Multivariable Mendelian Randomization Analysis Research Articles

Genetically predicted smoking and body mass index mediate the relationship between insomnia and myocardial infarction

ObjectiveThis study aimed to investigate the causal relationship between insomnia and the risk of myocardial infarction (MI) and explore potential mediators such as smoking initiation, alcohol consumption and body mass index (BMI) using mendelian randomization (MR) analysis.MethodsData from 1,207,228 individuals of European ancestry were obtained from the UK Biobank and 23andMe for insomnia-related genetic associations. Genetic instruments for MI, smoking initiation, alcohol consumption, and BMI were derived from large-scale genome-wide association studies. Univariate MR analysis mainly utilized the inverse variance weighting method, and multivariable MR analysis assessed the mediation effects of smoking initiation and BMI.ResultsThe univariate MR analysis revealed a 96% increased risk of MI in individuals with insomnia [odds ratio (OR) = 1.96; 95% CI: 1.67, 2.31]. Smoking initiation and BMI were identified as potential mediators. The multivariable MR analysis indicated smoking initiation accounted for 29% of the total effect (95% CI: 13%, 61%), while BMI accounted for 15% (95% CI: 7%, 27%), with a combined mediation proportion of 54% (95% CI: 31%, 91%).ConclusionsThe results of this MR analysis demonstrate that insomnia increases the risk of MI. Quitting smoking and losing weight may reduce this risk; however, there is still a portion of the impact of insomnia on MI that cannot be explained. Therefore, further investigation into other potentially modifiable intermediate factors is necessary.

Modifiable risk factors that mediate the effect of insomnia on the risk of low back pain: a network mendelian randomization study

BackgroundLow back pain (LBP) and insomnia are common global health issues, but their relationship and potential mediators remain unclear. This study aimed to explore the impact of insomnia on LBP using mendelian randomization (MR) methods and analyze the mediating role of modifiable factors.MethodsUnivariable MR (UVMR) analysis was employed to examine the causal relationship between insomnia and LBP, as well as the association between modifiable factors [smoking, alcohol consumption, body mass index (BMI), and type 2 diabetes (T2DM)] and LBP. Subsequently, multivariable MR (MVMR) analysis was conducted to explore the impact of insomnia on the mediation of LBP risk by modifiable factors.ResultsIn the UVMR analysis, insomnia [odds ratio (OR) = 2.95, 95%CI: 2.33–3.72)] and BMI (OR = 1.18, 95%CI: 1.02–1.37) were positively associated with the prevalence of LBP. The effects of smoking, alcohol consumption, and T2DM on LBP were not significant (P > 0.05). In the MVMR analysis, the proportion of mediation of BMI on the relationship between insomnia and LBP was 7.12%.ConclusionThis study revealed the causal relationship between insomnia and LBP using MR methods for the first time, and identified the mediating role of BMI. These findings offer new insights into understanding the relationship between insomnia and LBP, informing the prevention and treatment of these two health issues.

Evaluating the causal effects between Grave’s disease and diabetes mellitus: a bidirectional Mendelian randomization study

BackgroundGraves’ disease (GD) is an autoimmune disease associated with an increased incidence of other autoimmune diseases. To investigate the causality between GD and Diabetes mellitus (DM), we designed bidirectional two-sample Mendelian randomization (MR) and multivariable MR (MVMR) studies.MethodsSingle-nucleotide polymorphisms (SNPs) associated with GD, thyroid peroxidase (TPO), thyroglobulin (Tg), thyroid-stimulating hormone (TSH), type 1 diabetes (T1D), and type 2 diabetes (T2D) were obtained from the IEU Open GWAS and FinnGen biobank databases. For the forward MR study, we used GD (sample size = 458,620) as the exposure and T1D (sample size = 520,580) and T2D (sample size = 211,766) as the outcomes. Next, high risk of T1D and T2D were used as exposure variables, and GD was used as the outcome variable for the reverse MR analysis. Finally, MVMR analysis was conducted to investigate the probable relationship between DM and indicators for thyroid function like TPO, Tg, and TSH. The inverse variance weighting (IVW) was used as the main method. Finally, the heterogeneity and sensitivity were assessed.ResultsThere were 27, 88, and 55 SNPs associated with GD, T1D, and T2D, respectively. A significant causal connection between higher genetic liability of GD and the risk of T2D (OR [95% CI] = 1.059 [1.025–1.095], P = 5.53e-04) was found in the forward MR analysis. Comparatively, the significant causal relationship between higher genetic liability of GD and the risk of T1D was not demonstrated (OR [95% CI] = 0.998[0.927,1.074], P=0.949). However, reverse MR suggested that there was a genetic susceptibility to T1D that increased the likelihood of developing GD (OR [95% CI] = 1.173[1.117,1.231], P = 1.913e-10), while T2D did not (OR [95% CI] = 0.963 [0.870–1.066], P = 0.468). Furthermore, there was inadequate evidence to suggest that abnormal TSH, TPO, and Tg levels increase the risk of incident T1D or T2D in individuals with GD. MVMR revealed no causal relationship among Tg, TSH, TPO, T1D, or T2D.ConclusionThere was no increased risk of T1D with an increase in genetic susceptibility to GD, although higher genetic susceptibility to T1D has been shown to be associated with increased risk of developing GD. A unidirectional causal relationship between the genetic liability for GD and increased risk of T2D was observed using MR analyses. MVMR analysis showed no statistically relevant causality between the genetic liability for TSH, TPO, or Tg and the risk of either T1D or T2D.

