Two-sample Mendelian Randomization Analysis Research Articles

Mendelian randomization reveals that abnormal lipid metabolism mediates the causal relationship between body mass index and keratoconus

Previous studies suggest that a high body mass index (BMI) may be a risk factor for keratoconus (KC), but the causal relationship remains unclear. This study used Mendelian randomization (MR) to investigate this connection and explore the mediating role of circulating serum metabolites and inflammatory factors in this association. Two-sample MR analysis was conducted to assess the relationship between BMI and KC. The study employed a two-step MR approach to evaluate the mediating roles of 91 inflammatory markers and 249 serum metabolites in the BMI-KC relationship. Inverse variance weighting (IVW) was the primary method, and multiple sensitivity analyses were performed to ensure robustness. IVW analysis revealed a positive causal relationship between BMI and KC (OR IVW = 1.811, 95% CI 1.005–3.262, P = 0.048). Although IL-12β and IL-4 were causally associated with KC, they did not mediate the BMI-KC relationship. Five serum metabolites were identified as potential mediators, with HDL cholesterol and triglyceride ratios showing significance. This study clarified the causal relationship between high BMI and KC, suggesting that high BMI may induce KC through lipid metabolism abnormalities. These findings underscore the importance of managing BMI for KC prevention.

Can depression lead to chronic constipation, or does chronic constipation worsen depression? NHANES 2005–2010 and bidirectional mendelian randomization analyses

BackgroundDepression and chronic constipation often co-occur, but the reciprocal influence between the two remains unclear. The purpose of this study is to explore the potential association between depression and chronic constipation.MethodsThis study initially utilized data from National Health and Nutrition Examination Survey (NHANES) 2005–2010 to explore the correlation between depression scores and chronic constipation, assessing the non-linear relationship between the two. Subsequently, we conducted a two-sample Mendelian randomization (MR) analysis to evaluate the causal relationship between depression and major depression with chronic constipation. The Inverse Variance Weighting (IVW) method served as the primary reference, supplemented by sensitivity tests. Finally, a reverse MR analysis was performed to assess the presence of any reverse causation. The STROBE-MR checklist for the reporting of MR studies was used in this study.ResultsIn the NHANES analysis, survey-weighted logistic regression revealed a significantly positive correlation between depression scores and chronic constipation (OR = 1.04, 95% CI = 1.02–1.07, p = 0.002), even after adjusting for the included covariates. The nonlinear analysis using Restricted Cubic Splines (RCS) enhanced the robustness of the association (P-non-liner = 0.01). The MR analysis also confirmed the causal relationship between depression (OR = 11.43, 95% CI = 1.85–70.67, p = 0.008) and major depression (OR = 1.12, 95% CI = 1.03–1.22, p = 0.007) with chronic constipation, passing rigorous sensitivity tests. No evidence of reverse causation was observed in the reverse MR analysis (P > 0.05).ConclusionsDepression is positively correlated with the risk of chronic constipation. Therefore, enhancing attention to chronic constipation in patients with depression may be effective in clinical practice.

The role of mitochondrial DNA copy number in autoimmune disease: a bidirectional two sample mendelian randomization study.

Mitochondrial DNA (mtDNA) plays an important role in autoimmune diseases (AD), yet the relationship between mitochondria and autoimmune disease is controversial. This study employed bidirectional Mendelian randomization (MR) to explore the causal relationship between mtDNA copy number and 13 ADs (including ankylosing spondylitis [AS], Crohn's disease [CD], juvenile rheumatoid arthritis [JRA], polymyalgia rheumatica [PMR], psoriasis [PSO], rheumatoid arthritis [RA], Sjogren's syndrome [SS], systemic lupus erythematosus [SLE], thyrotoxicosis, type 1 diabetes mellitus [T1DM], ulcerative colitis [UC], and vitiligo). A two-sample MR analysis was performed to assess the causal relationship between mtDNA copy number and AD. Genome-wide association study (GWAS) for mtDNA copy number were obtained from the UK Biobank (UKBB), while those associated with AD were sourced from the FinnGen Biobank. Inverse variance weighting (IVW) was the primary analysis method, complemented by three sensitivity analyses (MR-Egger, weighted median, weighted mode) to validate the results. IVW MR analysis identified significant associations between mtDNA copy number and CD (OR=2.51, 95% CI 1.56-4.22, P<0.001), JRA (OR=1.87, 95% CI 1.17-7.65, P=0.022), RA (OR=1.71, 95%CI 1.18-2.47, P=0.004), thyrotoxicosis (OR=0.51, 95% CI0.27-0.96, P=0.038), and T1DM (OR=0.51, 95% CI 0.27-0.96, P=0.038). Sensitivity analyses indicated no horizontal pleiotropy. Our study revealed a potential causal relationship between mtDNA copy number and ADs, indicating that these markers may be relevant in exploring new therapeutic approaches.

