Infections with the coronavirus disease 2019 (COVID-19) and disorders of the heart and blood vessels are causally related. To ascertain the causal relationship between COVID-19 and cardiovascular disease (CVD), we carried out a Mendelian randomization (MR) study through a method known as inverse variance weighting (IVW). When analyzing multiple SNPs, MR can meta-aggregate the effects of multiple loci by using IVW meta-pooling method. The weighted median (WM) is the median of the distribution function obtained by ranking all individual SNP effect values according to their weights. WM yields robust estimates when at least 50% of the information originates from valid instrumental variables (IVs). Directed gene pleiotropy in the included IVs is permitted because MR-Egger does not require a regression straight line through the origin. For MR estimation, IVW, WM and MR-Egger were employed. Sensitivity analysis was conducted using funnel plots, Cochran\'s Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis. SNPs related to exposure to COVID-19 and CVD were compiled. CVD for COVID-19 infection, COVID-19 laboratory/self-reported negative, and other very severe respiratory diagnosis and population were randomly assigned using MR. The COVID-19 laboratory/self-reported negative results and other very severe respiratory confirmed cases versus MR analysis of CVD in the population (p ​> ​0.05); COVID-19 infection to CVD (p ​= ​0.033, OR ​= ​1.001, 95%CI: 1.000-1.001); and the MR-Egger results indicated that COVID-19 infection was associated with CVD risk. This MR study provides preliminary evidence for the validity of the causal link between COVID-19 infection and CVD.

Clinical investigations have highlighted disruptions in bone metabolic processes and abnormal fluctuations in serum indicator levels during the onset of leg disease (LD) in broilers. However, the presence of a genetic causal relationship for this association remains undetermined. Therefore, the aim of this study is to discern the risk factors underlying LD development using 1235 sequenced white-feathered broilers. We employed Mendelian randomization (MR) analysis to assess the associations of bone strength (BS), bone mineral density (BMD), tibial bone weight (TBW), tibial bone length (TBL), tibial bone diameter (TBD), bone ash (BA), ash calcium (Ash Ca), ash phosphorus (Ash P), serum calcium (Ca), serum phosphorus (P), serum alkaline phosphatase (ALP), and serum osteoprotegerin (OPG) with the incidence of LD. Compelling evidence underscores a causal link between the risk of developing LD and decreased BMD (odds ratio (OR) = 0.998; 95% CI: 0.983, 0.993; P < 0.001) and narrower TBD (OR = 0.985, 95% CI: 0.975, 0.994, P = 0.002). Additionally, serum OPG concentrations (OR: 0.995, 95% CI: 0.992, 0.999, P = 0.008) were associated with BMD (OR = 0.0078, 95% CI = 0.0043 to 0.0140, P < 0.001), indicating a robust genetic relationship between ALP concentrations (OR: 0.988, 95% CI: 0.984, 0.993, P < 0.001) and TBD (OR = 0.0046, 95% CI = 0.0026, 0.0083, P < 0.001). Moreover, elevated serum Ca (OR: 0.564, 95% CI: 0.487, 0.655, P < 0.001) and P (OR: 0.614, 95% CI: 0.539, 0.699, P < 0.001) levels were associated with a narrower TBD. Elevated serum levels of Ca, P, ALP, and OPG contribute to disturbances in bone metabolism, while decreased BMD and narrower TBD are associated with a greater risk of developing LD in broilers. This discovery elucidates the metabolic risk factors for LD in broilers and could provide information on LDs, such as osteoporosis, in humans.

The coronavirus disease 2019 (COVID-19) pandemic poses an enormous threat to public health worldwide. Many retrospective studies and case reports to date have shown associations between severe COVID-19 and diseases of multi-organs. However, the research on the causal mechanisms behind this phenomenon is neither extensive nor comprehensive. We conducted a proteome-wide Mendelian randomization (MR) study using summary statistics from a Genome-Wide Association Studies (GWAS) of severe COVID-19 and diseases related to seven organs: lung, spleen, liver, heart, kidney, testis, and thyroid, based on the European ancestry. The primary analytical method used is the radial inverse variance-weighted (radial IVW) method, supplemented with the inverse variance-weighted (IVW), weighted-median (WM), MR-Egger methods. Our findings have confirmed the association between severe COVID-19 and multiple organ-related diseases, such as Hypothyroidism, strict autoimmune (HTCBSA), Thyroid disorders (TD), and Graves\' disease (GD). And we have also identified certain proteins that are associated with organ-related diseases, such as Superoxide Dismutase 2 (SOD2) and TEK Receptor Tyrosine Kinase (TEK), which are also considered potential drug targets. Phenotype scanning and sensitivity analyses were implemented to consolidate the results for Mendelian randomization. This study provides a compelling foundation for investigating COVID-19 caused diseases in future studies.

