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1.
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
2.
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
3.
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
4.
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
5.
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
6.
Sci Rep ; 12(1): 16157, 2022 09 28.
Article in English | MEDLINE | ID: covidwho-2050541

ABSTRACT

Observational studies have indicated an association between iron status and risk of sepsis and COVID-19. We estimated the effect of genetically-predicted iron biomarkers on risk of sepsis and risk of being hospitalized with COVID-19, performing a two-sample Mendelian randomization study. For risk of sepsis, one standard deviation increase in genetically-predicted serum iron was associated with odds ratio (OR) of 1.14 (95% confidence interval [CI] 1.01-1.29, P = 0.031). The findings were supported in the analyses for transferrin saturation and total iron binding capacity, while the estimate for ferritin was inconclusive. We found a tendency of higher risk of hospitalization with COVID-19 for serum iron; OR 1.29 (CI 0.97-1.72, P = 0.08), whereas sex-stratified analyses showed OR 1.63 (CI 0.94-2.86, P = 0.09) for women and OR 1.21 (CI 0.92-1.62, P = 0.17) for men. Sensitivity analyses supported the main findings and did not suggest bias due to pleiotropy. Our findings suggest a causal effect of genetically-predicted higher iron status and risk of hospitalization due to sepsis and indications of an increased risk of being hospitalized with COVID-19. These findings warrant further studies to assess iron status in relation to severe infections, including the potential of improved management.


Subject(s)
COVID-19 , Sepsis , Biomarkers , COVID-19/genetics , Female , Ferritins , Genome-Wide Association Study , Humans , Iron/metabolism , Male , Mendelian Randomization Analysis , Polymorphism, Single Nucleotide , Sepsis/genetics , Transferrin/metabolism
7.
Endocrinology ; 163(11)2022 10 11.
Article in English | MEDLINE | ID: covidwho-2021399

ABSTRACT

Several observational studies have confirmed the relationship between thyroid hormones and coronavirus disease 2019 (COVID-19), but this correlation remains controversial. We performed a two-sample Mendelian randomization (MR) analysis based on the largest publicly available summary datasets. Summary statistics with 49 269 individuals for free thyroxine (FT4) and 54 288 for thyroid stimulating hormone (TSH) were used as exposure instruments. Genome-wide association studies of susceptibility (cases = 38 984; controls = 1 644 784), hospitalization (cases: 9986 = controls = 1 877 672), and very severe disease (cases = 5101; controls = 1 383 241) of COVID-19 were used as the outcome. We used the inverse-variance weighted (IVW) method as the primary analysis, and utilized MR-Egger regression, weighted median, and robust adjusted profile score (RAPS) for sensitivity analysis. Genetic predisposition to higher serum levels of FT4 within the normal range was negatively associated with the risk of COVID-19 hospitalization (odds ratio [OR] = 0.818; 95% CI, 0.718-0.932; P = 2.6 × 10-3) and very severe disease (OR = 0.758; 95% CI, 0.626-0.923; P = 5.8 × 10-3), but not susceptibility. There is no evidence that genetically predicted circulating TSH levels are associated with COVID-19 susceptibility and severity risk. Neither apparent pleiotropy nor heterogeneity were detected in the sensitivity analysis. In summary, we found that higher FT4 levels may reduce the risk of COVID-19 severity, suggesting that thyroid function testing may be required for patients with COVID-19.


Subject(s)
COVID-19 , Thyroid Gland , COVID-19/diagnosis , Disease Susceptibility , Genome-Wide Association Study , Humans , Mendelian Randomization Analysis/methods , Thyroid Gland/physiopathology , Thyrotropin , Thyroxine
8.
Psychiatry Res ; 317: 114809, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-1996499

ABSTRACT

The coronavirus SARS-CoV-2 invades the central nervous system, impacting the mental health of COVID-19 patients. We performed a two-sample Mendelian randomization analysis to assess the potential causal effects of COVID-19 on schizophrenia. Our analysis indicated that genetic liability to hospitalized COVID-19 was associated with an increased risk for schizophrenia (OR: 1.11, 95% CI: 1.02-1.20, P = 0.013). However, genetic liability to SARS-CoV-2 infection was not associated with the risk of schizophrenia (1.06, 0.83-1.37, P = 0.643). Severe COVID-19 was associated with an 11% increased risk for schizophrenia, suggesting that schizophrenia should be assessed as one of the post-COVID-19 sequelae.