Relationship between hearing impairment and dementia and cognitive function: a Mendelian randomization study

BackgroundThere is a substantial body of observational research indicating an association between hearing impairment and dementia, yet the causal relationship and underlying mechanisms remain uncertain. This study aims to investigate the causal relationship between hearing impairment and its subtypes with dementia and cognitive function using two-sample Mendelian randomization (MR) analysis.MethodsWe performed two-sample MR analysis to examine the causal effects of hearing impairment and its subtypes, including conductive and sensorineural hearing loss (CSHL), conductive hearing loss (CHL), sensorineural hearing loss (SHL), and sudden sensorineural hearing loss (SIHL), on six dementia phenotypes (overall dementia, Alzheimer’s disease [AD], Lewy body dementia [DLB], frontotemporal dementia [FTD], Parkinson’s disease dementia, and vascular dementia) and four cognitive functions. Additionally, multivariable MR (MVMR) analysis was employed to investigate potential mediating mechanisms.ResultsGenetically determined CSHL was associated with an elevated risk of DLB (odds ratio [OR] 1.69; 95% CI 1.08 to 2.63; P = 0.021) and FTD (OR 1.66; 1.04 to 2.67; P = 0.035), but not AD (P = 0.958). Genetic predisposition to CHL was found to link with increased risks of AD (OR 1.07; 1.01 to 1.14; P = 0.031). Genetically determined SHL was causally associated with an elevated risk of semantic dementia (OR 3.81; 1.09 to 13.37; P = 0.037). Genetically predicted CHL and SIHL were both causally associated with lower general cognitive performance (β -0.015 and − 0.043; P = 0.007 and 0.013) and fluid intelligence score (β -0.045 and − 0.095; P = 0.037 and 0.040). In MVMR analysis, the causal relationship between hearing impairment and dementia was mediated by loneliness, depressed mood, and brain cortical volume, particularly the medial temporal lobe, but not by aging or ischemic stroke.ConclusionOverall, the study provides evidence supporting a causal relationship between hearing impairment and increased risks of different types of dementia (including AD, FTD, and DLB), as well as poorer general cognitive function. These findings underscore the importance of addressing hearing impairment as a modifiable risk factor for dementia.

A genetically informed study reveals modifiable pathways in skin cancer

BackgroundIdentifying modifiable risk factors is essential for the prevention of skin cancer; however, establishing causality can be challenging in conventional epidemiological studies. This study aimed to determine the causal associations of potentially modifiable risk factors with skin cancer using Mendelian randomization (MR).MethodsGenetic instruments for 53 risk factors, including socioeconomic status, dietary and lifestyle factors, anthropometric measures, medication use, and comorbidities, were identified from previous genome-wide association studies. Two-sample MR analyses were performed using summary statistics for three major types of skin cancer: melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). Findings were verified using multiple MR methods under different assumptions and replication datasets.ResultsGenetic liability to sunburn occasions, actinic keratosis, and prior skin cancers was associated with a higher risk of all three types of skin cancer, whereas genetic liability to vitiligo was associated with a lower risk. For specific skin cancer types, genetically predicted higher nevus counts and occupational class were associated with an increased risk of melanoma. Genetic liability to rheumatoid arthritis, type 2 diabetes, and increased physical activity were associated with a lower risk of BCC. Genetically predicated body mass index showed a negative association with BCC, and a positive association with SCC.ConclusionsOur study reaffirmed several previously established risk factors and identified novel potential risk factors for skin cancer. Further work is needed to unravel the biological pathways in different skin cancer types and translate our findings to inform public health policies.

The Relationship between Negative Emotions and Atrial Fibrillation: A Mendelian Randomization Study.

The relationship between negative emotions and atrial fibrillation (AF) has garnered significant attention, yet observational studies have yielded contradictory findings regarding the causal associations between the two. Our study sought to provide genetic evidence for a causal relationship between negative emotions and AF through Mendelian randomization (MR) study. Utilizing genetic variations associated with negative emotions and AF as instrumental variables (IVs), a two-sample MR study was implemented. The potential causality between the two was initially assessed by using negative emotions as exposure and AF as outcome. Subsequently, potential reverse causality was evaluated by using AF as exposure and negative emotions as outcome. The inverse variance weighted (IVW) method served as the primary analysis for the two-sample MR, supplemented by weighted median method, MR-Egger regression, Simple mode method, and Weighted mode method. Sensitivity analyses were performed using the MR pleiotropy residual sum and outlier test (MR-PRESSO), Cochran Q test, and leave-one-out analysis to ensure the robustness of the results. The two-sample MR analyses revealed that genetic susceptibility to AF had no potential causal effect on negative emotions (p > 0.05). Conversely, genetic susceptibility to negative emotions was positively correlated with an increased relative risk of AF [odds ratio (OR), 1.173, 95% confidence interval (CI): 1.115-1.235, p = 8.475 × 10-10]. Furthermore, neither horizontal pleiotropy nor heterogeneity was detected in the analysis. Genetic evidence from the study supports a potential causal link between negative emotions and AF. The study suggests that negative emotions may elevate the risk of AF, and the escalation of negative emotions in AF patients is more likely attributable to modifiable factors rather than genetically related factors.