BACKGROUND: Human aging and white blood cell (WBC) count are complex traits influenced by multiple genetic factors. Predictors of chronological age have been developed using epigenetic clocks. However, the bidirectional causal effects between epigenetic clocks and WBC count have not been fully examined.
METHODS: This study employed Mendelian randomization (MR) to analyze summary statistics from four epigenetic clocks involving 34,710 participants, alongside data from the Blood Cell Consortium encompassing 563,946 individuals. We primarily explored bidirectional causal relationships using the random-effects inverse-variance weighted method, supplemented by additional MR methods for comprehensive analysis. Additionally, multivariate MR was applied to investigate independent effects of WBC count on epigenetic age acceleration.
RESULTS: In the two-sample univariate MR (UVMR) analysis, we observed that a decrease in lymphocyte count markedly accelerated aging according to the PhenoAge, GrimAge, and HannumAge metrics (all P < 0.01, β < 0), though it did not affect Intrinsic Epigenetic Age Acceleration (IEAA). Conversely, an increase in neutrophil count significantly elevated PhenoAge levels (β: 0.38; 95% CI 0.14, 0.61; P = 1.65E-03 < 0.01). Reverse MR revealed no significant causal impacts of epigenetic clocks on overall WBC counts. Furthermore, in multivariate MR, the impact of lymphocyte counts on epigenetic aging metrics remained statistically significant. We also identified a marked causal association between neutrophil counts and PhenoAge, GrimAge, and HannumAge, with respective results showing strong associations (PhenoAge β: 0.78; 95% CI 0.47, 1.09; P = 8.26E-07; GrimAge β: 0.55; 95% CI 0.31, 0.79; P = 5.50E-06; HannumAge β: 0.42; 95% CI 0.18, 0.67; P = 6.30E-04). Likewise, eosinophil cell count demonstrated significant association with HannumAge (β: 0.33; 95% CI 0.13, 0.53; P = 1.43E-03 < 0.01).
CONCLUSIONS: These findings demonstrated that within WBCs, lymphocyte and neutrophil counts exert irreversible and independent causal effects on the acceleration of PhenoAge, GrimAge, and HannumAge. Our findings highlight the critical role of WBCs in influencing epigenetic clocks and underscore the importance of considering immune parameters when interpreting epigenetic age.

BACKGROUND: Telomere shortening and epigenetic modifications are key factors in aging and hematologic diseases. This study investigates the relationship of telomere length and epigenetic age acceleration (EAA) with hematologic cancers, blood cells, and biochemical markers through the epigenetic clocks.
METHODS: This study primarily utilizes genome-wide association studies of populations of European descent as instrumental variables, exploring the causal relationships between exposures and outcomes through a bidirectional two-sample Mendelian randomization (MR) approach. MR techniques include inverse variance weighted (IVW), MR Egger, and weighted median modes. Heterogeneity and pleiotropy in MR are assessed using Cochran\'s Q test and the MR Egger intercept, with the robustness of the conclusions further validated by multivariable MR (MVMR).
RESULTS: Our research shows that longer telomere lengths significantly increase the risk of multiple myeloma, leukemia, and lymphoma (OR > 1, P < 0.05) and establish a causal relationship between telomere length and red blood cell indices such as RBC (OR = 1.121, PIVW = 0.034), MCH (OR = 0.801, PIVW = 2.046e-06), MCV (OR = 0.801, PIVW = 0.001), and MCHC (OR = 0.813, PIVW = 0.002). Additionally, MVMR analysis revealed an association between DNA methylation PhenoAge acceleration and alkaline phosphatase (OR = 1.026, PIVW = 0.007).
CONCLUSIONS: The study clarifies the relationships between telomere length, EAA, and hematological malignancies, further emphasizing the prognostic significance of telomere length and EAA. This deepens our understanding of the pathogenesis of hematological diseases, which can inform risk assessment and therapeutic strategies.

