MR Pleiotropy Residual Sum And Outlier Research Articles

The causal relationship between psoriasis and artificial joint re-operation after arthroplasty: A two-sample Mendelian randomization study.

Psoriasis is observationally associated with a higher risk of complications of arthroplasty; however, the causal effects of psoriasis on complications of arthroplasty are yet to be established. This study was to explore the causal effect of psoriasis on artificial joint re-operation after arthroplasty through two-sample Mendelian randomization (MR). In the MR analysis, psoriasis was selected as the exposure in this study while single-nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS) were selected as the instrumental variables (IVs). Summary statistics data on artificial joint re-operation was extracted from publicly available GWAS data, including 218 792 European descent individuals. MR analysis was performed using the standard inverse variance weighted method (IVW). Furthermore, MR Egger, weighted median, simple mode, weighted mode, and the MR-PRESSO (Mendelian Randomization Pleiotropy Residual Sum and Outlier) test were also done to verify the results. Finally, the sensitivity analysis was executed. The IVW showed that psoriasis increases the risk of artificial joint re-operation (OR=1.12; 95% CI=(1.01, 1.25); p=0.036). This outcome was also verified by other methods including weighted median (OR=1.16; 95% CI=(1.03, 1.31); p=0.015), MR Egger (OR=1.22; 95% CI=(1.03, 1.44); p=0.038), and weighted mode (OR=1.16; 95% CI=(1.03, 1.30); p=0.025). No heterogeneity and directional pleiotropy were observed upon sensitivity analysis. The present study showed that psoriasis has a potential causal effect on artificial joint re-operation after arthroplasty. Further studies are warranted to elucidate the underlying mechanisms of causal associations between psoriasis on re-operation.

Genetic evidence reveals a causal relationship between rheumatoid arthritis and interstitial lung disease.

Background/purpose: Previous epidemiological studies have associated interstitial lung disease (ILD) with rheumatoid arthritis (RA), yet the causality of this relationship remains uncertain. This study aimed to investigate the genetic causal link between ILD and RA. Methods: Genome-wide association study (GWAS) statistics for ILD and RA were collected from public datasets. Relevant single-nucleotide polymorphisms (SNPs) were selected by executing quality control steps from the GWAS summary results. A two-sample bidirectional Mendelian randomization (MR) analysis was performed to assess the causal relationship between the two conditions. The MR analysis primarily used the inverse variance weighting (IVW), weighted median (WM), and MR-Egger regression methods. Sensitivity analyses, including MR-Egger, leave-one-out, and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), were conducted to evaluate the heterogeneity and pleiotropy. Replication analyses using Asian datasets were also conducted to enhance the robustness of our findings. Results: In the European population, RA was found to increase the risk of ILD by 9.6% (OR: 1.096, 95% CI: 1.023-1.174, p = 0.009). Conversely, ILD was associated with a 12.8% increased risk of RA (OR: 1.128, 95% CI: 1.013-1.256, p = 0.029). Replication analyses from Asian GWAS further supported these findings, particularly the increased risk of ILD attributable to RA (OR: 1.33, 95% CI: 1.18-1.49, p-value <0.001). Conclusion: Our findings underscore the clinical importance of screening for ILD in RA patients and suggest that effective management of RA could significantly benefit ILD patients. The potential applicability of novel RA treatments to ILD warrants further exploration. Additionally, racial disparities in the manifestation of these diseases should not be overlooked, as they may offer new perspectives for targeted therapies in diverse populations.

The Causal Relationship Between Gastroesophageal Reflux Disease and Chronic Obstructive Pulmonary Disease: A Bidirectional Two-Sample Mendelian Randomization Study.

Gastroesophageal reflux disease (GERD) and Chronic Obstructive Pulmonary Disease (COPD) often coexist and have been associated in observational studies. However, the real potential causal relationship between GERD and COPD is unknown and not well established. In this study, we conducted a bidirectional two-sample Mendelian randomization(MR) to estimate whether GERD and COPD are causal. The GERD genetic data is from summary level data of a genome-wide association (GWAS) meta-analysis (Ncases = 71,522, Ncontrol=26,079). The COPD GWAS are available from the FinnGen (Ncases=16,410, Ncontrol=283,589). MR-Egger regression, Weighted Median, and Inverse-variance weighted (IVW) were used for MR analysis from the R package "TwoSampleMR", and IVW was the dominant estimation method. Additionally, the MR pleiotropy residual sum and outlier (MR-PRESSO), Cochran Q statistic, and leave-one-out analysis were used to detect and correct for the effect of heterogeneity and horizontal pleiotropy. MR analysis indicated that GERD was causally associated with an increased risk of COPD (IVW odds ratio (OR): 1.3760, 95% confidence interval (CI): 1.1565-1.6371, P=0.0003), and vice versa (IVW OR: 1.1728, 95% CI:1.0613-1.2961, P=0.0018). The analyses did not reveal any pleiotropy or heterogeneity. Our study revealed possible evidence for a bidirectional causal relationship between GERD and COPD. Implementing screening and preventive strategies for GERD in individuals with COPD, and vice versa, will be crucial in future healthcare management. Further studies are needed to elucidate the mechanisms underlying the causal relationship between GERD and COPD.