Causal links between circulatory inflammatory cytokines and risk of digestive polyps: a Mendelian randomization analysis.

There is a high morbidity of polyps in the digestive tract, and certain subtypes of polyps are thought to induce cancer progression and often recur, which may be associated with chronic inflammation. Mendelian randomization (MR) can help identify potential causative relationships and inform early treatment action. We performed a bidirectional two-sample MR analysis implementing the results from genome-wide association studies for 41 serum cytokines from 8,293 Finnish individuals, and three types of polyps from European ancestry, respectively, including gastric polyp (6,155 cases vs. 341,871 controls), colonic polyp (22,049 cases vs. 332,368 controls) and gallbladder polyp (458 cases vs. 340,083 controls). Inverse-variance weighted (IVW), weight median (WM), and MR-Egger methods were used for calculating causal estimates. Furthermore, Bayesian model averaging MR (MR-BMA) method was employed to detect the dominant causal circulatory cytokines with adjustment for pleiotropy effects. Our univariable MR using inverse-variance weight method identified causal associations of IL-2ra (OR: 0.892, 95%CI: 0.828-0.961, p = 0.003), MIG (OR: 1.124, 95%CI: 1.046-1.207, p = 0.001) and IL-18 (OR: 0.912, 95%CI: 0.852-0.977, p = 0.008) with gastric polyp, MIP1b (OR: 0.956, 95%CI: 0.927-0.987, p = 0.005) and IL-6 (OR: 0.931, 95%CI: 0.870-0.995, p = 0.035) with colonic polyp and IL-9 (OR: 0.523, 95%CI: 0.345-0.794, p = 0.0007) with gallbladder polyp. Finally, our MR-BMA analysis prioritized MIG (MIP = 0.332, MACE = 0.022; PP: 0.264, MSCE = 0.059), IL-18 (MIP = 0.302, MACE = -0.020; PP: 0.243, MSCE = -0.059) and IL-2ra (MIP: 0.129; MACE: -0.005; PP: 0.112, MSCE: -0.031) for gastric polyp, and MIP1b (MIP = 0.752, MACE = -0.033; PP: 0.665, MSCE = -0.044) and IL-6 (MIP: 0.196; MACE: -0.012; PP: 0.140, MSCE: -0.064) for colonic polyp, and IL-9 (MIP = 0.936, MACE = -0.446; PP: 0.781, MSCE = -0.478) for gallbladder polyp as the top-ranked protective factors. Our research advances the current understanding of the function of certain inflammatory biomarker pathways in the genesis and malignant mutation of polyps in the digestive tract. Deeper substantiation is necessary to assess the potential of these cytokines as pharmacological or lifestyle targets for digestive polyps prevention.

The levels of amino acid metabolites in serum induce the pathogenesis of atopic dermatitis by mediating the inflammatory protein S100A12

Atopic dermatitis (AD) is a chronic inflammatory skin disease affecting tens of millions of people globally. The causal relationship between metabolites and AD pathology has not yet been formally indicated, and the mediating mechanism by which metabolites affect AD has not yet been explored. This study aimed to determine the genetic relationship between metabolites and AD and to determine the pathways through which amino acid metabolites affect AD. Meta-analysis integrates the results of multiple GWAS analyses using METAL software. Using bidirectional two-sample Mendelian randomization (MR), we analyzed the causal relationships between metabolites and AD. The principal MR test of causal effects was conducted using inverse-variance weighted regression, and we used reverse MR analysis to exclude reverse causality. We also performed the MR-PRESSO test to detect and correct for possible pleiotropic effects, and used the Cochran Q test to assess heterogeneity. Two-step MR was utilized to analyze the mediating factors between amino acid metabolites and the onset of AD. The correlation between mediating factors (inflammatory protein S100A12) and immune cell infiltration was analyzed using the edgeR and GSVA software packages. Using single-cell sequencing data from skin tissues of patients with AD, we studied the regulatory role of the S100A12 gene in immune cells. Multiple drug databases and macromolecular docking were used to search for S100A12-targeting drugs. Bidirectional two-sample MR analyses indicated that twenty-two metabolites and one inflammatory protein (S100A12) were significantly associated with AD pathogenesis. S100A12 is a mediator of amino acid metabolites (N6-methyllysine; N2-acetyl,N6,N6-dimethyllysine and N6,N6-dimethyllysine) that are genetically associated with AD. S100A12 was positively correlated with the infiltration of multiple immune cell types in lesional AD skin. The amino acid metabolites N6-methyllysine; N2-acetyl,N6,N6-dimethyllysine and N6,N6-dimethyllysine influence AD pathogenesis by mediating S100A12 expression.

