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1.
J Transl Med ; 19(1): 528, 2021 12 24.
Article in English | MEDLINE | ID: covidwho-1638964

ABSTRACT

BACKGROUND: Emerging evidence shows that periodontal disease (PD) may increase the risk of Coronavirus disease 2019 (COVID-19) complications. Here, we undertook a two-sample Mendelian randomization (MR) study, and investigated for the first time the possible causal impact of PD on host susceptibility to COVID-19 and its severity. METHODS: Summary statistics of COVID-19 susceptibility and severity were retrieved from the COVID-19 Host Genetics Initiative and used as outcomes. Single nucleotide polymorphisms associated with PD in Genome-wide association study were included as exposure. Inverse-variance weighted (IVW) method was employed as the main approach to analyze the causal relationships between PD and COVID-19. Three additional methods were adopted, allowing the existence of horizontal pleiotropy, including MR-Egger regression, weighted median and weighted mode methods. Comprehensive sensitivity analyses were also conducted for estimating the robustness of the identified associations. RESULTS: The MR estimates showed that PD was significantly associated with significantly higher susceptibility to COVID-19 using IVW (OR = 1.024, P = 0.017, 95% CI 1.004-1.045) and weighted median method (OR = 1.029, P = 0.024, 95% CI 1.003-1.055). Furthermore, it revealed that PD was significantly linked to COVID-19 severity based on the comparison of hospitalization versus population controls (IVW, OR = 1.025, P = 0.039, 95% CI 1.001-1.049; weighted median, OR = 1.030, P = 0.027, 95% CI 1.003-1.058). No such association was observed in the cohort of highly severe cases confirmed versus those not hospitalized due to COVID-19. CONCLUSIONS: We provide evidence on the possible causality of PD accounting for the susceptibility and severity of COVID-19, highlighting the importance of oral/periodontal healthcare for general wellbeing during the pandemic and beyond.


Subject(s)
COVID-19 , Periodontal Diseases , COVID-19/genetics , Genome-Wide Association Study , Humans , Mendelian Randomization Analysis , Periodontal Diseases/complications , Periodontal Diseases/genetics , Polymorphism, Single Nucleotide
2.
Epidemiol Infect ; 150: e14, 2021 12 16.
Article in English | MEDLINE | ID: covidwho-1627666

ABSTRACT

Vulnerability to coronavirus disease (COVID)-19 varies due to differences in interferon gamma (IFNγ) immunity. We investigated whether a key modifiable interferon precursor, interleukin-18, was related to COVID-19, overall and by severity, using Mendelian randomisation. We used four established genome-wide significant genetic predictors of interleukin-18 applied to the most recent genome-wide association study of COVID-19 (June 2021) to obtain Mendelian randomisation inverse variance weighted estimates by severity, i.e. any (cases = 112 612, non-cases = 2 474 079), hospitalised (cases = 24 274, non-cases = 2 061 529) and very severe (cases = 8779, non-cases = 1 001 875) COVID-19. To be comprehensive, we also conducted an exploratory analysis for IFNγ and two related cytokines with less well-established genetic predictors, i.e. interleukin-12 and interleukin-23. Genetically predicted interleukin-18 was associated with lower risk of any COVID-19 (odds ratio (OR) 0.96 per standard deviation, 95% confidence interval (0.94-0.99, P-value 0.004)) and of very severe COVID-19 (OR 0.88, 95% CI 0.78-0.999, P-value 0.048). Sensitivity analysis and a more liberal genetic instrument selection gave largely similar results. Few genome-wide significant genetic predictors were available for IFNγ, interleukin-12 or interleukin-23, and no associations with COVID-19 were evident. Interleukin-18 could be a modifiable target to prevent COVID-19 and should be further explored in an experimental design.