Causal associations of birth body size and adult body size with systemic lupus erythematosus: a bidirectional mendelian randomization study.

Body size is associated with the onset of systemic lupus erythematosus (SLE). However, the evidence for this association is inconclusive. In this study, we aimed to investigate the causal relationship between body size and SLE. We performed a bidirectional Mendelian randomization (MR) analysis that utilized summary statistics sourced from genome-wide association study (GWAS) data obtained from the IEU Open GWAS project website. The inverse variance weighting (IVW) method was used to evaluate the causality, and four additional MR methods were used to supplement the IVW results. Sensitivity analyses were performed using the Cochran's Q test, MR-Egger regression, leave-one-out analysis, and the Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) global test. In the forward direction analysis, the IVW model demonstrated that birth weight (odds ratio (OR), 1.811; 95% confidence interval (CI), 1.174-2.793; p < 0.05) and adult height (OR, 1.225; 95% CI, 1.046-1.434; p < 0.05) were positively associated with SLE. Four additional MR scans were performed parallel to the IVW results. Conversely, SLE was a weak causal factor for increased height (OR, 1.010; 95% CI, 1.002-1.018; p < 0.05) using the IVW method. Heterogeneity, MR-Egger intercept, and leave-one-out analyses indicated that the results were robust. The MR-PRESSO suggested the presence of pleiotropy. Following the exclusion of instrumental variables (IVs) inducing pleiotropy, subsequent MR analysis yielded consistent results, thereby reinforcing the robustness of our findings. Positive causal associations were observed between birth weight, adult height, and SLE incidence. In the reverse analysis, SLE was a weak causal factor for adult height.

Genetic Insights into Glycine's Protective Role Against CAD - European and East Asia, 2015 and 2020.

The purpose of this study is to examine the potential causal relationship between levels of circulating glycine and coronary artery disease (CAD) using a two-step Mendelian randomization (MR) analysis. We analyzed data from genome-wide association studies (GWAS) conducted on European and East Asian populations. To assess the causal effects of circulating glycine levels on the risk of CAD. We used the inverse-variance weighting (IVW), weighted median (WM), MR-Egger, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) methods. Furthermore, we conducted mediation analysis to investigate the contribution of blood pressure and other cardiovascular disease-related traits. The two-step Mendelian randomization analysis revealed that higher levels of glycine in the blood were associated with a reduced risk of CAD in Europeans [odds ratio ( OR)=0.84, 95% confidence interval ( CI): 0.72, -0.98; P=0.029] and East Asians: ( OR=0.76, 95% CI: 0.66, -0.89; P=3.57×10 -4). Sensitivity analysis confirmed the robustness of these findings. Additionally, our results suggest that about 6.06% of the observed causal effect is mediated through genetically predicted systolic blood pressure (SBP) in the European population. Our results contribute to the current knowledge regarding the involvement of glycine in the progression of CAD, and provide valuable methodological insights for the prevention and treatment of this condition.

Causal link between gut microbiota and osteoporosis analyzed via Mendelian randomization.

