Causal associations between severe COVID-19 and diseases of seven organs: a proteome-wide mendelian randomization study
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ABSTRACT:
SUBMITTER: Shen Y
PROVIDER: S-EPMC11347274 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:In November 2021, the COVID-19 pandemic death toll surpassed five million individuals. We applied Mendelian randomization including >3,000 blood proteins as exposures to identify potential biomarkers that may indicate risk for hospitalization or need for respiratory support or death due to COVID-19, respectively. After multiple testing correction, using genetic instruments and under the assumptions of Mendelian Randomization, our results were consistent with higher blood levels of five proteins GCNT4, CD207, RAB14, C1GALT1C1, and ABO being causally associated with an increased risk of hospitalization or respiratory support/death due to COVID-19 (ORs = 1.12-1.35). Higher levels of FAAH2 were solely associated with an increased risk of hospitalization (OR = 1.19). On the contrary, higher levels of SELL, SELE, and PECAM-1 decrease risk of hospitalization or need for respiratory support/death (ORs = 0.80-0.91). Higher levels of LCTL, SFTPD, KEL, and ATP2A3 were solely associated with a decreased risk of hospitalization (ORs = 0.86-0.93), whilst higher levels of ICAM-1 were solely associated with a decreased risk of respiratory support/death of COVID-19 (OR = 0.84). Our findings implicate blood group markers and binding proteins in both hospitalization and need for respiratory support/death. They, additionally, suggest that higher levels of endocannabinoid enzymes may increase the risk of hospitalization. Our research replicates findings of blood markers previously associated with COVID-19 and prioritises additional blood markers for risk prediction of severe forms of COVID-19. Furthermore, we pinpoint druggable targets potentially implicated in disease pathology.
| S-EPMC8893330 | biostudies-literature
Project description:Plasma proteins are promising biomarkers and potential drug targets in lung cancer. To evaluate the causal association between plasma proteins and lung cancer, we performed proteome-wide Mendelian randomization meta-analysis (PW-MR-meta) based on lung cancer genome-wide association studies (GWASs), protein quantitative trait loci (pQTLs) of 4,719 plasma proteins in deCODE and 4,775 in Fenland. Further, causal-protein risk score (CPRS) was developed based on causal proteins and validated in the UK Biobank. 270 plasma proteins were identified using PW-MR meta-analysis, including 39 robust causal proteins (both FDR-q < 0.05) and 78 moderate causal proteins (FDR-q < 0.05 in one and p < 0.05 in another). The CPRS had satisfactory performance in risk stratification for lung cancer (top 10% CPRS:Hazard ratio (HR) (95%CI):4.33(2.65-7.06)). The CPRS [AUC (95%CI): 65.93 (62.91-68.78)] outperformed the traditional polygenic risk score (PRS) [AUC (95%CI): 55.71(52.67-58.59)]. Our findings offer further insight into the genetic architecture of plasma proteins for lung cancer susceptibility.
| S-EPMC10850776 | biostudies-literature
Project description:Genome-wide association studies (GWAS) have identified numerous risk loci for venous thromboembolism (VTE), but it is challenging to decipher the underlying mechanisms. We employed an integrative analytical pipeline to transform genetic associations to identify novel plasma proteins for VTE. Proteome-wide association studies (PWAS) were determined by functional summary-based imputation leveraging data from a genome-wide association analysis (14,429 VTE patients, 267,037 controls), blood proteomes (1348 cases), followed by Mendelian randomization, Bayesian colocalization, protein-protein interaction, and pathway enrichment analysis. Twenty genetically regulated circulating protein abundances (F2, F11, ABO, PLCG2, LRP4, PLEK, KLKB1, PROC, KNG1, THBS2, SERPINA1, RARRES2, CEL, GP6, SERPINE2, SERPINA10, OBP2B, EFEMP1, F5, and MSR1) were associated with VTE. Of these 13 proteins demonstrated Mendelian randomized correlations. Six proteins (F2, F11, PLEK, SERPINA1, RARRES2, and SERPINE2) had strong support in colocalization analysis. Utilizing multidimensional data, this study suggests PLEK, SERPINA1, and SERPINE2 as compelling proteins that may provide key hints for future research and possible diagnostic and therapeutic targets for VTE.
