accuracy of expression prediction in blood, successfully builds expression prediction models for genes with low expression heritability, and achieves higher statistical power than several benchmark methods. Finally, we conduct a case study of COVID-19 severity with SUMMIT and identify 11 likely causal genes associated with COVID-19 severity.


Subject(s)
COVID-19 , Transcriptome , Humans , Genome-Wide Association Study/methods , COVID-19/genetics , Quantitative Trait Loci/genetics , Multifactorial Inheritance , Polymorphism, Single Nucleotide , Genetic Predisposition to Disease/genetics
18.
Adv Immunol ; 156: 25-54, 2022.
Article in English | MEDLINE | ID: covidwho-2085835

ABSTRACT

Autoimmune diseases (ADs) often arise from a combination of genetic and environmental triggers that disrupt the immune system's capability to properly tolerate body self-antigens. Familial studies provided the earliest insights into the risk loci of such diseases, while genome-wide association studies (GWAS) significantly broadened the horizons. A drug targeting a prominent pathological pathway can be applied to multiple indications sharing overlapping mechanisms. Advances in genomic technologies used in genetic studies provide critical insights into future research on gene-environment interactions in autoimmunity. This Review summarizes the history and recent advances in the understanding of genetic susceptibility to ADs and related immune disorders, including coronavirus disease 2019 (COVID-19), and their indications for the development of diagnostic or prognostic markers for translational applications.


Subject(s)
Autoimmune Diseases , COVID-19 , Humans , Animals , Autoimmunity/genetics , Genetic Predisposition to Disease , Genome-Wide Association Study , COVID-19/genetics , Autoimmune Diseases/genetics
19.
Front Public Health ; 10: 995664, 2022.
Article in English | MEDLINE | ID: covidwho-2080299

ABSTRACT

Background: Sleep disturbance including insomnia and sleep duration is associated with an increased risk of infectious. With the ongoing coronavirus disease 2019 (COVID-19) pandemic, it is important to explore potential causal associations of sleep disturbance on COVID-19 susceptibility and hospitalization. Method: Insomnia and sleep duration were selected as exposure. Outcomes included susceptibility and hospitalization for COVID-19. Two sample mendelian randomization design was used to assess causality between sleep and COVID-19. Inverse variance weighted method was used as main analysis method to combine the ratio estimates for each instrumental variable to obtain the causal effect. Cochran's Q statistic was used to test for global heterogeneity. MR-Egger and weighting median estimator (WME) were used as sensitivity analysis to ensure the stability and reliability of the results. MR-Egger intercept term was used to test the mean pleiotropy. In addition, the direct effects of insomnia and sleep duration on COVID-19 susceptibility and hospitalization were estimated using multivariable mendelian randomization (MVMR). Results: Univariate MR provided no evidence of a causal associations of insomnia on COVID-19 susceptibility (OR = 1.10, 95% CI:0.95, 1.27; p = 0.21) and hospitalization (OR = 0.61, 95% CI:0.40, 0.92; p = 0.02); as does sleep duration (ORCOIVD - 19susceptibility = 0.93, 95% CI:0.86, 1.01; p = 0.07; ORCOIVD - 19 hospitalization = 1.21, 95% CI: 0.99, 1.47; p = 0.08). MVMR results showed that insomnia may be a risk factor for increased susceptibility to COVID-19 (OR = 1.65, 95% CI: 1.34, 2.05; p <0.001); and sleep duration was also associated with increased COVID-19 susceptibility (OR = 1.31, 95% CI: 1.18, 1.46; p < 0.001). Conclusion: Insomnia and extreme sleep duration may risk factors for increased COVID-19 susceptibility. Relieving insomnia and maintaining normal sleep duration may be powerful measures to reduce COVID-19 infections.


Subject(s)
COVID-19 , Sleep Initiation and Maintenance Disorders , COVID-19/epidemiology , Genome-Wide Association Study , Hospitalization , Humans , Mendelian Randomization Analysis/methods , Reproducibility of Results , Sleep , Sleep Initiation and Maintenance Disorders/epidemiology
20.
Glob Health Epidemiol Genom ; 2022: 7405349, 2022.
Article in English | MEDLINE | ID: covidwho-2079092

ABSTRACT

Host genetic factors are known to modify the susceptibility, severity, and outcomes of COVID-19 and vary across populations. However, continental Africans are yet to be adequately represented in such studies despite the importance of genetic factors in understanding Africa's response to the pandemic. We describe the development of a research resource for coronavirus host genomics studies in South Africa known as COVIGen-SA-a multicollaborator strategic partnership designed to provide harmonised demographic, clinical, and genetic information specific to Black South Africans with COVID-19. Over 2,000 participants have been recruited to date. Preliminary results on 1,354 SARS-CoV-2 positive participants from four participating studies showed that 64.7% were female, 333 had severe disease, and 329 were people living with HIV. Through this resource, we aim to provide insights into host genetic factors relevant to African-ancestry populations, using both genome-wide association testing and targeted sequencing of important genomic loci. This project will promote and enhance partnerships, build skills, and develop resources needed to address the COVID-19 burden and associated risk factors in South African communities.


Subject(s)
COVID-19 , Female , Humans , Male , South Africa/epidemiology , COVID-19/epidemiology , COVID-19/genetics , Genome-Wide Association Study , SARS-CoV-2/genetics , Genomics
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