Osteoporosis (OP) is closely associated with gut microbiota (GM), yet the nature of their causal relationship remains elusive. Therefore, this study aims to reverse causality between GM and OP by using population cohorts and two-sample MR (TSMR) analysis. In this study, we conducted an extensive genome-wide association study (GWAS) using publicly accessible summary statistics data for GM and OP. Employing rigorous criteria (p < 1*e-5), we identified independent genetic loci that exhibited significant associations with GM relative abundances as instrumental variables (IVs). A causal evaluation was primarily carried out using the inverse variance-weighted (IVW) method, supplemented by additional analyses such as MR-Egger, weighted median, simple mode, and weighted mode. We unveiled that increased abundances of the family Pasteurellaceae, order Pasteurellales, and genus Ruminococcaceae UCG004 were linked to an increased risk of OP. Conversely, the family Oxalobacteraceae, unknown family id.1000006161, genus Lachnospiraceae NK4A136 group, unknown genus id.1000006162, and order NB1n were associated with a reduced risk of OP. To ensure the reliability of our findings, we conducted quality assessments through Cochrane's Q test and a leave-one-out analysis. Furthermore, the stability and consistency of the results were confirmed by the MR-Egger intercept test, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) global test, and sensitivity analysis (p > 0.05). Our study reveals the causal relationships between 211 GM taxa and OP, pinpointing specific GM taxa associated with the risk of OP. This research sheds light on the genetic mechanisms that underlie GM-mediated OP and opens up promising avenues for identifying valuable biomarkers and potential therapeutic targets in future OP research. This study establishes a substantial GM-OP link with specific taxa being identified, offering biomarkers for early detection, tailored interventions, and improved patient education. These findings enhance OP diagnosis, prevention, and treatment, promising more effective, individualized care and inspiring future research.

Uric acid levels and heart failure: A mendelian randomization study

Background and aimsUric acid, the end-product of purine metabolism within the human body, has been the subject of studies exploring its potential association with cardiovascular and cerebrovascular diseases. However, the precise relationship between uric acid levels and heart failure remains elusive. Methods and resultsIn this particular study, aggregated data from genome-wide association studies on uric acid and heart failure were utilized to perform a two-sample Mendelian randomization (MR) analysis utilizing R software. The aim was to uncover any causal link between these variables. The primary outcome was assessed using inverse variance weighted (IVW) methodology, while sensitivity analyses employed MR-Egger, weighted median (WME), and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) techniques. IVW results revealed a possible causal relationship between elevated uric acid levels and an increased risk of heart failure (OR: 1.09, 95 % CI: 1.01–1.17, P < 0.05). Encouragingly, the directions provided by MR-Egger and WME aligned with IVW findings, and no anomalies were detected in the remaining sensitivity analyses. ConclusionThese outcomes indicate the stability of the results of the study, thereby suggesting that heightened uric acid levels may contribute to an augmented risk of heart failure.

Association between circulating unsaturated fatty acid and preeclampsia: a two-sample Mendelian randomization study

Objective In recent years, several studies have reported an association between unsaturated fatty acids (UFAs) and the risk of developing preeclampsia; however, its exact causal effect is unclear. This study assessed the causal association between circulating UFAs and preeclampsia. Methods A two-sample Mendelian randomization (MR) study using publicly available genome-wide association study (GWAS) summary data for circulating UFA s (N = 114,999) and preeclampsia (N = 118,291) was performed. Single nucleotide polymorphisms (SNPs) significantly associated with exposure was selected as instrumental variables (IVs). The inverse variance weighted (IVW) test was used as the primary method for estimating causality in MR analysis, while MR pleiotropy residual sum and outlier (MR-PRESSO) and MR-Egger regression methods were used to assess horizontal pleiotropy. Cochran’s Q test was used to evaluate heterogeneity among SNPs, and leave-one-out sensitivity analysis was used to determine the effect of individual SNPs on the results of the MR analysis. Bonferroni correction was used as a correction for multiple corrections. Results Two-sample MR analysis suggested that the ratio of monounsaturated fatty acids (MUFAs) to total fatty acids (OR 1.150, 95% CI 1.006–1.315, p = 0.041), the ratio of polyunsaturated fatty acids (PUFAs) to total fatty acids (OR 0.805, 95% CI 0.658–0.986, p = 0.036) and the ratio of PUFAs to MUFAs (OR 0.807, 95% CI 0.694–0.938, p = 0.005) were causally associated with preeclampsia. After Bonferroni correction, the causal association between the ratio of polyunsaturated to MUFAs and preeclampsia remained statistically different. Conclusions This MR analysis provides evidence for a genetic causal association between circulating UFAs and preeclampsia.

Causal effect of age first had sexual intercourse and lifetime number of sexual partners on cervical cancer