Subject(s)
COVID-19 , Schizophrenia , Humans , SARS-CoV-2 , Schizophrenia/epidemiology , Mendelian Randomization Analysis , Hospitalization , Genome-Wide Association Study
9.
Nutrients ; 14(14)2022 Jul 06.
Article in English | MEDLINE | ID: covidwho-1969397

ABSTRACT

Poor diet is a leading cause of morbidity and mortality [...].


Subject(s)
Mendelian Randomization Analysis , Outcome Assessment, Health Care , Morbidity , Risk Factors
10.
J Med Virol ; 94(11): 5345-5353, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-1935703

ABSTRACT

Several traditional observational studies suggested an association between COVID-19 and leukocyte telomere length (LTL), a biomarker for biological age. However, whether there was a causal association between them remained unclear. We aimed to investigate whether genetically predicted COVID-19 is related to the risk of LTL, and vice versa. We performed bidirectional Mendelian randomization (MR) study using summary statistics from the genome-wide association studies of critically ill COVID-19 (n = 1 388 342) and LTL (n = 472 174) of European ancestry. The random-effects inverse-variance weighted estimation method was applied as the primary method with several other estimators as complementary methods. Using six single-nucleotide polymorphisms (SNPs) of genome-wide significance as instrumental variables for critically ill COVID-19, we did not find a significant association of COVID-19 on LTL (ß = 0.0075, 95% confidence interval [CI]: -0.018 to 0.021, p = 0.733). Likewise, using 97 SNPs of genome-wide significance as instrumental variables for LTL, we did not find a significant association of LTL on COVID-19 (odds ratio = 1.00, 95% CI: 0.79-1.28, p = 0.973). Comparable results were obtained using MR-Egger regression, weighted median, and weighted mode approaches. We did not find evidence to support a causal association between COVID-19 and LTL in either direction.


Subject(s)
COVID-19 , Genome-Wide Association Study , COVID-19/genetics , Critical Illness , Humans , Mendelian Randomization Analysis , Polymorphism, Single Nucleotide , Telomere/genetics
11.
Transl Psychiatry ; 12(1): 283, 2022 Jul 14.
Article in English | MEDLINE | ID: covidwho-1931377

ABSTRACT

Emerging evidence has suggested a close correlation between COVID-19 and neurodegenerative disorders. However, whether there exists a causal association and the effect direction remains unknown. To examine the causative role of COVID-19 in the risk of neurodegenerative disorders, we estimated their genetic correlation, and then conducted a two-sample Mendelian randomization analysis using summary statistics from genome-wide association studies of susceptibility, hospitalization, and severity of COVID-19, as well as six major neurodegenerative disorders including Alzheimer's disease (AD), amyotrophic lateral sclerosis, frontotemporal dementia, Lewy body dementia, multiple sclerosis, and Parkinson's disease. We identified a significant and positive genetic correlation between hospitalization of COVID-19 and AD (genetic correlation: 0.23, P = 8.36E-07). Meanwhile, hospitalization of COVID-19 was significantly associated with a higher risk of AD (OR: 1.02, 95% CI: 1.01-1.03, P: 1.19E-03). Consistently, susceptibility (OR: 1.05, 95% CI: 1.01-1.09, P: 9.30E-03) and severity (OR: 1.01, 95% CI: 1.00-1.02, P: 0.012) of COVID-19 were nominally associated with higher risk of AD. The results were robust under all sensitivity analyses. These results demonstrated that COVID-19 could increase the risk of AD. Future development of preventive or therapeutic interventions could attach importance to this to alleviate the complications of COVID-19.