Subject(s)
COVID-19/genetics , Interleukin-18/genetics , COVID-19/pathology , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Male , Mendelian Randomization Analysis , Odds Ratio , Polymorphism, Single Nucleotide , SARS-CoV-2 , Severity of Illness Index
3.
Cells ; 10(12)2021 12 11.
Article in English | MEDLINE | ID: covidwho-1572377

ABSTRACT

The SARS-CoV-2 (COVID-19) pandemic has caused millions of deaths worldwide. Early risk assessment of COVID-19 cases can help direct early treatment measures that have been shown to improve the prognosis of severe cases. Currently, circulating miRNAs have not been evaluated as canonical COVID-19 biomarkers, and identifying biomarkers that have a causal relationship with COVID-19 is imperative. To bridge these gaps, we aim to examine the causal effects of miRNAs on COVID-19 severity in this study using two-sample Mendelian randomization approaches. Multiple studies with available GWAS summary statistics data were retrieved. Using circulating miRNA expression data as exposure, and severe COVID-19 cases as outcomes, we identified ten unique miRNAs that showed causality across three phenotype groups of COVID-19. Using expression data from an independent study, we validated and identified two high-confidence miRNAs, namely, hsa-miR-30a-3p and hsa-miR-139-5p, which have putative causal effects on developing cases of severe COVID-19. Using existing literature and publicly available databases, the potential causative roles of these miRNAs were investigated. This study provides a novel way of utilizing miRNA eQTL data to help us identify potential miRNA biomarkers to make better and early diagnoses and risk assessments of severe COVID-19 cases.


Subject(s)
COVID-19/genetics , Circulating MicroRNA/genetics , MicroRNAs/genetics , Patient Acuity , SARS-CoV-2/genetics , Biomarkers/blood , COVID-19/blood , Circulating MicroRNA/blood , Genome-Wide Association Study , Humans , Mendelian Randomization Analysis , MicroRNAs/blood , SARS-CoV-2/metabolism
4.
BMC Med Genomics ; 14(1): 269, 2021 11 13.
Article in English | MEDLINE | ID: covidwho-1515444

ABSTRACT

BACKGROUND: As the number of COVID-19 deaths continues to rise worldwide, the identification of risk factors for the disease is an urgent issue, and it remains controversial whether atherogenic lipid-related traits including serum apolipoprotein B, low-density lipoprotein (LDL)-cholesterol, and triglyceride levels, are risk factors. The aim of this study was to estimate causal effects of lipid-related traits on COVID-19 risk in the European population using a two-sample Mendelian randomization (MR) approach. METHODS: We used summary statistics from a genome-wide association study (GWAS) that included 441,016 participants from the UK Biobank as the exposure dataset of lipid-related traits and from COVID-19 Host Genetics Initiative GWAS meta-analyses of European ancestry as the outcome dataset for COVID-19 susceptibility (32,494 cases and 1,316,207 controls), hospitalization (8316 cases and 1,549,095 controls), and severity (4792 cases and 1,054,664 controls). We performed two-sample MR analyses using the inverse variance weighted (IVW) method. As sensitivity analyses, the MR-Egger regression, weighted median, and weighted mode methods were conducted as were leave-one-out sensitivity analysis, the MR-PRESSO global test, PhenoScanner searches, and IVW multivariable MR analyses. A P value below 0.0055 with Bonferroni correction was considered statistically significant. RESULTS: This MR study suggested that serum apolipoprotein B or LDL-cholesterol levels were not significantly associated with COVID-19 risk. On the other hand, we inferred that higher serum triglyceride levels were suggestively associated with higher risks of COVID-19 susceptibility (odds ratio [OR] per standard deviation increase in lifelong triglyceride levels, 1.065; 95% confidence interval [CI], 1.001-1.13; P = 0.045) and hospitalization (OR, 1.174; 95% CI, 1.04-1.33; P = 0.012), and were significantly associated with COVID-19 severity (OR, 1.274; 95% CI, 1.08-1.50; P = 0.004). Sensitivity and bidirectional MR analyses suggested that horizontal pleiotropy and reverse causation were unlikely. CONCLUSIONS: Our MR study indicates a causal effect of higher serum triglyceride levels on a greater risk of COVID-19 severity in the European population using the latest and largest GWAS datasets to date. However, as the underlying mechanisms remain unclear and our study might be still biased due to possible horizontal pleiotropy, further studies are warranted to validate our findings and investigate underlying mechanisms.