Plasma proteome-wide analysis of cerebral small vessel disease identifies novel biomarkers and disease pathways.

Cerebral small vessel disease (SVD), as defined by neuroimaging characteristics such as white matter hyperintensities (WMHs), cerebral microhemorrhages (CMHs), and lacunar infarcts, is highly prevalent and has been associated with dementia risk and other clinical sequelae. Although conditions such as hypertension are known to contribute to SVD, little is known about the diverse set of subclinical biological processes and molecular mediators that may also influence the development and progression of SVD. To better understand the mechanisms underlying SVD and to identify novel SVD biomarkers, we used a large-scale proteomic platform to relate 4,877 plasma proteins to MRI-defined SVD characteristics within 1,508 participants of the Atherosclerosis Risk in Communities (ARIC) Study cohort. Our proteome-wide analysis of older adults (mean age: 76) identified 13 WMH-associated plasma proteins involved in synaptic function, endothelial integrity, and angiogenesis, two of which remained associated with late-life WMH volume when measured nearly 20 years earlier, during midlife. We replicated the relationship between 9 candidate proteins and WMH volume in one or more external cohorts; we found that 11 of the 13 proteins were associated with risk for future dementia; and we leveraged publicly available proteomic data from brain tissue to demonstrate that a subset of WMH-associated proteins was differentially expressed in the context of cerebral atherosclerosis, pathologically-defined Alzheimer's disease, and cognitive decline. Bidirectional two-sample Mendelian randomization analyses examined the causal relationships between candidate proteins and WMH volume, while pathway and network analyses identified discrete biological processes (lipid/cholesterol metabolism, NF-kB signaling, hemostasis) associated with distinct forms of SVD. Finally, we synthesized these findings to identify two plasma proteins, oligodendrocyte myelin glycoprotein (OMG) and neuronal pentraxin receptor (NPTXR), as top candidate biomarkers for elevated WMH volume and its clinical manifestations.

Effect of inflammatory factors on myocardial infarction

BackgroundCohort studies have increasingly shown associations between inflammatory markers and myocardial infarction (MI); however, the specific causal relationships between inflammatory markers and the development of MI remain unclear.Methods and resultsBy utilizing publicly accessible genome-wide association studies, we performed a two-sample Mendelian randomization (MR) analysis to explore the causal associations between inflammatory markers and myocardial infarction (MI). A random-effects inverse-variance weighted method was used to calculate effect estimates. The study included a total of 395,795 European participants for MI analysis and various sample sizes for inflammatory factors, ranging from 3,301 to 563,946 participants.Neutrophil count was found to increase the risk of MI (odds ratio [OR] = 1.08; 95% confidence interval [CI], 1.00–1.17; p = 0.04). C-reactive protein levels correlated positively with MI. No associations were observed with IL-1 beta, IL-6, IL-18, procalcitonin, TNF-α, total white cell count, or neutrophil percentage of white cells. Neutrophil count and C-reactive protein were inversely associated with lactate dehydrogenase: neutrophil cell count (OR 0.95; 95% CI, 0.93–0.98; p < 0.01) and C-reactive protein (OR 0.96; 95% CI, 0.92–1.00; p = 0.02). No associations of MI with myoglobin, troponin I, and creatine kinase-MB levels were found.ConclusionsThis two-sample MR analysis revealed a causal positive association of MI with neutrophil count, C-reactive protein level, and the myocardial injury marker lactate dehydrogenase. These results indicate that monitoring C-reactive protein and neutrophil counts may be useful in management of MI patients.