Subject(s)
Alzheimer Disease , COVID-19 , Neurodegenerative Diseases , Alzheimer Disease/epidemiology , Alzheimer Disease/genetics , Genome-Wide Association Study/methods , Humans , Mendelian Randomization Analysis/methods , Neurodegenerative Diseases/epidemiology , Neurodegenerative Diseases/genetics
12.
Andrologia ; 54(10): e14527, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-1927556

ABSTRACT

Coronavirus disease 19 (COVID-19) and erectile dysfunction (ED) have been linked in some observational research, but the causality of this association in the European population is uncertain. Therefore, the research intended to investigate the causality of susceptibility to COVID-19 on ED. We used Mendelian randomization (MR) analysis for this research. The subjects were from two genome-wide association studies (GWAS) of the European population, including COVID-19 (14,134 cases and 1,284,876 controls) and ED (6175 cases and 217,630 controls). We utilized the inverse variance-weighted (IVW) to evaluate the causality of COVID-19 genetic susceptibility on ED. Heterogeneity and pleiotropy were determined using the Cochran's Q test and MR-Egger regression. The robustness of the findings was verified using the Leave-one-out method. We obtained six single nucleotide polymorphisms (SNPs) as COVID-19 genetic instrumental variables (IVs), and there was no significant pleiotropy, heterogeneity or bias in these IVs. MR analysis revealed the causality of genetic susceptibility to COVID-19 on elevated risk of ED (ORIVW  = 1.235, 95% CI: 1.044-1.462, p < 0.05). The present study suggested the causality of genetic susceptibility to COVID-19 on elevated ED risk among the European population. Therefore, in order to decrease the ED risk, the European population ought to positively prevent COVID-19.


Subject(s)
COVID-19 , Erectile Dysfunction , COVID-19/epidemiology , COVID-19/genetics , Erectile Dysfunction/epidemiology , Erectile Dysfunction/genetics , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Male , Mendelian Randomization Analysis , Polymorphism, Single Nucleotide
13.
EBioMedicine ; 81: 104112, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1906948

ABSTRACT

BACKGROUND: Recent omic studies prioritised several drug targets associated with coronavirus disease 2019 (COVID-19) severity. However, little evidence was provided to systematically estimate the effect of drug targets on COVID-19 severity in multiple ancestries. METHODS: In this study, we applied Mendelian randomization (MR) and colocalization approaches to understand the putative causal effects of 16,059 transcripts and 1608 proteins on COVID-19 severity in European and effects of 610 proteins on COVID-19 severity in African ancestry. We further integrated genetics, clinical and literature evidence to prioritise drug targets. Additional sensitivity analyses including multi-trait colocalization and phenome-wide MR were conducted to test for MR assumptions. FINDINGS: MR and colocalization prioritized four protein targets, FCRL3, ICAM5, ENTPD5 and OAS1 that showed effect on COVID-19 severity in European ancestry. One protein target, SERPINA1 showed a stronger effect in African ancestry but much weaker effect in European ancestry (odds ratio [OR] in Africans=0.369, 95%CI=0.203 to 0.668, P = 9.96 × 10-4; OR in Europeans=1.021, 95%CI=0.901 to 1.157, P = 0.745), which suggested that increased level of SERPINA1 will reduce COVID-19 risk in African ancestry. One protein, ICAM1 showed suggestive effect on COVID-19 severity in both ancestries (OR in Europeans=1.152, 95%CI=1.063 to 1.249, P = 5.94 × 10-4; OR in Africans=1.481, 95%CI=1.008 to 2.176; P = 0.045). The OAS1, SERPINA1 and ICAM1 effects were replicated using updated COVID-19 severity data in the two ancestries respectively, where alternative splicing events in OAS1 and ICAM1 also showed marginal effects on COVID-19 severity in Europeans. The phenome-wide MR of the prioritised targets on 622 complex traits provided information on potential beneficial effects on other diseases and suggested little evidence of adverse effects on major complications. INTERPRETATION: Our study identified six proteins as showing putative causal effects on COVID-19 severity. OAS1 and SERPINA1 were targets of existing drugs in trials as potential COVID-19 treatments. ICAM1, ICAM5 and FCRL3 are related to the immune system. Across the six targets, OAS1 has no reliable instrument in African ancestry; SERPINA1, FCRL3, ICAM5 and ENTPD5 showed a different level of putative causal evidence in European and African ancestries, which highlights the importance of more powerful ancestry-specific GWAS and value of multi-ancestry MR in informing the effects of drug targets on COVID-19 across different populations. This study provides a first step towards clinical investigation of beneficial and adverse effects of COVID-19 drug targets. FUNDING: No.