Subject(s)
Apolipoprotein B-100 , COVID-19 , Cholesterol, LDL , Genetic Predisposition to Disease , Quantitative Trait, Heritable , SARS-CoV-2/metabolism , Triglycerides , Apolipoprotein B-100/blood , Apolipoprotein B-100/genetics , COVID-19/blood , COVID-19/genetics , Cholesterol, LDL/blood , Cholesterol, LDL/genetics , Female , Genome-Wide Association Study , Humans , Male , Mendelian Randomization Analysis , Risk Factors , Severity of Illness Index , Triglycerides/blood , Triglycerides/genetics
5.
BMC Nephrol ; 22(1): 381, 2021 11 13.
Article in English | MEDLINE | ID: covidwho-1515439

ABSTRACT

BACKGROUND: Kidney dysfunction occurs in severe COVID-19, and is a predictor of COVID-19 mortality. Whether kidney dysfunction causes severe COVID-19, and hence is a target of intervention, or whether it is a symptom, is unclear because conventional observational studies are open to confounding. To obtain unconfounded estimates, we used Mendelian randomization to examine the role of kidney function in severe COVID-19. METHODS: We used genome-wide significant, uncorrelated genetic variants to predict kidney function, in terms of estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR), and then assessed whether people with genetically instrumented higher eGFR or lower UACR, an indication of better kidney function, had a lower risk of severe COVID-19 (8779 cases, 1,001,875 controls), using the largest available cohorts with extensive genotyping. For comprehensiveness, we also examined their role in COVID-19 hospitalization (24,274 cases, 2,061,529 controls) and all COVID-19 (1,12,612 cases, 2,474,079 controls). RESULTS: Genetically instrumented higher eGFR was associated with lower risk of severe COVID-19 (odds ratio (OR) 0.90, 95% confidence interval (CI) 0.83, 0.98) but not related to COVID-19 hospitalization or infection. Genetically instrumented UACR was not related to COVID-19. CONCLUSIONS: Kidney function appears to be one of the key targets for severe COVID-19 treatment. Use of available medications to improve kidney function, such as antihypertensives, might be beneficial for COVID-19 treatment, with relevance to drug repositioning.


Subject(s)
COVID-19/complications , COVID-19/genetics , Glomerular Filtration Rate/genetics , Kidney/physiopathology , Patient Acuity , Albuminuria/urine , Case-Control Studies , Creatinine/urine , Genetic Variation , Genome-Wide Association Study , Hospitalization , Humans , Mendelian Randomization Analysis , Risk Factors , SARS-CoV-2 , /genetics
6.
J Am Heart Assoc ; 10(22): e022433, 2021 11 16.
Article in English | MEDLINE | ID: covidwho-1511553

ABSTRACT

Background The relationship between COVID-19 and ischemic stroke is poorly understood due to potential unmeasured confounding and reverse causation. We aimed to leverage genetic data to triangulate reported associations. Methods and Results Analyses primarily focused on critical COVID-19, defined as hospitalization with COVID-19 requiring respiratory support or resulting in death. Cross-trait linkage disequilibrium score regression was used to estimate genetic correlations of critical COVID-19 with ischemic stroke, other related cardiovascular outcomes, and risk factors common to both COVID-19 and cardiovascular disease (body mass index, smoking and chronic inflammation, estimated using C-reactive protein). Mendelian randomization analysis was performed to investigate whether liability to critical COVID-19 was associated with increased risk of any cardiovascular outcome for which genetic correlation was identified. There was evidence of genetic correlation between critical COVID-19 and ischemic stroke (rg=0.29, false discovery rate [FDR]=0.012), body mass index (rg=0.21, FDR=0.00002), and C-reactive protein (rg=0.20, FDR=0.00035), but no other trait investigated. In Mendelian randomization, liability to critical COVID-19 was associated with increased risk of ischemic stroke (odds ratio [OR] per logOR increase in genetically predicted critical COVID-19 liability 1.03, 95% CI 1.00-1.06, P-value=0.03). Similar estimates were obtained for ischemic stroke subtypes. Consistent estimates were also obtained when performing statistical sensitivity analyses more robust to the inclusion of pleiotropic variants, including multivariable Mendelian randomization analyses adjusting for potential genetic confounding through body mass index, smoking, and chronic inflammation. There was no evidence to suggest that genetic liability to ischemic stroke increased the risk of critical COVID-19. Conclusions These data support that liability to critical COVID-19 is associated with an increased risk of ischemic stroke. The host response predisposing to severe COVID-19 is likely to increase the risk of ischemic stroke, independent of other potentially mitigating risk factors.