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Project description:BackgroundThe etiology of prostate cancer remained elusive, whether plasma protein levels are associated with prostate cancer is still unknown.MethodsWe have performed Mendelian randomization analyses to calculate the causal effects of plasma proteins on the risk of prostate cancer in the PRACTICAL consortium dataset using cis-protein quantitative trait loci (cis-pQTL) variants as instrumental variables for plasma proteins, and cis-expression quantitative trait locus (cis-eQTL) for the circulating gene expression. We also replicated the findings in the FinnGen consortium.ResultsGenetically proxied levels of 4 plasma proteins (CREB3L4, HDGF, SERPINA3, GNPNAT1) were identified as positively correlated with an increased risk of prostate cancer, while an increase in genetically proxied levels of 5 plasma proteins (TNFRSF6B, GSK3A, EIF4B, CLIC1, SMAD2) were significantly associated with a decreased risk of prostate cancer in the PRACTICAL consortium. Among the identified proteins, the causal effects of six proteins including CREB3L4, HDGF, SERPINA3, TNFRSF6B, EIF4B, and SMAD2 remained significant in the replication analyses in the FinnGen consortium and when combined with meta-analyses (SMAD2: OR 0.710, 95% CI 0.578-0.873, p-value = 0.001; CREB3L4: OR 1.260, 95% CI 1.164-1.364, p-value < 0.0001; HDGF: OR 1.072, 95% CI 1.021-1.125, p-value = 0.005; SERPINA3: OR 1.138, 95% CI 1.091-1.187, p-value < 0.0001; TNFRSF6B: OR 0.656, 95% CI 0.496-0.869, p-value = 0.003; EIF4B: OR 0.701, 95% CI 0.618-0.796, p-value < 0.0001). SMAD2 and CREB3L4 gene expressions proxied with cis-expression quantitative trait loci are also significantly associated with the risk of prostate cancer in both consortiums and when combined with meta-analyses (SMAD2: OR 0.787, 95% CI 0.719-0.861, p-value = 1.00 × 10-4; CREB3L4: OR 1.219, 95% CI 1.033-1.438, p-value = 0.019).ConclusionsOur consistent results highlighted the important roles of plasma SMAD2 and CREB3L4 in the risk of prostate cancer. Further investigations on these proteins may reveal their potential in the prevention and treatment of prostate cancer.
| S-EPMC11853923 | biostudies-literature
Project description:Interstitial lung disease (ILD) has shown limited treatment advancements, with minimal exploration of circulating protein biomarkers causally linked to ILD and its subtypes beyond idiopathic pulmonary fibrosis (IPF). In this study, we aimed to identify potential drug targets and circulating protein biomarkers for ILD and its subtypes. We utilized the most recent large-scale plasma protein quantitative trait loci (pQTL) data detected from the antibody-based method and ILD and its subtypes' GWAS data from the updated FinnGen database for Mendelian randomization analysis. To enhance the reliability of causal associations, we conducted external validation and sensitivity analyses, including Bayesian colocalization and bidirectional Mendelian randomization analysis. Our study identified eight plasma proteins genetically associated with ILD or its subtypes. Among these, three proteins-CDH15 (Cadherin-15), LTBR (Lymphotoxin-beta receptor), and ADAM15 (A disintegrin and metalloproteinase 15)-emerged as priority biomarkers and potential therapeutic targets, demonstrating more reliable associations by passing a series of sensitivity analyses compared to the others. Based on these findings, we propose for the first time that CDH15, ADAM15, and LTBR hold promise as novel potential circulating protein biomarkers and therapeutic targets for the diagnosis and treatment of ILD, IPF, and sarcoidosis, respectively, especially ADAM15, and these findings have the potential to provide new perspectives for advancing the research on the heterogeneity of ILD.
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Project description:Background: CD40 and CD40L have been reported as associated with aortic dissection (AD) and aortic aneurysm (AA), but the causality of the associations has not been established yet. Methods: We conducted a two-sample Mendelian randomization (MR) study to assess the causal inference between CD40/CD40L and aortic diseases including AD and AA. The instrumental variables (IVs) for CD40 and CD40L were selected from a high-quality protein quantitative trait loci dataset released by a genomic study involving 30,931 individuals of European ancestry. The genome-wide association studies summary statistics for AD and AA were from the FinnGen Release 7, with 288638 controls for all outcomes of interests, 680 cases for AD and 6,092 cases for AA, also from European ancestry. For AA subtypes, there were 5,881 cases of thoracic AA (TAA) and 2,434 cases of abdominal AA (AAA) respectively. Inverse-variance weighted and Wald ratio were applied for calculating causal estimates. Horizontal pleiotropy and heterogeneity were assessed using MR-Egger regression analysis and Cochran Q test, respectively. Leave-one-out analyses were further performed. Results: Three single-nucleotide polymorphisms (SNPs) for CD40 and one SNP for CD40L were selected as IVs. We found genetic proxied CD40 levels inversely associated with the risk of AD (odds ratio [OR]: 0.777, 95% confidence interval [CI]: 0.618-0.978, p = 0.031) and AA (OR: 0.905, 95% CI: 0.837-0.978, p = 0.012), consistent across TAA (both p < 0.050). There were trends of increased risks of AD and AA in the presence of CD40L while not reaching statistical significance. No significant horizontal pleiotropy or heterogeneity was observed. Conclusion: Our MR study provides evidence supporting the causal association between CD40 and the reduced risks of both AD and AA.