Gut microbiota causally impacts adrenal function: a two-sample mendelian randomization study

Some studies have reported that the gut microbiota can influence adrenal-related hormone levels. However, the causal effects of the gut microbiota on adrenal function remain unknown. Therefore, we employed a two-sample Mendelian randomization (MR) study to systematically investigate the impact of gut microbiota on the function of different regions of the adrenal gland. The summary statistics for gut microbiota and adrenal-related hormones used in the two-sample MR analysis were derived from publicly available genome-wide association studies (GWAS). In the MR analysis, inverse variance weighting (IVW) was used as the primary method, with MR-Egger, weighted median, and cML-MA serving as supplementary methods for causal inference. Sensitivity analyses such as the MR-Egger intercept test, Cochran’s Q test, and leave-one-out analysis were used to assess pleiotropy and heterogeneity. We identified 27 causal relationships between 23 gut microbiota and adrenal function using the IVW method. Among these, Sellimonas enhanced the function of the adrenal cortex reticularis zone (beta = 0.008, 95% CI: 0.002–0.013, P = 0.0057). The cML-MA method supported our estimate (beta = 0.009, 95% CI: 0.004–0.013, P = 2 × 10− 4). Parasutterella, Sutterella, and Anaerofilum affect the functioning of different regions of the adrenal gland. Notably, pleiotropy was not observed. Our findings revealed that the gut microbiota is causally associated with adrenal function. This enhances our understanding of the gut-microbiota-brain axis and provides assistance in the early diagnosis and treatment of adrenal-related diseases in clinical practice.

Assessing the causal relationship between non-small cell lung cancer and sepsis: a Mendelian randomization study

BackgroundA Two-sample Mendelian randomization (MR) Analysis was used to assess the causal relationship between non-small cell lung cancer (NSCLC) and sepsis.MethodSingle nucleotide polymorphisms (SNPs) closely associated with NSCLC were utilized as instrumental variables (IVs) in this study. The Inverse Variance Weighted (IVW) method was used as the primary method for MR analysis, supplemented by the Weighted median, Weighted model, and MR-Egger regression method. Sensitivity analysis was conducted to improve result robustness, and data from various sources were validated and integrated. Bonferroni tests were applied to adjust for multiple comparisons.ResultsAfter Bonferroni tests correcting the combined results, MR analysis revealed a significant association between genetically predicted NSCLC and an increased susceptibility to sepsis (odds ratios [OR]: 1.140, 95% confidence interval [CI]: 1.085–1.199, P = 2.61 × 10− 7). The combined results demonstrated that NSCLC is associated with a heightened risk of sepsis in patients under 75 years of age (OR: 1.085, 95%CI: 1.037–1.353, P = 3.84 × 10− 4). Furthermore, lung adenocarcinoma (LUAD) was found to be potentially associated with an increased susceptibility to sepsis (OR: 1.040, 95% CI: 1.009–1.073, P = 1.16 × 10− 2). These results withstood multiple sensitivity analyses, demonstrating their robustness.ConclusionThis study confirms that NSCLC can significantly increase susceptibility to sepsis at the genetic level, providing valuable insights for the early identification of individuals at risk for sepsis.

Association of the gut microbiome and different phenotypes of COPD and asthma: a bidirectional Mendelian randomization study.

Mounting evidence has revealed the association between gut microbiota and both chronic obstructive pulmonary disease (COPD) and asthma; however, the causal association between gut microbiota and specific disease phenotypes remains to be determined. This study employed bidirectional two-sample Mendelian randomization (MR) analyses to investigate the potential causal relationship between gut microbiota and these conditions. The research utilized genome-wide association study (GWAS) data from the MiBioGen consortium for gut microbiota and the integrative epidemiology unit (IEU) Open GWAS for these conditions. Four MR analysis methods were employed: the inverse variance weighted (IVW) test, MR-Egger, weighted median, and weighted mode methods. The IVW method results are considered the primary findings. Sensitivity analyses, including heterogeneity tests, horizontal pleiotropy analysis, and leave-one-out analysis, were used to enhance robustness. Our MR study identified eight gut microbiota taxa potentially associated with the risk of different types of COPD and asthma. These include two taxa for early-onset COPD: Streptococcaceae [odds ratio (OR) = 1.315, 95% confidence interval (CI) = 1.071-1.616, P = 0.009] and Holdemanella (OR = 1.199, 95% CI = 1.063-1.352, P = 0.003); three for later-onset COPD: Acidaminococcaceae (OR = 1.312, 95% CI = 1.098-1.567, P = 0.003), Holdemania (OR = 1.165, 95% CI = 1.039-1.305, P = 0.009), and Marvinbryantia (OR = 0.814, 95% CI = 0.697-0.951, P = 0.009); one for allergic asthma: Butyricimonas (OR = 0.794, 95% CI = 0.693-0.908, P = 0.001); and two for non-allergic asthma: Clostridia (OR = 1.255, 95% CI = 1.043-1.511, P = 0.016) and Clostridiales (OR = 1.256, 95% CI = 1.048-1.506, P = 0.014).IMPORTANCEIndividuals with diverse phenotypes of chronic obstructive pulmonary disease (COPD) and asthma exhibit different responses to the conventional "one treatment fits all" approach. Recent research has revealed the significant role of the gut-lung axis in both COPD and asthma. However, the specific impact of gut microbiota on different subtypes of these conditions remains poorly understood. Our study has identified eight gut microbiota that may be associated with the risk of different types of COPD and asthma. These findings provide evidence suggesting a potential causal relationship between gut microbiota and various phenotypes of COPD and asthma. This offers a new perspective on the origins of different disease phenotypes and points toward future exploration of phenotype-specific and personalized therapies.