Subject(s)
Brain Ischemia , COVID-19 , Ischemic Stroke , Body Mass Index , Brain Ischemia/epidemiology , Brain Ischemia/genetics , Brain Ischemia/virology , C-Reactive Protein , COVID-19/epidemiology , Genome-Wide Association Study , Humans , Inflammation , Ischemic Stroke/epidemiology , Ischemic Stroke/genetics , Ischemic Stroke/virology , Mendelian Randomization Analysis , Polymorphism, Single Nucleotide , Risk Factors , Smoking
7.
Commun Biol ; 4(1): 1230, 2021 10 28.
Article in English | MEDLINE | ID: covidwho-1493231

ABSTRACT

Observational studies suggest smoking, cannabis use, alcohol consumption, and substance use disorders (SUDs) may impact risk for respiratory infections, including coronavirus 2019 (COVID-2019). However, causal inference is challenging due to comorbid substance use. Using summary-level European ancestry data (>1.7 million participants), we performed single-variable and multivariable Mendelian randomization (MR) to evaluate relationships between substance use behaviors, COVID-19 and other respiratory infections. Genetic liability for smoking demonstrated the strongest associations with COVID-19 infection risk, including the risk for very severe respiratory confirmed COVID-19 (odds ratio (OR) = 2.69, 95% CI, 1.42, 5.10, P-value = 0.002), and COVID-19 infections requiring hospitalization (OR = 3.49, 95% CI, 2.23, 5.44, P-value = 3.74 × 10-8); these associations generally remained robust in models accounting for other substance use and cardiometabolic risk factors. Smoking was also strongly associated with increased risk of other respiratory infections, including asthma-related pneumonia/sepsis (OR = 3.64, 95% CI, 2.16, 6.11, P-value = 1.07 × 10-6), chronic lower respiratory diseases (OR = 2.29, 95% CI, 1.80, 2.91, P-value = 1.69 × 10-11), and bacterial pneumonia (OR = 2.14, 95% CI, 1.42, 3.24, P-value = 2.84 × 10-4). We provide strong genetic evidence showing smoking increases the risk for COVID-19 and other respiratory infections even after accounting for other substance use behaviors and cardiometabolic diseases, which suggests that prevention programs aimed at reducing smoking may be important for the COVID-19 pandemic and have substantial public health benefits.


Subject(s)
COVID-19 , Pandemics , Smoking , Female , Humans , Male , Mendelian Randomization Analysis
10.
Sci Rep ; 11(1): 18262, 2021 09 14.
Article in English | MEDLINE | ID: covidwho-1410889

ABSTRACT

A growing body of evidence suggests that vitamin D deficiency has been associated with an increased susceptibility to viral and bacterial respiratory infections. In this study, we aimed to examine the association between vitamin D and COVID-19 risk and outcomes. We used logistic regression to identify associations between vitamin D variables and COVID-19 (risk of infection, hospitalisation and death) in 417,342 participants from UK Biobank. We subsequently performed a Mendelian Randomisation (MR) study to look for evidence of a causal effect. In total, 1746 COVID-19 cases (399 deaths) were registered between March and June 2020. We found no significant associations between COVID-19 infection risk and measured 25-OHD levels after adjusted for covariates, but this finding is limited by the fact that the vitamin D levels were measured on average 11 years before the pandemic. Ambient UVB was strongly and inversely associated with COVID-19 hospitalization and death overall and consistently after stratification by BMI and ethnicity. We also observed an interaction that suggested greater protective effect of genetically-predicted vitamin D levels when ambient UVB radiation is stronger. The main MR analysis did not show that genetically-predicted vitamin D levels are causally associated with COVID-19 risk (OR = 0.77, 95% CI 0.55-1.11, P = 0.160), but MR sensitivity analyses indicated a potential causal effect (weighted mode MR: OR = 0.72, 95% CI 0.55-0.95, P = 0.021; weighted median MR: OR = 0.61, 95% CI 0.42-0.92, P = 0.016). Analysis of MR-PRESSO did not find outliers for any instrumental variables and suggested a potential causal effect (OR = 0.80, 95% CI 0.66-0.98, p-val = 0.030). In conclusion, the effect of vitamin D levels on the risk or severity of COVID-19 remains controversial, further studies are needed to validate vitamin D supplementation as a means of protecting against worsened COVID-19.