Exploring the relationship between cathepsin and age-related macular degeneration using Mendelian randomization

PurposeAge-related macular degeneration (AMD) is the leading cause of low vision and even blindness in the elderly population worldwide. However, no studies have been conducted to analyze the causal relationship between the cathepsin family and AMD. The present study aimed to explore and analyze this potential association using Mendelian randomization (MR).MethodsIn this study, AMD was classified into two types: exudative AMD and atrophic AMD. Inverse-variance weighting (IVW) was used as the main analysis method. The association between nine cathepsins and the two classifications of AMD were analyzed using multivariable Mendelian randomization (MVMR). Sensitivity analysis included Cochran’s Q-test and the MR-Egger intercept test.ResultsTwo-sample MR analysis showed that higher levels of cathepsin L2 were associated with a delay in the development of atrophic AMD (IVW: p = 0.017; OR = 0.885; 95% CI = 0.799–0.979). Reverse MR analysis indicated that cathepsin E levels were increased in individuals with atrophic (IVW: p = 0.023; OR = 1.058; 95% CI = 1.007–1.111) and exudative AMD (IVW: p = 0.018; OR = 1.061; 95% CI 1 = 1.010–1.115). MVMR analysis indicated a causal relationship between cathepsin G (IVW: p = 0.025; OR = 1.124; 95% CI = 1.014–1.245), cathepsin O (IVW: p = 0.043, OR = 1.158, 95% CI = 1.004–1.336), and exudative AMD after coordinating for other types of cathepsin.ConclusionThis study demonstrated a potential link between the cathepsin family and the onset of AMD. Elevated serum concentrations of cathepsin L2 may serve as a protective factor for atrophic AMD, while increased levels of serum cathepsin G and O concentrations may promote the development of exudative AMD. Besides, the development of AMD may be associated with elevated serum concentrations of cathepsin E.

Causal association between allergic diseases and celiac disease: a bidirectional two-sample and multivariable Mendelian-randomization study

Objective This study aimed to assess the causality of allergic diseases and celiac disease. Methods We collected summary-level data from publicly available genome-wide association studies to conduct our bidirectional two-sample and multivariable Mendelian randomization analysis. Furthermore, a series of sensitivity analyses were applied to validate our findings. Results In bidirectional two-sample MR analyses, we found a significant causal effect of atopic dermatitis (AD) on CD (Inverse-variance weighted (IVW): odds ratio [OR] = 1.302, 95% confidence interval [CI] = 1.152-1.471, P < 0.001). We also found a significant causal effect of allergic rhinitis (AR) on CD (IVW: OR = 4.181, 95% CI = 1.495-11.697, P = 0.006). However, the MR-Egger method indicated a different causal effect direction compared to the IVW and weighted median method. After Bonferroni correction, the result of asthma on CD is suggestive of a causal effect (IVW: OR = 1.186, 95% CI = 1.021-1.378, P = 0.026). No causal effects were found when CD was considered as an exposure variable. In MVMR analyses, after separately and jointly adjusting for the influence of smoking and BMI, the causal effect of AD on CD remained robust. Conclusions Our study suggests that AD is a risk factor for CD and it is considered suggestive of a causal relationship between asthma and CD. Further research is needed to explore the potential mechanisms underlying this causal effect.