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Project description:ObjectiveSMI (severe mental illness) has been identified as a risk factor for sepsis in observational studies; however, the causal association between them has yet to be firmly established. We conducted MR (mendelian randomization) to unveil the causal relationship between SMI and sepsis as well as sepsis mortality.MethodsGWAS (Genome-wide association) data for major depression and schizophrenia were selected as exposure. GWAS data for sepsis and sepsis mortality were selected as outcome. Genetic variants significantly associated with the exposure (P value<1x10-6) were selected as instruments. We primarily employed the IVW (inverse-variance weighted) method for analysis. Furthermore, we employed Cochrane's Q test to assess heterogeneity and the MR-Egger intercept test to identify horizontal pleiotropy.ResultsWe selected 108 SNPs (single nucleotide polymorphism) used to predict major depression and 260 SNPs that predicted schizophrenia. Genetically predicted major depression was suggestively linked to a higher sepsis risk (OR=1.13, 95%CI 1.02-1.26, P=0.023). In contrast, MR analysis did not find an association between schizophrenia and sepsis risk (OR=1.00, 95%CI 0.97-1.04, P=0.811). Furthermore, no significant causal evidence was found for genetically predicted SMI in sepsis mortality. Moreover, no heterogeneity and horizontal pleiotropy were detected.ConclusionOur research revealed a suggestive association between genetically predicted major depression and an elevated risk of sepsis in individuals of European ancestry. This finding can serve as a reminder for clinicians to consider the possibility of subsequent infection and sepsis in depressive patients, which may help reduce the incidence of sepsis in individuals with depression.
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Project description:Skin cancer is one of the most common cancers worldwide. Some risk factors including sun exposure and MC1R variants are recognized; however, the identification of additional genetic factors is essential for the development of novel therapeutic strategies. Here, we conducted a proteome-wide Mendelian randomization (MR) using plasma protein quantitative trait loci (pQTLs) from a published study and the UK Biobank genome-wide association study (GWAS) of skin cancers. We replicated the published result of ASIP, which was significantly associated with increased risks of basal cell carcinoma (BCC) and malignant melanoma. Moreover, we newly identified CTSS, which was significantly associated with a decreased risk of BCC. A series of replication analyses using the DeCODE pQTLs and the FinnGen GWAS, and sensitivity analyses including Steiger filtering, reverse MR, and Bayesian colocalization, supported our primary results. Our findings highlighted the possibility of prioritizing proteins for novel therapeutic or preventive targets and biomarkers for skin cancers.
| S-EPMC11659389 | biostudies-literature
Project description:AimsPrevious studies investigated the associations between sleep traits and cardiac diseases, but the evidence for the causal inferences was unclear. This study aimed to explore the causal relationship between sleep and cardiac diseases by virtue of Mendelian randomization (MR).Methods and resultsSummary-level data for exposure variables (sleep duration, chronotype, and insomnia) and outcome variables (ischaemic heart disease, atrial fibrillation, myocardial infarction, and heart failure) were derived from UK Biobank. Data from the FinnGen consortium was used as a robustness check. In MR analysis, the inverse variance weighted (IVW) method was applied to infer causality between exposure and outcome. MR-Egger regression was used to identify pleiotropy, and MR-PRESSO outlier test was used to remove the pleiotropy of the genetic instruments. Based on UK Biobank, MR analysis suggested that sleep duration was weakly associated with atrial fibrillation (OR = 0.9999, 95% CI: 0.9998-0.9999) and ischaemic heart disease (OR = 0.9997, 95% CI: 0.9995-0.9998). Insomnia was associated with ischaemic heart disease (OR = 1.0117, 95% CI: 1.0051-1.0183) and myocardial infarction (OR = 1.0049, 95% CI: 1.0019-1.0079). No associations were found between chronotype and cardiac diseases (P > 0.05). We did not find pleiotropy except for insomnia with ischaemic heart disease and myocardial infarction using MR-Egger regression, and MR-PRESSO analysis consistent with IVW. Finally, we obtained the same direction as with UK Biobank using the FinnGen data.ConclusionsSleep duration and insomnia might be the potential causal risk factors of cardiac diseases. As the OR was small, these associations are probably not clinically relevant. Further validation studies are needed.
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Project description:Many researchers have explored the potential association between one neurosurgical disease and coronavirus disease 2019 (COVID-19), but few systematically analyzed the association and causality between COVID-19 and various neurosurgical diseases. A Mendelian randomization analysis was conducted to evaluate the causal association between COVID-19 (including critically ill COVID-19, hospitalized COVID-19, and respiratory syndrome coronavirus 2 (SARS-CoV-2) infection) and 30 neurosurgical diseases within European populations. The consequences of inverse variance weighted models suggest that genetic susceptibility of critically ill COVID-19 may increase the risk of cerebral infarction (odds ratio [OR] = 1.02; p-value = 0.006), genetic susceptibility of SARS-CoV-2 infection may increase the risk of stroke (OR = 1.02; p-value = 0.047), and conversely, genetic susceptibility of hospitalized COVID-19 may reduce the risk of pituitary adenoma and craniopharyngioma (OR = 0.90; p-value = 0.032). In addition, evidences revealed potential associations between genetic susceptibility of COVID-19 and spinal stenosis (OR = 1.03; p-value = 0.028), diffuse brain injury (OR = 1.21; p-value = 0.040) and focal brain injury (OR = 1.12; p-value = 0.040). By testing for heterogeneity and pleiotropy, the above causal conclusions are robust. In summary, our analysis shows that COVID-19 has an independent and powerful causal influence on multiple neurosurgical disorders.
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