Subject(s)
COVID-19/pathology , Calcifediol/blood , Aged , Biological Specimen Banks , COVID-19/mortality , COVID-19/virology , Female , Humans , Logistic Models , Male , Mendelian Randomization Analysis , Middle Aged , Odds Ratio , Prospective Studies , Risk Factors , SARS-CoV-2/isolation & purification , United Kingdom
12.
PLoS One ; 16(9): e0256988, 2021.
Article in English | MEDLINE | ID: covidwho-1394552

ABSTRACT

Epidemiological studies suggest that individuals with comorbid conditions including diabetes, chronic lung, inflammatory and vascular disease, are at higher risk of adverse COVID-19 outcomes. Genome-wide association studies have identified several loci associated with increased susceptibility and severity for COVID-19. However, it is not clear whether these associations are genetically determined or not. We used a Phenome-Wide Association (PheWAS) approach to investigate the role of genetically determined COVID-19 susceptibility on disease related outcomes. PheWAS analyses were performed in order to identify traits and diseases related to COVID-19 susceptibility and severity, evaluated through a predictive COVID-19 risk score. We utilised phenotypic data in up to 400,000 individuals from the UK Biobank, including Hospital Episode Statistics and General Practice data. We identified a spectrum of associations between both genetically determined COVID-19 susceptibility and severity with a number of traits. COVID-19 risk was associated with increased risk for phlebitis and thrombophlebitis (OR = 1.11, p = 5.36e-08). We also identified significant signals between COVID-19 susceptibility with blood clots in the leg (OR = 1.1, p = 1.66e-16) and with increased risk for blood clots in the lung (OR = 1.12, p = 1.45 e-10). Our study identifies significant association of genetically determined COVID-19 with increased blood clot events in leg and lungs. The reported associations between both COVID-19 susceptibility and severity and other diseases adds to the identification and stratification of individuals at increased risk, adverse outcomes and long-term effects.


Subject(s)
COVID-19/genetics , Obesity/genetics , Thrombophlebitis/genetics , Thrombosis/genetics , COVID-19/epidemiology , COVID-19/virology , Cardiovascular Diseases/genetics , Cardiovascular Diseases/pathology , Cardiovascular Diseases/virology , Female , Genetic Predisposition to Disease , Humans , Male , Mendelian Randomization Analysis , Obesity/epidemiology , Obesity/virology , Phenomics , Phenotype , Polymorphism, Single Nucleotide/genetics , SARS-CoV-2/pathogenicity , Thrombophlebitis/epidemiology , Thrombophlebitis/virology , Thrombosis/epidemiology , Thrombosis/virology
13.
Int J Mol Sci ; 22(17)2021 Aug 26.
Article in English | MEDLINE | ID: covidwho-1374426

ABSTRACT

The current spreading coronavirus SARS-CoV-2 is highly infectious and pathogenic. In this study, we screened the gene expression of three host receptors (ACE2, DC-SIGN and L-SIGN) of SARS coronaviruses and dendritic cells (DCs) status in bulk and single cell transcriptomic datasets of upper airway, lung or blood of COVID-19 patients and healthy controls. In COVID-19 patients, DC-SIGN gene expression was interestingly decreased in lung DCs but increased in blood DCs. Within DCs, conventional DCs (cDCs) were depleted while plasmacytoid DCs (pDCs) were augmented in the lungs of mild COVID-19. In severe cases, we identified augmented types of immature DCs (CD22+ or ANXA1+ DCs) with MHCII downregulation. In this study, our observation indicates that DCs in severe cases stimulate innate immune responses but fail to specifically present SARS-CoV-2. It provides insights into the profound modulation of DC function in severe COVID-19.