Evaluating the relationship between standing height, body mass index, body fat percentage with risk of inguinal hernia: a Mendelian randomization study

Observational studies have suggested links between standing height, BMI, body fat percentage, and inguinal hernia risk, but with inconsistent results. We conducted Mendelian randomization (MR) method to investigate their causal relationships. Independent SNPs associated with standing height, BMI, and body fat percentage were extracted from GWAS data as instrumental variables (IVs). Two-sample MR initially explored causal relationships between these factors and inguinal hernia risk. Multivariable Mendelian randomization (MVMR) assessed the direct causal effects of exposures on inguinal hernia. Positive findings from the MVMR analysis were independently validated. The inverse-variance weighted Methods (IVW), weighted median(WM), and MR-Egger were used for the MR estimates. Sensitivity analyses were used to examine the stability and reliability of the results. Two-sample MR analysis revealed a suggestive causal association between height and inguinal hernia (OR = 1.091, 95% CI = 1.003–1.186, P = 0.042). BMI (OR = 0.846, 95% CI = 0.774–0.924, P < 0.001) and body fat percentage (OR = 0.793, 95% CI = 0.690–0.911, P = 0.001) were significantly protective factors. After MVMR adjustment, BMI (OR = 0.746,95%CI = 0.638–0.872, P < 0.001) remained protective. Independent validation yielded consistent result. Genetically predicted BMI is a significant protective factor for inguinal hernia, providing valuable guidance for individualized prevention strategies.

The causal effects of lifestyle, circulating, pigment, and metabolic factors on early age-related macular degeneration: a comprehensive Mendelian randomization study

PurposeEarly detection of lifestyle factors, skin and hair color, circulating parameters, and metabolic comorbidities is crucial for personalized prevention and treatment of early age-related macular degeneration (AMD). This study aimed to assess the relationships between genetically predicted comprehensive risk factors and early AMD.Methods and resultsPublicly available genome-wide association study (GWAS) data were utilized to identify genetic variants significantly associated with each trait. We applied a Bonferroni-corrected significance level of P < 0.0017. P values between 0.0017 and 0.05 were considered suggestive associations. Univariable Mendelian randomization (MR) analyses revealed that elevated serum HDL-C, lower serum TG, and decreased three circulating fatty acids levels were robust indicators of an increased risk of early AMD (all P < 0.0017), with odds ratios (ORs) and 95% confidence intervals (CIs) of 1.218 (1.140–1.303), 0.784 (0.734–0.837), 0.772 (0.698–0.855), 0.776 (0.706–0.852), and 0.877 (0.798–0.963), respectively. Additionally, the “never eat wheat products”, “age started wearing glasses”, and “skin color” were significantly associated with the risk of early AMD (both P < 0.0017), with ORs (95% CIs) of 23.853 (2.731–208.323), 1.605 (1.269–2.030) and 1.190 (1.076–1.317), respectively. Multivariable MR analysis confirmed that elevated serum HDL-C (OR = 1.187, 1.064–1.324) increased the risk of early AMD, while higher serum TG (OR = 0.838, 0.738–0.950) was associated with a significantly lower risk. Furthermore, validation results indicated that serum HDL-C 1.201 (1.101–1.310) and TG 0.795 (0.732–0.864) were significantly associated with the risk of early AMD. There were suggestive associations of smoothies, chronotype, and hair color (0.0017 < P < 0.05), but sun/UV protection, smoking, BMI, diabetes, high blood pressure, cardiovascular diseases, fresh fruit intake, fish oil/cod liver oil supplement, sleeplessness, serum C-reactive protein level, and iron level were not associated with the risk of early AMD.ConclusionsOur comprehensive MR analysis demonstrated that elevated circulating HDL-C levels increase the risk of early AMD, while TG and fatty acid levels are associated with a decreased risk. These findings provide robust evidence for improved diagnosis and personalized prevention and treatment of early AMD.

Coffee and Risk of Pancreatic Cancer: Insights from Two-Sample and Multivariable Mendelian Randomization Analyses

Background: The association between coffee and pancreatic cancer risk has reported inconsistent results. Therefore, a Mendelian randomization (MR) study was undertaken to investigate the association between coffee and pancreatic cancer from a genetic perspective. Methods: In East Asian and European populations, independent genetic variants strongly associated with coffee were chosen as instrumental variables (IVs) from relevant genome-wide association studies (GWASs). GWAS data for pancreatic cancer were obtained from the JENGER (Japanese Encyclopedia of Genetic Associations by Riken) project and GWAS catalog database. Two-sample (TSMR) and multivariable Mendelian randomization (MVMR) analyses were conducted to investigate the genetically predicted causal relationship between coffee consumption and pancreatic cancer. A fixed-effect meta-analysis was employed to aggregate estimates from the two populations to reveal the overall association. Results: Both in East Asian and European populations, an increase in coffee intake of a cup per day was not associated with pancreatic cancer risk, regardless of coffee type (including caffeine drinks, instant coffee, decaffeinated coffee, ground coffee, etc.). The results aligned with the findings of the meta-analysis (OR = 1.100, 95%CI = 0.862–1.403, p = 0.450). Also, for coffee intake with positive results in the TSMR analysis (OR = 1.739, 95%CI 1.104–2.739, p = 0.017), consistent negative results were observed after adjusting for potential confounders (smoking traits, drinking, type 2 diabetes, body mass index) in the MVMR analyses. Conclusions: This study found no genetically predicted causal relationship between coffee consumption and pancreatic cancer risk.