ObjectiveIn this study, we aimed to investigate whether age first had sexual intercourse (AFSI) and lifetime number of sexual partners (LNSP) have a direct causal effect on cervical cancer by Mendelian randomization (MR) analysis. MethodsFour approaches were used for MR Analysis, including MR-Egger, weighted method, weighted median, and inverse variance weighted (IVW). MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) as well as MR-Egger regression analysis were conducted to detect whether there was pleiotropy between IVs and outcome, and the outlier SNPs can be detected by MR-PRESSO. The presence or absence of heterogeneity among IVs was suggested according to Cochran's Q statistic. Leave-one-out sensitivity analysis was performed to identify and remove SNPs which could independently change the results. We corrected the results using Bonferroni correction. ResultsFrom the results of IVW, AFSI had a negative effect on cervical cancer (OR = 0.996, 95 % CI: 0.995, 0.998 P = 1.70E-07), which still persisted after Bonferroni correction. However, no causal effect of LNSP on cervical cancer was found according to the IVW results (OR = 1.003, 95 % CI: 1.000, 1.007, P = 0.071). From the results of MR-PRESSO and MR-Egger, no SNP with horizontal pleiotropy between cervical cancer was detected and no SNP was identified as an outlier SNP. Cochran's Q statistic suggested that no heterogeneity existed among IVs of AFSI and LNSP. According to Leave-one-out analysis, the results of MR did not change after excluding any single IV. ConclusionThis MR study reveals that early AFSI has a causal effect on cervical cancer.

Causal effects of potential risk factors on postpartum depression: a Mendelian randomization study.

Postpartum depression (PPD) is a type of depressive episode related to parents after childbirth, which causes a variety of symptoms not only for parents but also affects the development of children. The causal relationship between potential risk factors and PPD remains comprehensively elucidated. Linkage disequilibrium score regression (LDSC) analysis was conducted to screen the heritability of each instrumental variant (IV) and to calculate the genetic correlations between effective causal factors and PPD. To search for the causal effect of multiple potential risk factors on the incidence of PPD, random effects of the inverse variance weighted (IVW) method were applied. Sensitivity analyses, including weighted median, MR-Egger regression, Cochrane's Q test, and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO), were performed to detect potential Mendelian randomization (MR) assumption violations. Multivariable MR (MVMR) was conducted to control potential multicollinearity. A total of 40 potential risk factors were investigated in this study. LDSC regression analysis reported a significant genetic correlation of potential traits with PPD. MR analysis showed that higher body mass index (BMI) (Benjamini and Hochberg (BH) corrected p = 0.05), major depression (MD) (BH corrected p = 5.04E-19), and schizophrenia (SCZ) (BH corrected p = 1.64E-05) were associated with the increased risk of PPD, whereas increased age at first birth (BH corrected p = 2.11E-04), older age at first sexual intercourse (BH corrected p = 3.02E-15), increased average total household income before tax (BH corrected p = 4.57E-02), and increased years of schooling (BH corrected p = 1.47E-11) led to a decreased probability of PPD. MVMR analysis suggested that MD (p = 3.25E-08) and older age at first birth (p = 8.18E-04) were still associated with an increased risk of PPD. In our MR study, we found multiple risk factors, including MD and younger age at first birth, to be deleterious causal risk factors for PPD.

Exploration of the causal effects of leukocyte telomere length and four gastrointestinal diseases: a two-sample bidirectional Mendelian randomization study

BackgroundTo explore the underlying causality between leukocyte telomere length (LTL) and four gastrointestinal diseases, we designed a two-sample bidirectional Mendelian randomization study.MethodsTwo-sample Mendelian randomization (MR) was used to explore genetic causality between LTL and four gastrointestinal diseases, including irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), gastrointestinal ulcers disease (GUD), and nonalcoholic fatty liver disease (NAFLD). We utilized inverse-variance weighted (IVW) as the primary method for MR analysis. Supplementary analyses were conducted using methods such as MR-Egger regression, weighted-median, Maximum Likelihood (MaxLik), Robust adjusted profile score (MR-RAPS), Contamination mixture (ConMix), and MR-mix. Cochran’s Q was calculated to check for heterogeneity. The MR-Egger regression and MR pleiotropy residual sum and outlier (MR-PRESSO) were detected for pleiotropy.ResultsThe IVW analysis suggests that there may be a potential causal relationship between LTL and two diseases (odds ratio (OR): 1.062; 95% confidence interval (CI): 1.003, 1.124; p = 0.038 for IBS and OR: 0.889; 95% CI: 0.798, 0.990; p = 0.032 for GERD). However, other methods do not entirely align with the results of the IVW analysis. In the reverse MR analysis, we did not find statistically significant associations between LTL and these four diseases.ConclusionThe current evidence does not definitively rule out a causal relationship between LTL and these four gastrointestinal diseases but suggests a potential association between LTL and IBS, or LTL and GERD. Exploring the relationship between gastrointestinal diseases and LTL may offer new insights into the onset, progression, and treatment of these diseases.