Subject(s)
COVID-19/immunology , Cell Adhesion Molecules/genetics , Dendritic Cells/immunology , Gene Expression Regulation/immunology , Lectins, C-Type/genetics , Receptors, Cell Surface/genetics , SARS-CoV-2/immunology , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/diagnosis , COVID-19/pathology , COVID-19/virology , Cell Adhesion Molecules/metabolism , Datasets as Topic , Dendritic Cells/metabolism , Genome-Wide Association Study , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Immunity, Innate , Lectins, C-Type/metabolism , Lung/immunology , Lung/pathology , Lung/virology , Mendelian Randomization Analysis , Nasopharynx/immunology , Nasopharynx/pathology , Nasopharynx/virology , RNA-Seq , Receptors, Cell Surface/metabolism , Severity of Illness Index , Single-Cell Analysis
14.
Brief Bioinform ; 22(6)2021 11 05.
Article in English | MEDLINE | ID: covidwho-1324577

ABSTRACT

We aimed to investigate the genetic mechanisms associated with coronavirus disease of 2019 (COVID-19) outcomes in the host and to evaluate the possible associations between smoking and drinking behavior and three COVID-19 outcomes: severe COVID-19, hospitalized COVID-19 and COVID-19 infection. We described the genomic loci and risk genes associated with the COVID-19 outcomes, followed by functional analyses of the risk genes. Then, a summary data-based Mendelian randomization (SMR) analysis, and a transcriptome-wide association study (TWAS) were performed for the severe COVID-19 dataset. A two-sample Mendelian randomization (MR) analysis was used to evaluate the causal associations between various measures of smoking and alcohol consumption and the COVID-19 outcomes. A total of 26 protein-coding genes, enriched in chemokine binding, cytokine binding and senescence-related functions, were associated with either severe COVID-19 or hospitalized COVID-19. The SMR and the TWAS analyses highlighted functional implications of some GWAS hits and identified seven novel genes for severe COVID-19, including CCR5, CCR5AS, IL10RB, TAC4, RMI1 and TNFSF15, some of which are targets of approved or experimental drugs. According to our studies, increasing consumption of cigarettes per day by 1 standard deviation is related to a 2.3-fold increase in susceptibility to severe COVID-19 and a 1.6-fold increase in COVID-19-induced hospitalization. Contrarily, no significant links were found between alcohol consumption or binary smoking status and COVID-19 outcomes. Our study revealed some novel COVID-19 related genes and suggested that genetic liability to smoking may quantitatively contribute to an increased risk for a severe course of COVID-19.


Subject(s)
Alcohol Drinking/adverse effects , COVID-19/epidemiology , Genome-Wide Association Study , SARS-CoV-2/genetics , Smoking/adverse effects , COVID-19/etiology , COVID-19/genetics , COVID-19/virology , Gene Expression Profiling , Genetic Predisposition to Disease , Humans , Mendelian Randomization Analysis , Polymorphism, Single Nucleotide/genetics , Risk Factors , SARS-CoV-2/pathogenicity
15.
EBioMedicine ; 70: 103485, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1322072

ABSTRACT

Background Older age is the most powerful risk factor for adverse coronavirus disease-19 (COVID-19) outcomes. It is uncertain whether leucocyte telomere length (LTL), previously proposed as a marker of biological age, is also associated with COVID-19 outcomes. Methods We associated LTL values obtained from participants recruited into UK Biobank (UKB) during 2006-2010 with adverse COVID-19 outcomes recorded by 30 November 2020, defined as a composite of any of the following: hospital admission, need for critical care, respiratory support, or mortality. Using information on 130 LTL-associated genetic variants, we conducted exploratory Mendelian randomisation (MR) analyses in UKB to evaluate whether observational associations might reflect cause-and-effect relationships. Findings Of 6775 participants in UKB who tested positive for infection with SARS-CoV-2 in the community, there were 914 (13.5%) with adverse COVID-19 outcomes. The odds ratio (OR) for adverse COVID-19 outcomes was 1·17 (95% CI 1·05-1·30; P = 0·004) per 1-SD shorter usual LTL, after adjustment for age, sex and ethnicity. Similar ORs were observed in analyses that: adjusted for additional risk factors; disaggregated the composite outcome and reduced the scope for selection or collider bias. In MR analyses, the OR for adverse COVID-19 outcomes was directionally concordant but non-significant. Interpretation Shorter LTL is associated with higher risk of adverse COVID-19 outcomes, independent of several major risk factors for COVID-19 including age. Further data are needed to determine whether this association reflects causality. Funding UK Medical Research Council, Biotechnology and Biological Sciences Research Council and British Heart Foundation.