The role of digital device use on the risk of migraine: a univariable and multivariable Mendelian randomization study

BackgroundThe pervasive integration of digital devices into daily life has raised concerns about their potential health impacts. This study aimed to explore the causal relationships between digital device use and the risk of migraine using Mendelian randomization (MR).MethodsGenetic data on digital device use and migraines were sourced from large-scale genome-wide association studies conducted by the UK Biobank, the FinnGen study, and the International Headache Genetics Consortium. Univariable MR (UVMR), meta-analysis, and multivariable MR (MVMR) approaches were conducted to explore and verify the causal effects of digital device use (including mobile phone use, computer use, playing computer games, and watching television) on migraine risk. Sensitivity analyses were conducted using Cochran’s Q, MR-Egger intercept test, MR pleiotropy residual sum and outlier, MR Radial, MR Steiger, and leave-one-out methods.ResultsUVMR analyses revealed that genetically predicted mobile phone use was significantly associated with an increased risk of overall migraine (odds ratio [OR] = 2.39, p = 9.78e-5) and migraine without aura (MO) (OR = 2.25, p = 0.024). Additionally, there were significant positive associations between genetically predicted television watching and the risk of overall migraine (OR = 1.63, p = 2.12e-5) and MO (OR = 2.10, p = 4.98e-5). These results were further supported by the meta-analysis and MVMR analysis. Sensitivity analysis indicated no heterogeneity or pleiotropy.ConclusionThis comprehensive MR study provides preliminary evidence for the causal impact of mobile phone use and television watching on the risk of migraines. Further studies are needed to explore these associations across different populations.

Immune cells mediate the causal relationship between uveitis and colorectal cancer via Mendelian randomization analysis

Colorectal cancer (CRC) is one of the most common and deadly malignancies worldwide, and immune regulation plays a critical role in its development. This study investigates the causal relationships between uveitis, specific immune cell traits, and CRC using Mendelian Randomization (MR) analyses. A total of 21 single nucleotide polymorphisms (SNPs) associated with uveitis were identified, and the analysis revealed that a 1 log-odds increase in uveitis was linked to a statistically significant 3.0% reduction in CRC odds (IVW OR = 0.970, 95% CI: 0.946–0.995, P = 0.021). This protective effect was also observed using the weighted median approach (OR = 0.963, 95% CI: 0.931–0.997, P = 0.034), reinforcing the robustness of the findings. Furthermore, both univariable and multivariable MR analyses highlighted the significant causal influence of specific immune cell traits on CRC odds. Notably, the levels of extracellular monocyte HLA-DR expression emerged as a critical factor, with an associated increase in CRC odds (IVW OR = 1.084, 95% CI: 1.008–1.165, P = 0.030). The proportion of CRC odds mediated by the levels of extracellular monocyte HLA-DR expression, calculated as the ratio of the indirect effect to the total effect using estimates from multivariable MR analyses, was approximately 34.1%(95% CI: 10.23−58.04%). These findings underscore the complex interplay between immune regulation and carcinogenesis, offering insights into potential mechanisms underlying CRC development and suggesting avenues for targeted prevention and therapeutic strategies.

Causal associations between kidney function and aortic valve stenosis: a bidirectional Mendelian randomization analysis

Background Aortic valve stenosis (AVS) is currently the most common heart valve disease. The results of observational studies on the incidence of AVS in the renal dysfunction population are contradictory due to the short follow-up period and different diagnostic criteria, etc. This study aimed to explore the causal relationship between kidney function and AVS using Mendelian randomization (MR) analysis. Methods We acquired summary statistics of estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD) from the CKDGen Consortium and a study on AVS from the FinnGen biobank. Univariate and multivariable MR analyses were conducted to evaluate the causal associations. The MR-Egger intercept and MR-PRESSO Global test were applied to assess the pleiotropic effects. The heterogeneity of MR results was tested by Cochran’s Q statistic. Moreover, the Bonferroni and FDR corrections were performed for multiple tests. Results Genetically predicted decreased eGFR may be associated with a raised risk of AVS (OR = 0.045, p = 1.317e-04 by IVW; OR = 0.002, p = 0.004 by MR-Egger, OR = 0.091, p = 0.057 by WM). The causal association still established after multiple comparisons. Quality control analyses indicated the absence of heterogeneity and pleiotropy in our MR research. In addition, the causality of eGFR and AVS remained significant in multivariable MR analysis after adjusting BMI, hypertension, T2DM, LDL-C, and smoking. Conclusion Our MR study discovered that reduced eGFR may be a causative risk factor for AVS. In addition, the evidence did not support a significant causal association of AVS on kidney function.