Causal relationship between beta-2 microglobulin and B-cell malignancies: genome-wide meta-analysis and a bidirectional two-sample Mendelian randomization study.

Beta-2 microglobulin (β2M) is acknowledged as a prognostic biomarker for B-cell malignancies. However, insights into the impact of β2M on B-cell malignancy risk, and vice versa, are limited. We conducted a genome-wide meta-analysis (GWMA), bidirectional two-sample Mendelian randomization (TSMR) analysis, and pathway enrichment analysis to explore the causal relationship between β2M and B-cell malignancies and the underlying biological processes. The GWMA identified 55 lead SNPs across five genomic regions (three novel: WDR72, UMOD, and NLRC5) associated with β2M. In the UKB, genetically predicted β2M showed a positive association with diffuse large B-cell lymphoma (DLBCL; odds ratio [OR]: 1.742 per standard deviation increase in β2M; 95% confidence interval [CI]: 1.215-2.498; P = 3.00 × 10-3; FDR = 7.50× 10-3) and Hodgkin lymphoma (HL; OR: 2.270; 95% CI: 1.525-3.380; P = 5.15 × 10-5; FDR =2.58 × 10-4). However, no associations were found with follicular lymphoma (FL), chronic lymphoid leukemia (CLL), or multiple myeloma (MM). Reverse TSMR analysis revealed no association between genetically predicted B-cell malignancies and β2M. In FinnGen, β2M was found to be associated with an increased risk of DLBCL (OR: 2.098; 95% CI: 1.358-3.242; P = 8.28 × 10-4; FDR = 4.14 × 10-3), HL (OR: 1.581; 95% CI: 1.167-2.142; P = 3.13 × 10-3; FDR = 5.22 × 10-3), and FL (OR: 2.113; 95% CI: 1.292-3.455; P = 2.90 × 10-3; FDR = 5.22 × 10-3). However, no association was found with CLL or MM. Reverse TSMR analysis indicated that genetically predicted DLBCL, FL, and MM may perturb β2M levels. Pathway enrichment analysis suggested that the innate immune system represents a convergent biological process underlying β2M, DLBCL, and HL. Our findings suggested that elevated levels of β2M were associated with an increased risk of DLBCL and HL, which is potentially linked to dysfunction of the innate immune system.

Investigating the Causal Effects of Exercise-Induced Genes on Sarcopenia

Exercise is increasingly recognized as an effective strategy to counteract skeletal muscle aging and conditions such as sarcopenia. However, the specific exercise-induced genes responsible for these protective effects remain unclear. To address this, we conducted an eight-week aerobic exercise regimen on late-middle-aged mice and developed an integrated approach that combines mouse exercise-induced genes with human GWAS datasets to identify causal genes for sarcopenia. This approach led to significant improvements in the skeletal muscle phenotype of the mice and the identification of exercise-induced genes and miRNAs. By constructing a miRNA regulatory network enriched with transcription factors and GWAS signals related to muscle function and traits, we focused on 896 exercise-induced genes. Using human skeletal muscle cis-eQTLs as instrumental variables, 250 of these exercise-induced genes underwent two-sample Mendelian randomization analysis, identifying 40, 68, and 62 causal genes associated with sarcopenia and its clinical indicators—appendicular lean mass (ALM) and hand grip strength (HGS), respectively. Sensitivity analyses and cross-phenotype validation confirmed the robustness of our findings. Consistently across the three outcomes, RXRA, MDM1, RBL2, KCNJ2, and ADHFE1 were identified as risk factors, while NMB, TECPR2, MGAT3, ECHDC2, and GINM1 were identified as protective factors, all with potential as biomarkers for sarcopenia progression. Biological activity and disease association analyses suggested that exercise exerts its anti-sarcopenia effects primarily through the regulation of fatty acid oxidation. Based on available drug–gene interaction data, 21 of the causal genes are druggable, offering potential therapeutic targets. Our findings highlight key genes and molecular pathways potentially responsible for the anti-sarcopenia benefits of exercise, offering insights into future therapeutic strategies that could mimic the safe and mild protective effects of exercise on age-related skeletal muscle degeneration.