Subject(s)
COVID-19/virology , Leukocytes/pathology , SARS-CoV-2/genetics , Telomere/genetics , Aged , Biological Specimen Banks , COVID-19/pathology , Cohort Studies , Female , Humans , Male , Mendelian Randomization Analysis , Middle Aged , Risk Factors , United Kingdom
16.
J Transl Med ; 19(1): 300, 2021 07 10.
Article in English | MEDLINE | ID: covidwho-1304407

ABSTRACT

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has struck globally and is exerting a devastating toll on humans. The pandemic has led to calls for widespread vitamin D supplementation in public. However, evidence supporting the role of vitamin D in the COVID-19 pandemic remains controversial. METHODS: We performed a two-sample Mendelian randomization (MR) analysis to analyze the causal effect of the 25-hydroxyvitamin D [25(OH)D] concentration on COVID-19 susceptibility, severity and hospitalization traits by using summary-level GWAS data. The causal associations were estimated with inverse variance weighted (IVW) with fixed effects (IVW-fixed) and random effects (IVW-random), MR-Egger, weighted edian and MR Robust Adjusted Profile Score (MR.RAPS) methods. We further applied the MR Steiger filtering method, MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) global test and PhenoScanner tool to check and remove single nucleotide polymorphisms (SNPs) that were horizontally pleiotropic. RESULTS: We found no evidence to support the causal associations between the serum 25(OH)D concentration and the risk of COVID-19 susceptibility [IVW-fixed: odds ratio (OR) = 0.9049, 95% confidence interval (CI) 0.8197-0.9988, p = 0.0473], severity (IVW-fixed: OR = 1.0298, 95% CI 0.7699-1.3775, p = 0.8432) and hospitalized traits (IVW-fixed: OR = 1.0713, 95% CI 0.8819-1.3013, p = 0.4878) using outlier removed sets at a Bonferroni-corrected p threshold of 0.0167. Sensitivity analyses did not reveal any sign of horizontal pleiotropy. CONCLUSIONS: Our MR analysis provided precise evidence that genetically lowered serum 25(OH)D concentrations were not causally associated with COVID-19 susceptibility, severity or hospitalized traits. Our study did not provide evidence assessing the role of vitamin D supplementation during the COVID-19 pandemic. High-quality randomized controlled trials are necessary to explore and define the role of vitamin D supplementation in the prevention and treatment of COVID-19.


Subject(s)
COVID-19 , Mendelian Randomization Analysis , Genome-Wide Association Study , Hospitalization , Humans , Pandemics , Polymorphism, Single Nucleotide/genetics , SARS-CoV-2 , Vitamin D
17.
Elife ; 102021 07 06.
Article in English | MEDLINE | ID: covidwho-1298242

ABSTRACT

Background: To understand a causal role of modifiable lifestyle factors in angiotensin-converting enzyme 2 (ACE2) expression (a putative severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] receptor) across 44 human tissues/organs, and in coronavirus disease 2019 (COVID-19) susceptibility and severity, we conducted a phenome-wide two-sample Mendelian randomization (MR) study. Methods: More than 500 genetic variants were used as instrumental variables to predict smoking and alcohol consumption. Inverse-variance weighted approach was adopted as the primary method to estimate a causal association, while MR-Egger regression, weighted median, and MR pleiotropy residual sum and outlier (MR-PRESSO) were performed to identify potential horizontal pleiotropy. Results: We found that genetically predicted smoking intensity significantly increased ACE2 expression in thyroid (ß=1.468, p=1.8×10-8), and increased ACE2 expression in adipose, brain, colon, and liver with nominal significance. Additionally, genetically predicted smoking initiation significantly increased the risk of COVID-19 onset (odds ratio=1.14, p=8.7×10-5). No statistically significant result was observed for alcohol consumption. Conclusions: Our work demonstrates an important role of smoking, measured by both status and intensity, in the susceptibility to COVID-19. Funding: XJ is supported by research grants from the Swedish Research Council (VR-2018-02247) and Swedish Research Council for Health, Working Life and Welfare (FORTE-2020-00884).