Subject(s)
COVID-19 , Mendelian Randomization Analysis , COVID-19/drug therapy , COVID-19/genetics , Genome-Wide Association Study , Humans , Odds Ratio , Phenotype , Polymorphism, Single Nucleotide
14.
Int J Epidemiol ; 51(5): 1371-1383, 2022 10 13.
Article in English | MEDLINE | ID: covidwho-1908816

ABSTRACT

BACKGROUND: Due to its large impact on human health, socio-economic status (SES) could at least partially influence the established association between obesity and coronavirus disease 2019 (COVID-19) severity. To estimate the independent effect of body size and SES on the clinical manifestations of COVID-19, we conducted a Mendelian randomization (MR) study. METHODS: Applying two-sample MR approaches, we evaluated the effects of body mass index (BMI, n = 322 154), waist circumference (WC, n = 234 069), hip circumference (n = 213 019) and waist-hip ratio (n = 210 088) with respect to three COVID-19 outcomes: severe respiratory COVID-19 (cases = 8779, controls = 1 000 875), hospitalized COVID-19 (cases = 17 992, controls = 1 810 493) and COVID-19 infection (cases = 87 870, controls = 2 210 804). Applying a multivariable MR (MVMR) approach, we estimated the effect of these anthropometric traits on COVID-19 outcomes accounting for the effect of SES assessed as household income (n = 286 301). RESULTS: BMI and WC were associated with severe respiratory COVID-19 [BMI: odds ratio (OR) = 1.51, CI = 1.24-1.84, P = 3.01e-05; WC: OR = 1.48, 95% CI = 1.15-1.91, P = 0.0019] and hospitalized COVID-19 (BMI: OR = 1.50, 95% CI = 1.32-1.72, P = 8.83e-10; WC: OR = 1.41, 95% CI = 1.20-1.67, P = 3.72e-05). Conversely, income was associated with lower odds of severe respiratory (OR = 0.70, 95% CI = 0.53-0.93, P = 0.015) and hospitalized COVID-19 (OR = 0.78, 95% CI = 0.66-0.92, P = 0.003). MVMR analyses showed that the effect of these obesity-related traits on increasing the odds of COVID-19 negative outcomes becomes null when accounting for income. Conversely, the association of income with lower odds of COVID-19 negative outcomes is not affected when including the anthropometric traits in the multivariable model. CONCLUSION: Our findings indicate that SES contributes to the effect of obesity-related traits on COVID-19 severity and hospitalization.


Subject(s)
COVID-19 , Body Mass Index , COVID-19/epidemiology , Economic Status , Genome-Wide Association Study , Hospitalization , Humans , Mendelian Randomization Analysis , Obesity/epidemiology , Polymorphism, Single Nucleotide
15.
Thyroid ; 32(9): 1037-1050, 2022 09.
Article in English | MEDLINE | ID: covidwho-1901050