Genetically mimicked effects of thyroid dysfunction on diabetic retinopathy risk: a 2-sample univariable and multivariable Mendelian randomization study.

Thyroid dysfunction exhibits a heightened prevalence among people with diabetes compared to those without diabetes. Furthermore, TD emerges as a notable correlated risk factor for the onset of diabetic retinopathy. Using data from the FinnGen database (R9), we investigated the causal relationship between thyroid dysfunction (TD) and four stages of diabetic retinopathy (DR). A two-sample univariable Mendelian randomization (UVMR) approach was employed to estimate the total causal effect of TD on four stages of DR, while multivariable Mendelian randomization (MVMR) was used to assess the direct causal effect. The meta-analysis was conducted to summarize the collective effect of TD on four stages of DR. The inverse variance weighted (IVW) method was the primary approach for Mendelian randomization analysis, with heterogeneity, horizontal pleiotropy, and leave-one-out sensitivity analyses performed to validate the robustness of the findings. In UVMR analysis, thyrotoxicosis (TOS) was significantly associated with an increased risk of diabetic retinopathy across four stages (OR, 1.10-1.19; P<0.025). However, MVMR analysis, after adjusting for Graves' disease (GD) and/or rheumatoid arthritis (RA), revealed no significant association between TOS and the four stages of diabetic retinopathy. The Meta-analysis demonstrated the collective effect of TOS on diabetic retinopathy across all stages [OR=1.11; 95% CI (1.08-1.15); P<0.01]. In UVMR analysis, the estimates for hypothyroidism (HPT) and GD were similar to those for TOS. In the MVMR analysis, after adjusting for RA, the significant effect of HPT on DR and non-proliferative diabetic retinopathy (NPDR) remained. Additionally, MVMR analysis suggested that the estimates for GD on DR were not affected by TOS, except for GD-proliferative diabetic retinopathy (PDR). However, no significant correlation persisted after adjusting for RA, including for GD-PDR. Our study demonstrated a significant association between thyroid dysfunction TD and DR, with the relationship being particularly pronounced in HPT-DR.

Relationships of dietary habits with prostate cancer risk: results from Mendelian randomization analyses and the National Health and Nutrition Examination Survey.

Background: Prior investigations identified correlations between dietary habits and the risk of prostate cancer (PCa); however, the causative dynamics are unclear. Methods: Utilizing the Mendelian randomization (MR) framework, we investigated the causal links between dietary habits, daily nutrient intakes, and risk of PCa (79 148 cases and 61 106 controls). Exposure and outcome data were obtained from the UK Biobank and the Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome (PRACTICAL) consortium, respectively. Univariable and multivariable MR analyses were employed. Sensitivity analyses were performed to detect outliers, evaluate heterogeneity, and discern potential pleiotropic effects. Utilizing data from the National Health and Nutrition Examination Survey (NHANES) database (2009-2010), we selected 1294 and 1778 men aged ≥40 years from a pool of 10 537 participants, ensuring no missing information. Regression analyses examined the associations between leafy/lettuce salad intake, daily nutrient intake, and the odds of PCa. Results: Univariable MR (UVMR) analysis reveals that the intake of pork and salad/raw vegetable correlated with an elevated PCa risk. Subsequent to confounder adjustment via multivariable MR (MVMR) analysis, a causal link was established between salad/raw vegetable intake and an increased risk of PCa (odds ratio [OR]: 1.658, 95% confidence interval [95% CI]: 1.037-2.644, P = 0.046). The analysis based on NHANES datasets demonstrated a link between leafy/lettuce salad intake and heightened odds of PCa (OR: 1.025, 95% CI: 1.003-1.049, P = 0.038). Increased daily intakes of β-carotene (original OR: 1.00006, 95% CI: 1.00001-1.00011, P = 0.024) and vitamin B1 (OR: 1.474, 95% CI: 1.104-1.967, P = 0.014) were associated with a higher likelihood of PCa. Conclusions: These MR analyses substantiate the causal nexus between salad/raw vegetable intake and PCa risk. Similarly, leafy/lettuce salad intake and the odds of PCa were significantly correlated in the cross-sectional observational study. Moreover, higher daily intakes of β-carotene and vitamin B1 were linked to an increased likelihood of PCa. These findings provide practical dietary recommendations for PCa prevention and enhance early identification and diagnosis.