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/pathology , Mendelian Randomization Analysis , SARS-CoV-2/physiology , Tobacco Smoking/adverse effects , Adipose Tissue/metabolism , Alcohol Drinking/genetics , Angiotensin-Converting Enzyme 2/genetics , Brain/metabolism , COVID-19/virology , Causality , Colon/metabolism , Gene Expression Regulation , Humans , Liver/metabolism , Polymorphism, Single Nucleotide , Thyroid Gland/metabolism
18.
Genes (Basel) ; 12(7)2021 06 24.
Article in English | MEDLINE | ID: covidwho-1295801

ABSTRACT

ABO blood system is an inborn trait determined by the ABO gene. The genetic-phenotypic mechanism underneath the four mutually exclusive and collectively exhaustive types of O, A, B and AB could theoretically be elucidated. However, genetic polymorphisms in the human populations render the link elusive, and importantly, past studies using genetically determined rather than biochemically determined ABO types were not and could not be evaluated for the inference errors. Upon both blood-typing and genotyping a cohort of 1008 people of the Han Chinese population, we conducted a genome-wide association study in parallel with both binomial and multinomial log-linear models. Significant genetic variants are all mapped to the ABO gene, and are quantitatively evaluated for binary and multi-class classification performances. Three single nucleotide polymorphisms of rs8176719, rs635634 and rs7030248 would together be sufficient to establish a multinomial predictive model that achieves high accuracy (0.98) and F1 scores (micro 0.99 and macro 0.97). Using the set of identified ABO-associated genetic variants as instrumental variables, we demonstrate the application in causal analysis by Mendelian randomization (MR) studies on blood pressures (one-sample MR) and severe COVID-19 with respiratory failure (two-sample MR).


Subject(s)
ABO Blood-Group System/blood , ABO Blood-Group System/genetics , COVID-19/genetics , Polymorphism, Single Nucleotide , Adult , Blood Pressure/genetics , COVID-19/etiology , Cohort Studies , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Male , Mendelian Randomization Analysis , Middle Aged , Models, Statistical , Serologic Tests
19.
Front Public Health ; 9: 673451, 2021.
Article in English | MEDLINE | ID: covidwho-1278470

ABSTRACT

Observational studies have reported that the severity of COVID-19 depends not only on physical conditions but also on socioeconomic status, including educational level. Because educational attainment (EA), which measures the number of years of schooling, is moderately heritable, we investigated the causal association of EA on the risk of COVID-19 severity using the Mendelian randomization (MR) approach. A two-sample MR analysis was performed using publicly available summary-level data sets of genome-wide association studies (GWASs). A total of 235 single-nucleotide polymorphisms (SNPs) were extracted as instrumental variables for the exposure of EA from the Social Science Genetic Association Consortium GWAS summary data of 766,345 participants of European ancestry. The effect of each SNP on the outcome of COVID-19 severity risk was obtained from the GWAS summary data of 1,059,456 participants of European ancestry gathered from the COVID-19 Host Genetics Initiative. Using inverse variance weighted method, our MR study shows that EA was significantly associated with a lower risk of COVID-19 severity (odds ratio per one standard deviation increase in years of schooling, 0.540; 95% confidence interval, 0.376-0.777, P = 0.0009). A series of sensitivity analyses showed little evidence of bias. In conclusion, we show for the first time using a two-sample MR approach the associations between higher EA and the lower risk of COVID-19 severity in the European population. However, the genetic or epidemiological mechanisms underlying the association between EA and the risk of COVID-19 severity remain unknown, and further studies are warranted to validate the MR findings and investigate underlying mechanisms.


Subject(s)
COVID-19 , Mendelian Randomization Analysis , Genome-Wide Association Study , Humans , Polymorphism, Single Nucleotide , SARS-CoV-2
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