ABSTRACT

Background: Thyroid dysfunction has been observed among some patients with coronavirus disease (COVID-19). It is unclear whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (or its severity) leads to the development of thyroid dysfunction, or vice versa. In this study, we examined the bi-directional causal relationship between host genetic liability to three COVID-19 phenotypes (including SARS-CoV-2 infection, hospitalized and severe COVID-19) and three thyroid dysfunction traits (including hyperthyroidism, hypothyroidism, and autoimmune thyroid disease [AITD]) and three continuous traits of thyroid hormones (including thyrotropin [TSH] and free thyroxine [fT4] within reference range, and TSH in full range). Methods: Summary statistics from the largest available meta-analyses of human genome-wide association studies were retrieved for the following variables: SARS-CoV-2 infection (n = 1,348,701), COVID-19 hospitalization (n = 1,557,411), severe COVID-19 (n = 1,059,456), hyperthyroidism (n = 51,823), hypothyroidism (n = 53,423), AITD (n = 755,406), TSH within reference range (n = 54,288), fT4 within reference range (n = 49,269), and TSH in full range (n = 119,715). Using a two-sample Mendelian randomization (MR) approach, the inverse-variance weighted (IVW) method was adopted as the main MR analysis. Weighted median, contamination mixture, MR-Egger, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods were applied as sensitivity analyses. Results: Host genetic susceptibility to SARS-CoV-2 infection was causally associated with hypothyroidism in the main IVW analysis (per doubling in prevalence of SARS-CoV-2 infection, odds ratio [OR] = 1.335; 95% confidence interval [CI]: 1.167-1.526; p = 2.4 × 10-5, surpassing the Bonferroni multiple-testing threshold). Similar causal estimates were observed in the sensitivity analyses (weighted median: OR = 1.296; CI: 1.066-1.575; p = 9 × 10-3; contamination mixture: OR = 1.356; CI: 1.095-1.818; p = 0.013; MR-Egger: OR = 1.712; CI: 1.202-2.439; p = 2.92 × 10-3, and MR-PRESSO: OR = 1.335; CI: 1.156-1.542; p = 5.73 × 10-4). Host genetic liability to hospitalized or severe COVID-19 was not associated with thyroid dysfunction or thyroid hormone levels. In the reverse direction, there was no evidence to suggest that genetic predisposition to thyroid dysfunction or genetically determined thyroid hormone levels altered the risk of the COVID-19 outcomes. Conclusions: This bi-directional MR study supports that host response to SARS-CoV-2 viral infection plays a role in the causal association with increased risk of hypothyroidism. Long-term follow-up studies are needed to confirm the expected increased hypothyroidism risk.


Subject(s)
COVID-19 , Hyperthyroidism , Hypothyroidism , COVID-19/epidemiology , COVID-19/genetics , Genetic Predisposition to Disease , Genome-Wide Association Study/methods , Humans , Hyperthyroidism/epidemiology , Hyperthyroidism/genetics , Hypothyroidism/epidemiology , Hypothyroidism/genetics , Mendelian Randomization Analysis/methods , Polymorphism, Single Nucleotide , SARS-CoV-2 , Thyrotropin/genetics , Thyroxine
16.
J Med Virol ; 94(10): 4735-4743, 2022 10.
Article in English | MEDLINE | ID: covidwho-1898899

ABSTRACT

This study aimed to evaluate the host genetic liability of coronavirus disease 2019 (covid-19) with platelet traits using the Mendelian randomization (MR) approach. We conducted a bidirectional two-sample MR using summary statistics from the largest genome-wide association study of three variables, covid-19 severity (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection, covid-19 hospitalization, and severe covid-19, N = ~1 059 456-1 557 411) and four platelet traits (mean platelet volume [MPV], plateletcrit, platelet distribution width, and platelet count; N = 408 112). Inverse-variance weighted (IVW), median weighted, MR-Egger, and contamination mixture methods were used to estimate the causal association. Null and inconsistent associations in the IVW and sensitivity analyses were observed for SARS-CoV-2 infection and covid-19 hospitalization with platelet traits. For severe covid-19, significant associations with MPV and platelet count were observed in the IVW and sensitivity analyses, with the betaIVW of 0.01 (95% confidence interval [CI]: 0.005-0.016, p = 3.51 × 10-4 ) and -0.009 (95% CI: -0.015 to -0.002, p = 0.008) per doubling in odds of severe covid-19, respectively. Conversely, null associations were observed for platelet traits with covid-19 traits. In conclusion, host genetic liability to severe covid-19 was causally associated with increased MPV and reduced platelet count, which may provide insights into evaluating hypercoagulability and thromboembolic events in covid-19 patients.