Metabolic syndrome exhibits associations with diverse neurological disorders, and its potential influence on the cerebral cortex may be one of the many potential factors contributing to these adverse outcomes. In this study, we aimed to investigate the causal relationship between metabolic syndrome and changes in cerebral cortex structure using Mendelian randomization analysis. Genome-wide association study data for the 5 components of metabolic syndrome were obtained from individuals of European descent in the UK Biobank. Genome-wide association study data for 34 known cortical functional regions were sourced from the ENIGMA Consortium. Data on Alzheimer\'s disease, major depression, and anxiety disorder were obtained from the IEU Open genome-wide association study database. The causal links between metabolic syndrome elements and cerebral cortex architecture were evaluated using inverse variance weighting, Mendelian randomization-Egger, and weighted median techniques, with inverse variance weighting as the primary method. Inverse variance weighting, Mendelian randomization Egger, weighted median, simple mode, and weighted mode methods were employed to assess the relationships between metabolic syndrome and neurological diseases (Alzheimer\'s disease, major depression, and anxiety disorder). Outliers, heterogeneity, and pleiotropy were assessed using Cochran\'s Q test, MR-PRESSO, leave-one-out analysis, and funnel plots. Globally, no causal link was found between metabolic syndrome and overall cortical thickness or surface area. However, regionally, metabolic syndrome may influence the surface area of specific regions, including the caudal anterior cingulate, postcentral, posterior cingulate, rostral anterior cingulate, isthmus cingulate, superior parietal, rostral middle frontal, middle temporal, insula, pars opercularis, cuneus, and inferior temporal. It may also affect the thickness of the medial orbitofrontal, caudal middle frontal, paracentral, superior frontal, superior parietal, and supramarginal regions. These findings were nominally significant and withstood sensitivity analyses, showing no substantial heterogeneity or pleiotropy. Furthermore, we found an association between metabolic syndrome and the risk of Alzheimer\'s disease, major depression, and anxiety disorder. This study suggests a potential association between metabolic syndrome and changes in cerebral cortex structure, which may underlie certain neurological disorders. Furthermore, we found an association between metabolic syndrome and the risk of Alzheimer\'s disease, major depression, and anxiety disorder. Early diagnosis of metabolic syndrome holds significance in preventing these neurological disorders.

OBJECTIVE: Inflammatory cytokines have been linked to digestive system cancers, yet their exact causal connection remains uncertain. Consequently, we conducted a Mendelian randomization (MR) analysis to gauge how inflammatory cytokines are linked to the risk of five prevalent digestive system cancers (DSCs).
METHODS: We collected genetic variation data for 41 inflammatory cytokines from genome-wide association studies (GWAS), and the results data for five common diseases from the Finnish database. Our primary analytical approach involved employing the inverse-variance weighted, residual sum (IVW) method, complemented by the MR-Egger method, the weighted median method, simple mode analysis, and weighted mode analysis as supplementary analytical techniques. Furthermore, we conducted multiple sensitivity analyses.
RESULTS: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), macrophage colony-stimulating factor (M-CSF), and interleukin (IL)-18 showed a negative association with the risk of hepatocellular carcinoma. Conversely, TRAIL was inversely linked to the risk of gastric cancer, while IL-16 exhibited a positive correlation with gastric cancer risk. Stem cell factor (SCF) acted as a protective factor against pancreatic cancer. For colorectal cancer, IL-7, IL-9, IL-13, and vascular endothelial growth factor (VEGF) were identified as risk factors. Notably, our results did not indicate a significant correlation between inflammatory cytokines and the risk of esophageal cancer.
CONCLUSIONS: Our research unveils potential connections between 41 inflammatory cytokines and the risk of five common DSCs through a MR analysis. These associations offer valuable insights that could aid in the development of diagnostic biomarkers and the identification of novel therapeutic targets for DSCs.