Physical activity and idiopathic pulmonary fibrosis: A prospective cohort study in UK Biobank and Mendelian randomization analyses

IntroductionThe impact of physical activity on the incidence of idiopathic pulmonary fibrosis (IPF) remains less well studied. This study aimed to investigate the relationship between moderate-to-vigorous physical activity (MVPA) and the risk of developing IPF. MethodsWe analyzed data from a prospective cohort study within the UK Biobank involving 502,476 participants. Participants were categorized as meeting or not meeting the 2017 UK Physical Activity Guidelines (150 min of moderate activity or 75 min of vigorous activity per week). The cumulative incidence and hazard ratios (HRs) for IPF were analyzed using the Kaplan–Meier method, log-rank test, and Cox regression. Two-sample Mendelian randomization (MR) analyses were performed to identify potential causal links between physical activity and IPF risk. ResultsOver a median of 12.2 y follow-up, we identified 1,639 incident IPF cases and 395,172 controls. Individuals who met the physical activity guidelines had a significantly lower risk of IPF than those who did not meet the guidelines (adjusted HR = 0.843, 95 % confidence interval [CI] = 0.765–0.930).The cumulative incidence of IPF was lower in the meeting guideline group than in the nonmeeting guideline group (Log-rank P = 0.0019). Two-sample MR analysis revealed that a 1-standard deviation increase in moderate-to-vigorous physical activity was linked to a reduced IPF risk (odds ratio [OR] = 0.17, 95 % CIs = 0.04 to 0.81, P = 0.026). Moreover, an increase in the number of days per week of moderate physical activity was genetically correlated with decreased IPF risk (OR = 0.32, 95 % CIs = 0.15–0.70, P = 0.003). ConclusionHigher levels of moderate-to-vigorous physical activity are causally associated with a significant reduction in the risk of developing IPF.

A Mendelian analysis of the causality between inflammatory cytokines and digestive tract cancers.

In this study, we performed a two-sample Mendelian randomization (MR) analysis to assess the causality between inflammatory cytokines and the risk of digestive tract cancers (DTCs). Furthermore, we conducted a molecular docking study to predict the therapeutic mechanisms of traditional Chinese medicine (TCM) compounds in the treatment of DTCs. In our MR analysis, genetic variations associated with eight types of DTCs were utilized, which were sourced from a large publicly available genome-wide association study dataset (7929 cases and 1 742 407 controls of European ancestry) and inflammatory cytokines data from a genome-wide association study summary of 8293 European participants. Inverse-variance weighted method, MR-Egger, and weighted median were performed to analyze and strengthen the final results. We investigated the effects of 41 inflammatory molecules on 8 types of DTCs. Subsequently, the effect of DTCs on positive inflammatory factors was analyzed by means of inverse MR. Molecular docking was exploited to predict therapeutic targets with TCM compounds. Interleukin-7, interleukin-16, macrophage colony-stimulating factor, monokine induced by interferon-gamma, and vascular endothelial growth factor may be significantly associated with various types of DTCs. Five TCM compounds (baicalin, berberine, curcumin, emodin, and salidroside) demonstrated better binding energies to both interleukin-7 and vascular endothelial growth factor than carboplatin. This study provides strong evidence to support the potential causality of some inflammatory cytokines on DTCs and indicates the potential molecular mechanism of TCM compounds in the treatment of DTCs. Key message What is already known on this topic The increasing evidence indicates that inflammatory cytokines are implicated in the pathogenesis of digestive tract cancers (DTCs). Nevertheless, the causal relationship between inflammatory cytokines and DTCs remains indistinct. Additionally, certain traditional Chinese medicine compounds have been demonstrated to treat DTCs by influencing inflammatory factors, yet their underlying potential mechanisms remain ambiguous. What this study adds In this study, Mendelian randomization analysis was performed for the first time regarding the causality between human inflammatory cytokines and eight types of DTCs, which revealed that inflammatory factors may play different roles in different types of DTCs. Moreover, molecular docking of key inflammatory factors was implemented, indicating the targets for drug actions. How this study might affect research, practice, or policy This research has the potential to reveal the causality between 41 inflammatory factors and 8 DTCs, offering novel perspectives for the prevention and management strategies of DTCs. Additionally, it indicates the targets for the actions of traditional Chinese medicine on the key inflammatory factors of these cancers.

Proinflammatory Diet Increases the Risk of Irritable Bowel Syndrome: A Prospective Study of 129,408 UK Biobank Participants and Mendelian Randomization Analysis.