Subject(s)
COVID-19 , Genome-Wide Association Study , COVID-19/genetics , Humans , Mendelian Randomization Analysis , Polymorphism, Single Nucleotide , SARS-CoV-2/genetics
18.
Addiction ; 117(7): 2027-2036, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1891443

ABSTRACT

BACKGROUND AND AIMS: Smoking increases the risk of severe COVID-19, but whether lung function or chronic obstructive pulmonary disease (COPD) mediate the underlying associations is unclear. We conducted the largest Mendelian randomization study to date, to our knowledge, to address these questions. DESIGN: Mendelian randomization study using summary statistics from genome-wide association studies (GWAS), FinnGen and UK Biobank. The main analysis was the inverse variance weighted method, and we included a range of sensitivity analyses to assess the robustness of the findings. SETTING: GWAS which included international consortia, FinnGen and UK Biobank. PARTICIPANTS: The sample size ranged from 193 638 to 2 586 691. MEASUREMENTS: Genetic determinants of life-time smoking index, lung function [e.g. forced expiratory volume in 1 sec (FEV1 )], chronic obstructive pulmonary disease (COPD) and different severities of COID-19. RESULTS: Smoking increased the risk of COVID-19 compared with population controls for overall COVID-19 [odds ratio (OR) = 1.19 per standard deviation (SD) of life-time smoking index, 95% confidence interval (CI) = 1.11-1.27], hospitalized COVID-19 (OR = 1.67, 95% CI = 1.42-1.97) or severe COVID-19 (OR = 1.48, 95% CI = 1.10-1.98), with directionally consistent effects from sensitivity analyses. Lung function and COPD liability did not appear to mediate these associations. CONCLUSION: There is genetic evidence that smoking probably increases the risk of severe COVID-19 and possibly also milder forms of COVID-19. Decreased lung function and increased risk of chronic obstructive pulmonary disease do not seem to mediate the effect of smoking on COVID-19 risk.


Subject(s)
COVID-19 , Pulmonary Disease, Chronic Obstructive , COVID-19/genetics , Genome-Wide Association Study , Humans , Lung , Mendelian Randomization Analysis , Polymorphism, Single Nucleotide , Pulmonary Disease, Chronic Obstructive/epidemiology , Pulmonary Disease, Chronic Obstructive/genetics , Risk Factors , Smoking/adverse effects
19.
BMC Cardiovasc Disord ; 22(1): 262, 2022 06 11.
Article in English | MEDLINE | ID: covidwho-1886916

ABSTRACT

BACKGROUND: Previous studies have observed inconsistent associations between coronavirus disease 2019 (COVID-19) and heart failure (HF), but these studies were prone to bias based on reverse causality and residual confounding factors. We aimed to investigate genetic liability between COVID-19 and heart failure using a bidirectional Mendelian randomization study. METHODS: The causal relationship between COVID-19 (including COVID-19, hospitalized COVID-19 compared with the general population, and severe COVID-19) and HF are determined by using a bidirectional Mendelian randomization analysis. We drew on summary statistics from the largest HF genome-wide association study (GWAS) meta-analysis on individuals of European ancestry, which included 47,309 HF patients and 930,014 controls. The inverse variance weighted (IVW), an adaption of the Egger regression (MR-Egger), the weighted median, and weighted model were conducted for the Mendelian randomization analysis to estimate a causal effect. To confirm the stability, we performed a "leave-one-out" approach for the sensitivity analysis. RESULTS: Genetically predicted severe COVID-19 was not significantly associated with the risk of HF [odds ratio (OR), 1.003; 95% confidence interval (CI), 0.969-1.037; p = 0.867]. The IVW demonstrated that there was no association between genetically hospitalized COVID-19 infection and HF risk [OR, 1.009; 95% CI, 0.939-1.085; p = 0.797]. There was no evidence to support the association between genetically determined COVID-19 and the risk of HF [OR, 1.066; 95% CI, 0.955-1.190; p = 0.253]. In addition, genetically predicted HF was also not causally associated with COVID-19 [OR, 1.162; 95% CI, 0.824-1.639; p = 0.393]. MR-Egger analysis indicated no evidence of directional pleiotropy. CONCLUSION: The current bidirectional Mendelian randomization analysis overcomes the limitations of observational studies. Our findings indicated that there is no causal association between COVID-19 and HF.


Subject(s)
COVID-19 , Heart Failure , COVID-19/genetics , Genome-Wide Association Study , Heart Failure/diagnosis , Heart Failure/genetics , Humans , Mendelian Randomization Analysis , Polymorphism, Single Nucleotide
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