Causal association between gastrointestinal diseases and coronary artery disease: a bidirectional Mendelian randomization study.

Coronary artery disease (CAD) has been a dominating reason of mortality globally due to its complexity of etiology. A variety of gastrointestinal disorders (GDs) have been accounted to be related to CAD. Thus, this study aims to determine their causal relationship by two-sample Mendelian randomization (MR) analysis. Single-nucleotide polymorphisms (SNPs) relevant to 22 GDs were employed as instrumental variables from the genome-wide association summary (GWAS) datasets. Genetic associations with CAD and HF were acquired from UK Biobank, FinnGen, and other GWAS studies. We conducted a univariable MR (UVMR) analysis followed by a meta-analysis. A multivariable MR (MVMR) analysis was then performed with smoking and body mass index (BMI) as justifications. Also, a bi-directional MR analysis was leveraged to verify the reverse causal correlations. Generally, UVMR analyses separately observed the causal effects of GDs on CAD and HF. Genetic liability to gastroesophageal reflux disease displayed a positive association with both CAD (OR=1.19; 95%CI: 1.01-1.41) and HF (OR=1.22; 95%CI: 1.00-1.49) risk; genetic liability to celiac disease separately attributed to CAD (OR=1.02; 95%CI: 1.01-1.03) and HF (OR=1.01; 95%CI: 1.00-1.02), which also maintained after MVMR analysis. Besides, we observed mutually causal associations between CAD and celiac disease. Our work suggested that genetic susceptibility to some GDs might causally increase the risk of CAD and HF, emphasizing the importance of preventing CAD in patients with GDs.

Lifelong impacts of puberty timing on human plasma metabolic profiles: A metabolome-wide Mendelian randomization study.

The aim was to investigate the causal relationship between puberty timing and plasma metabolites, accounting for birth weight, childhood and adulthood adiposity. The meta-analysis of genome-wide association studies (GWAS) for puberty timing was extracted from the ReproGen Consortium, involving 329 345 women of European ancestry. Summary data for 174 plasma metabolites were retrieved from a recently conducted cross-platform GWAS that involved a meta-analysis of three cohort studies (i.e. the Fenland, European Prospective Investigation into Cancer-Norfolk and INTERVAL studies) and three publicly available studies and included up to 86 507 participants. We conducted a two-sample Mendelian randomization (MR) analysis to infer the causal relationship of puberty timing on 174 plasma metabolites, complemented by a two-step and multivariable Mendelian randomization (MVMR) analysis to assess direct and indirect effects. Additionally, summary-level data from the UK Biobank were used for our replication analysis. The results of the two-sample MR provide moderate evidence supporting a causal relationship between puberty timing and 23 of 174 plasma metabolites (i.e. 7 acylcarnitines, 8 amino acids, 2 biogenic amines and 6 lysophosphatidylcholines). Even after single-nucleotide polymorphisms associated with birth weight and childhood adiposity were excluded, causal effects persisted for 16 metabolites (i.e. 8 acylcarnitines, 4 amino acids, 2 biogenic amines and 2 lysophosphatidylcholines). The two-step MR analysis provided evidence that the relationship between puberty timing and plasma metabolites was mediated by adulthood adiposity. Additionally, moderate evidence emerged for an independent causal effect of puberty timing on 10 metabolites through an MVMR analysis (i.e. 5 acylcarnitines, 2 amino acids, 1 biogenic amine, 1 lysophosphatidylcholine and 1 phosphatidylcholine). Furthermore, the replication analysis suggested the robustness of our results. In summary, our study provides compelling evidence that puberty timing has a causal influence on certain plasma metabolites, although this influence is largely mediated by adulthood adiposity.

Breast cancer and neoplasms of the thyroid gland: a bidirectional two-sample Mendelian randomization study.