Hypertrophic scar (HS) results from burns or trauma, causing aesthetic and functional issues. However, observational studies have linked inflammatory cytokines to HS, but the causal pathways involved are unclear. We aimed to determine how circulating inflammatory cytokines contribute to HS formation. Two-sample Mendelian randomization (MR) was used to identify genetic variants associated with hypertrophic scar in a comprehensive, publicly available genome-wide association study (GWAS) involving 766 patients and 207,482 controls of European descent. Additionally, data on 91 plasma proteins were drawn from a GWAS summary involving 14,824 healthy participants. Causal relationships between exposures and outcomes were investigated primarily using the inverse variance weighted (IVW) method. Furthermore, a suite of sensitivity analyses, including MR‒Egger and weighted median approaches, were concurrently employed to fortify the robustness of the conclusive findings. Finally, reverse MR analysis was conducted to evaluate the plausibility of reverse causation between hypertrophic scar and the cytokines identified in our study. In inflammatory cytokines, there was evidence of inverse associations of osteoprotegerin(OPG) levels(OR = 0.59, 95% CI = 0.41 ∼ 0.85, p = 0.01), and leukemia inhibitory factor(LIF) levels(OR = 0.51, 95% CI = 0.32 ∼ 0.82, p = 0.01) are a nominally negative association with hypertrophic scar risk, while CUB domain-domain-containing protein 1(CDCP1) level(OR = 0.59, 95% CI = 0.41 ∼ 0.85, p = 0.01) glial cell line-derived neurotrophic factor(GDNF) levels(OR = 1.42, 95% CI = 1.03 ∼ 1.96, p = 0.01) and programmed cell death 1 ligand 1(PD-L1) levels(OR = 1.47, 95% CI = 1.92 ∼ 2.11, p = 0.04) showed a positive association with hypertrophic scar risk. These associations were similar in the sensitivity analyses. According to our MR findings, OPG and LIF have a protective effect on hypertrophic scar, while CDCP1, GDNF, and PD-L1 have a risk-increasing effect on Hypertrophic scar. Our study adds to the current knowledge on the role of specific inflammatory biomarker pathways in hypertrophic scar. Further validation is needed to assess the potential of these cytokines as pharmacological or lifestyle targets for hypertrophic scar prevention and treatment.

Despite observational studies suggesting a link between psoriatic disease (including psoriasis and psoriatic arthritis) and migraine, it is unclear whether there is a shared genetic etiology or a causal relationship between the two conditions. We aimed to reveal the genetic overlap and causality using the Mendelian randomization (MR) framework. The genetic analysis utilized summary data from the most extensive European genome-wide association study (GWAS) of migraine. Well-powered psoriatic disease GWAS data were obtained from two independent cohort studies, which served as discovery and validation datasets. Global and regional genetic correlations between psoriatic disease and migraine were assessed, and pleiotropic regions identified by pairwise GWAS analysis were further annotated. We further applied a two-sample MR multivariate MR to investigate the potential causal relationship between them. The global genetic correlation test indicated weak correlations between psoriatic disease and migraine, while regional correlation analyses delineated one significant shared locus between psoriasis and migraine. Pathway enrichment analysis revealed that shared genes were involved biological processes to the major histocompatibility and antigen processing and presentation. In terms of causality estimates, genetically predicted psoriasis (Pmeta = 0.003) and psoriatic arthritis (Pmeta = 0.028) were associated with an increased risk of migraine. Multivariate MR analysis indicated that psoriasis was an independent risk factor for migraine (P < 0.05). No significant associations were found in the reverse direction. Our study supported the causal role of psoriasis on migraine, and the central role for immunomodulatory etiology. These findings have significant implications for the management of migraine and clinical practice in patients with psoriasis.

UNASSIGNED: Observational epidemiological studies have indicated a potential association between asthma and sepsis, although the causal relationship between these 2 conditions remains uncertain. To further investigate this relationship, the present study utilized Mendelian randomization (MR) analysis approach to explore the potential links between asthma and various types of sepsis.
UNASSIGNED: In a large-scale genome-wide association study, single nucleotide polymorphisms (SNPs) associated with asthma were selected as instrumental variables. Three methods, including inverse-variance weighted (IVW), MR-Egger regression, and weighted median were used to assess the causal relationship between asthma and sepsis. The odds ratio (OR) and 95% confidence interval (CI) were used as the evaluation metrics for causal relationships, and sensitivity analysis was conducted to assess pleiotropy and instrument validity. Finally, a reverse MR analysis was conducted to investigate whether there is a causal relationship between sepsis and asthma.
UNASSIGNED: We found a positive association between asthma and an increased risk of sepsis (OR=1.18, P＜0.05), streptococcal sepsis (OR=1.23, P=0.04), pneumonia-related sepsis (OR=1.57, P＜0.05), pneumococcal sepsis (OR=1.58, P=0.01), other sepsis (OR=1.15, P＜0.05), and sepsis in intensive care unit (ICU) settings (OR=1.23, P=0.02). Sensitivity analysis showed consistent results without heterogeneity or pleiotropy. The reverse MR analysis reveals no causal relationship between various types of sepsis and asthma.
UNASSIGNED: Our study demonstrates a causal relationship between asthma and different types of sepsis. These findings suggest the importance of healthcare providers paying attention to the potential risk of sepsis in asthma patients and implementing appropriate preventive and intervention measures in a timely manner.