Patients with irritable bowel syndrome (IBS) often have chronic low-grade inflammation in the intestinal mucosa. Some dietary components are known to be associated with inflammation. However, there is currently limited research on the relationship between dietary inflammatory potential and the risk of IBS. A total of 129,408 participants in the UK Biobank were included in this study. Energy-Adjusted Dietary Inflammatory Index (E-DII) based on 26 nutrients and the Empirical Dietary Inflammatory Pattern (EDIP) based on 17 food groups were constructed, and on the basis of the tertiles, the continuous score was categorized into proinflammatory, neutral, and antiinflammatory categories. Associations between IBS and E-DII and EDIP were investigated by multivariable Cox proportional hazard models. Potential confounders including sociodemographic, lifestyle, body mass index (BMI), psychological state, type 2 diabetes, and thyroiditis were adjusted. In addition, subgroup analysis and sensitivity analysis were also performed. Finally, a two-sample Mendelian randomization (MR) analysis was employed to explore the independent causality of nutrients and dietary-derived serum antioxidants with IBS. In the cohort study, over a median follow-up period of 13.26years, 2421(1.87%) participants developed IBS. In the E-DII categories, after adjusting for the confounders, individuals in the proinflammatory diet category had a higher risk of IBS compared with the antiinflammatory category (HR 1.15, 95% CI 1.03-1.28, p = 0.015, p trend = 0.017) and neutral category (HR 1.13, 95% CI 1.01-1.26, p = 0.030, p trend = 0.017). In the EDIP categories, after adjusting for the confounders, individuals in the proinflammatory diet category had a higher risk of IBS compared with antiinflammatory category (HR 1.19, 95% CI 1.06-1.33, p = 0.002, p trend = 0.002) but no significant association compared with neutral category (HR 1.10, 95% CI 0.99-1.23, p = 0.067, p trend = 0.002). In the MR analysis, genetically determined intake levels of 16 nutrients and 6 dietary sources of circulating antioxidants did not have a causal effect on IBS. Our findings indicate that proinflammatory dietary components are independent risk factors for IBS. However, there is no causal relationship between individual nutrient intake or serum antioxidants from dietary sources and IBS.

Evidence of the association between asthma and lung cancer risk from mendelian randomization analysis

Asthma and lung cancer are both significant public health concerns worldwide. Previous observational studies have indicated a potential link between asthma and an increased risk of lung cancer, whereas the causal relationship remains uncertain. We aimed to investigate the potential causal relationship between asthma and lung cancer risk utilizing Mendelian randomization (MR) design.The present study employed a two-sample MR analysis utilizing summary statistics from genome-wide association studies (GWAS) with European descent of asthma and lung cancer. The MR analysis was performed using inverse variance weighting (IVW), supplemented with MR-Egger regression and weighted median method to investigate the potential causality between asthma and lung cancer. Furthermore, Sensitivity analyses were also conducted to ensure the reliability of the findings. The MR analysis showed that genetically predicted asthma had suggestive causal association with the elevated risk of lung cancer [odds ratio (OR), 1.05 (95%Cl,1.01–1.09), P = 0.01]. The consistent direction of effects observed in the three methods further supported this finding. In addition, sensitivity analyses demonstrated the reliability of the results. This study provided potential evidence supporting a causal association between asthma and lung cancer. These findings highlighted the importance of early detection and prevention strategies for lung cancer in individuals with asthma. Further research was needed to elucidate the underlying mechanisms linking asthma and lung cancer.

Associations between Disc Hemorrhage and Primary Open-Angle Glaucoma Based on Genome-Wide Association and Mendelian Randomization Analyses.

Background/Objectives: We aimed to investigate the genetic loci related to disc hemorrhage (DH) and the relationship of causation between DH and primary open-angle glaucoma (POAG) using a genome-wide association study (GWAS) in East Asian individuals. Methods: The GWAS included 8488 Koreans who underwent ocular examination including fundus photography to determine the presence of DH and POAG. We performed a GWAS to identify significant single-nucleotide polymorphisms (SNPs) associated with DH and analyzed the heritability of DH and genetic correlation between DH and POAG. The identified SNPs were utilized as instrumental variables (IVs) for two-sample Mendelian randomization (MR) analysis. The POAG outcome dataset was adopted from Biobank Japan data (n = 179,351). Results: We found that the rs62463744 (TMEM270;ELN), rs11658281 (CCDC42), and rs77127203 (PDE10A;LINC00473) SNPs were associated with DH. The SNP heritability of DH was estimated to be 6.7%, with an absence of a genetic correlation with POAG. MR analysis did not reveal a causal association between DH and POAG for East Asian individuals. Conclusions: The novel loci underlying DH in the Korean cohort revealed SNPs in the ELN, CCDC41, and LINC00473 genes. The absence of a causal association between DH and POAG implies that DH is a shared risk factor, rather than an independent culprit factor, and warrants further investigation.