With the rising incidence of breast cancer (BC) and neoplasms of the thyroid gland, a potential link between the two has drawn increasing attention. However, the causal relationship remains unclear due to various confounding factors. This study aims to investigate the causality between BC and thyroid tumors using Mendelian Randomization (MR) analysis. We conducted a bidirectional two-sample MR analysis, utilizing breast cancer-associated single nucleotide polymorphisms (SNPs) from the Breast Cancer Association Consortium (BCAC) and thyroid tumor-related SNPs from the FinnGen (https://www.finngen.fi/) database. First, we performed univariable MR (UVMR) to assess the causal relationship between BC and both malignant and benign thyroid tumors, followed by reverse causality analysis. To account for potential confounders, we applied multivariable MR (MVMR). The inverse-variance weighted (IVW) method was primarily used, with secondary analyses performed using the weighted median and MR-Egger regression approaches. UVMR analysis revealed a significant positive causal relationship between BC and malignant thyroid tumors (odds ratio [OR] and 95% confidence interval [CI]: 1.291, 1.143-1.458, P = 3.90×10-5). No causal relationship was found between BC and benign thyroid tumors. The MVMR analysis, adjusting for confounding factors such as smoking, drinking, and body mass index (BMI), confirmed the robustness of the results. This study provides genetic evidence supporting a causal relationship between BC and malignant thyroid tumors. These findings highlight the importance of thyroid cancer screening in BC patients. However, further MR studies or randomized controlled trials (RCTs) are necessary to assess small effects accurately.

HMGCR as a promising molecular target for therapeutic intervention in aortic aneurisms: a mendelian randomization study

BackgroundDespite the exploration of the connections between serum low-density lipoprotein cholesterol (LDL-C) levels and aneurisms in epidemiological studies, causality remains unclear. Therefore, this study aimed to assess the causal impact of LDL-C-lowering targets (HMGCR, PCSK9, NPC1L1, CETP, APOB, and LDLR) on various forms of aneurisms using Mendelian Randomization (MR) analysis.MethodsTwo genetic instruments acted as proxies for exposure to LDL-C-lowering drugs: expression quantitative trait loci of drug target genes and genetic variants linked to LDL-C near drug target genes. Summary-data-based MR (SMR), inverse-variance-weighted MR (IVW-MR), and multivariable MR (MVMR) methods were employed to compute the effect estimates.ResultsThe SMR analysis revealed substantial associations between increased HMGCR expression and a heightened risk of aortic aneurism (odds ratio [OR] = 1.603, 95% confidence interval [CI] = 1.209–2.124), thoracic aortic aneurism (OR = 1.666, 95% CI = 1.122–2.475), and abdominal aortic aneurism (OR = 1.910, 95% CI = 1.278–2.856). Likewise, IVW-MR analysis demonstrated positive correlations between HMGCR-mediated LDL-C and aortic aneurism (OR = 2.228, 95% CI = 1.702–2.918), thoracic aortic aneurism (OR = 1.751, 95% CI = 1.191–2.575), abdominal aortic aneurism (OR = 4.784, 95% CI = 3.257–7.028), and cerebral aneurism (OR = 1.993, 95% CI = 1.277–3.110). Furthermore, in the MVMR analysis, accounting for body mass index, smoking, and hypertension, a significant positive relationship was established between HMGCR-mediated LDL-C levels and the development of aortic aneurisms, encompassing both thoracic and abdominal subtypes. Similarly, consistent positive associations were observed for PCSK9 and CETP genes, as well as PCSK9-mediated and CETP-mediated LDL-C levels, with the occurrence of aortic aneurism and abdominal aortic aneurism. Nonetheless, the evidence for potential associations between APOB, NPC1L1 and LDLR with specific subtypes of aortic aneurisms lacked consistent support from both SMR and IVW-MR analyses.ConclusionsOur MR analysis offered compelling evidence of a plausible causal link between HMGCR and an increased risk of aortic aneurism, encompassing both thoracic and abdominal types. These groundbreaking findings further bolster the case for the deployment of HMGCR inhibitors in the treatment of aortic aneurisms, including both thoracic and abdominal variants.

Exploring the link between sedentary behavior and cognitive decline: a comprehensive study combining Mendelian randomization and animal model experiments.

The causal link between detrimental behaviors and cognitive performance remains unclear. This research seeks to investigate the causal impact of adjustable lifestyle factors on cognitive deterioration, including frequency of alcohol intake, onset of smoking, and sedentary activities like prolonged television viewing. This research combines large-scale genetic data obtained from univariable and multivariable Mendelian randomization analyses with experimental findings obtained from animal models. Our findings reveal that the odds ratio (OR) for cognitive function deterioration was 0.445 (inverse variance weighted [IVW] 95% CI: 0.370 to 0.536, p < 0.001) for each standard deviation increase in television watching time. After adjustment for body mass index (BMI), number of days walked /moderate activity over 10+ min and education in Multivariable Mendelian Randomization (MVMR), only the genetic predisposition to increased television watching time remained significantly associated with worse cognitive function (OR 0.659, 95% CI: 0.452 to 0.960, p = 0.030). The other two habits had no significant effects. Sensitivity analyses have confirmed that genetic pleiotropy did not influence the results. To further explore the relationship between sedentary behavior and cognitive function, as well as the underlying mechanisms, we conducted a restricted cage housing experiment and a physical exercise training experiment in mice. The results showed that physical exercise significantly improved spatial memory, as assessed by the Morris water maze, and increased exploratory interest, as evaluated by the open field test (OFT) and the elevated plus-maze test, compared to the sedentary control group. These cognitive advantages may be mediated through mechanisms involving free radical scavenging and enhanced synaptic plasticity. Our research provides genetic evidence indicating that extended television viewing is linked to an elevated risk of cognitive decline. Additionally, experimental data from mouse models suggest that physical exercise can counteract cognitive decline and anxiety-like behaviors induced by sedentary behavior. This protective effect is likely mediated by reactive oxygen species (ROS)-dependent mechanisms that enhance synaptic plasticity within the hippocampus.

Association between vitamin B6 levels and rheumatoid arthritis: a two-sample Mendelian randomization study.

Micronutrients play a crucial role in rheumatoid arthritis (RA). Changes in micronutrient levels in RA patients can lead to the worsening of their condition. Though significant correlations between RA and micronutrients have been found in earlier observational studies, their underlying causal relationship is still unknown. This study aimed to elucidate the causal genetic relationships between 15 micronutrients (copper, zinc, magnesium, vitamins A, C, E, D, B6, B12, folate, carotene, iron, selenium, calcium, potassium) and RA. The exposure factors and outcome data used in the two-sample Mendelian randomization (MR) were derived from publicly available summary statistics data of European populations. The GWAS data for exposure factors were obtained from the OpenGWAS database. For the outcome data of RA, we utilized data from the FinnGen database. We used the MR principle to remove confounding factors and conducted MR analyses using five methods: inverse variance weighted (IVW), MR Egger, weighted median, simple mode, and weighted mode, with IVW as the primary method. Then, we identified micronutrients related to RA and performed MR analyses on these elements, including heterogeneity analysis and pleiotropy analysis such as MR-Egger intercept, MR-PRESSO method, and "leave-one-out" analysis. Finally, we conducted multivariable MR analyses and performed sensitivity analyses again. The IVW analysis revealed a relationship between vitamin B6 and RA (p: 0.029, OR: 1.766, and 95% CI: 1.062-2.938). Sensitivity analysis confirmed the validity and reliability of this result. This study revealed a causal relationship between vitamin B6 and RA, with vitamin B6 being identified as a risk factor for RA. This finding could contribute to the diagnosis and supplementary treatment of RA patients, providing a reference for subsequent basic research and developing new drugs.

Circulating levels of cytokines and risk of urologic cancers: a two-sample Mendelian randomization study

BackgroundChronic inflammation is associated with the etiology of various cancers. However, there is a lack of systematic research in urologic cancers. This study aims to use a two-sample Mendelian randomization (MR) approach to evaluate the role of circulating cytokines in the development of urologic cancers.MethodsWe obtained the summary-level data for bladder cancer (373,295 cases and 372,016 controls), prostate cancer (462,933 cases and 459,664 controls), and kidney cancer (463,010 cases and 461,896 controls) from the UK Biobank. Genetic variations linked to 41 circulating cytokines were used as instrumental variables (IVs) in meta-analyses of genome-wide association studies (GWASs) involving 8,293 individuals from Finland. We primarily used the inverse-variance weighted (IVW) method to assess the potential associations between the 41 cytokines and the risk of 3 common urologic cancers. Weighted-median method, weighted mode and simple-median method were used to assess the sensitivity. Heterogeneity and pleiotropic outlier were evaluated by Cochran's Q test and MR-Egger regression. Genetic correlation, colocalization analysis and multivariable MR analysis were used to further validate the potential pleiotropy.ResultsAfter the Bonferroni correction, there was an observed association between elevated genetically predicted levels of CCL27 and a heightened risk for bladder cancer. Conversely, IL-12p70 levels were found to have a protective association against the risk of bladder cancer. Sensitivity analyses utilizing various IV sets and MR approach remained robust. Furthermore, we found potential associations of 7 cytokines with urologic cancers (4.07 × 10−4 ≤ P < 0.05).ConclusionOur study supported causal associations between CCL27, IL-12p70 and bladder cancer risk and potential associations of 7 cytokines with the risk of urologic cancers, helping us to further understand the pathogenesis of urologic cancers and providing clues for improving diagnostic accuracy and therapies.