A Mendelian randomization study on the causal association of circulating cytokines with colorectal cancer

Background Circulating cytokines have been associated with colorectal cancer (CRC). However, their causal correlation remains undetermined. This investigation uses genetic data to evaluate the mechanism that links circulating cytokines and CRC via Mendelian Randomization (MR). Methods A two-sample MR evaluation was carried out to investigate the mechanism associating circulating cytokines and CRC in individuals of European ancestry. The Genome-wide association studies statistics, which are publically accessible, were used. Eligible instrumental SNPs that were significantly related to the circulating cytokines were selected. Multiple MR analysis approaches were carried out, including Simple Mode, inverse variance weighted (IVW), MR-Egger, Weighted Mode, Weighted Median, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods. Results The evidence supporting the association of genetically predicted circulating levels with the increased risk of CRC was revealed; these included vascular endothelial growth factor (OR = 1.352, 95% CI: 1.019–1.315, P = 0.024), interleukin-12p70 (OR = 1.273, 95% CI: 1.133–1.430, P = 4.68×10−5), interleukin-13 (OR = 1.149, 95% CI: 1.012–1.299, P = 0.028), interleukin-10 (OR = 1.230, 95% CI: 1.013–1.493, P = 0.037), and interleukin-7 (OR = 1.191, 95% CI: 1.023–1.386 P = 0.024). Additionally, MR analysis negative causal association between macrophage colony stimulating factor and CRC (OR = 0.854, 95% CI: 0.764–0.955, P = 0.005). The data from Simple Mode, Weighted Median, MR-Egger, and Weighted Mode analyses were consistent with the IVW estimates. Furthermore, the sensitivity analysis indicated that the presence of no horizontal pleiotropy to bias the causal estimates. Conclusion This investigation identified a causal association between circulating cytokines levels risk of CRC and may provide a deeper understanding of the pathogenesis of CRC, as well as offer promising leads for the development of novel therapeutic targets for CRC.

Gut microbiota and autism spectrum disorders: a bidirectional Mendelian randomization study.

In recent years, observational studies have provided evidence supporting a potential association between autism spectrum disorder (ASD) and gut microbiota. However, the causal effect of gut microbiota on ASD remains unknown. We identified the summary statistics of 206 gut microbiota from the MiBioGen study, and ASD data were obtained from the latest Psychiatric Genomics Consortium Genome-Wide Association Study (GWAS). We then performed Mendelian randomization (MR) to determine a causal relationship between the gut microbiota and ASD using the inverse variance weighted (IVW) method, simple mode, MR-Egger, weighted median, and weighted model. Furthermore, we used Cochran's Q test, MR-Egger intercept test, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and leave-one-out analysis to identify heterogeneity and pleiotropy. Moreover, the Benjamin-Hochberg approach (FDR) was employed to assess the strength of the connection between exposure and outcome. We performed reverse MR analysis on the gut microbiota that were found to be causally associated with ASD in the forward MR analysis to examine the causal relationships. The enrichment analyses were used to analyze the biological function at last. Based on the results of IVW results, genetically predicted family Prevotellaceae and genus Turicibacter had a possible positive association with ASD (IVW OR=1.14, 95% CI: 1.00-1.29, P=3.7×10-2), four gut microbiota with a potential protective effect on ASD: genus Dorea (OR=0.81, 95% CI: 0.69-0.96, P=1.4×10-2), genus Ruminiclostridium5 (OR=0.81, 95% CI: 0.69-0.96, P=1.5×10-2), genus Ruminococcus1 (OR=0.83, 95% CI: 0.70-0.98, P=2.8×10-2), and genus Sutterella (OR=0.82, 95% CI: 0.68-0.99, P=3.6×10-2). After FDR multiple-testing correction we further observed that there were two gut microbiota still have significant relationship with ASD: family Prevotellaceae (IVW OR=1.24; 95% CI: 1.09-1.40, P=9.2×10-4) was strongly positively correlated with ASD and genus RuminococcaceaeUCG005 (IVW OR=0.78, 95% CI: 0.67-0.89, P=6.9×10-4) was strongly negatively correlated with ASD. The sensitivity analysis excluded the influence of heterogeneity and horizontal pleiotropy. Our findings reveal a causal association between several gut microbiomes and ASD. These results deepen our comprehension of the role of gut microbiota in ASD's pathology, providing the foothold for novel ideas and theoretical frameworks to prevent and treat this patient population in the future.

Causal relationship between frailty and chronic obstructive pulmonary disease or asthma: A two sample bidirectional Mendelian randomization study

BackgroundObservational studies have established a strong association between frailty and obstructive lung diseases. However, the causal nature of this association remains unclear. To address this gap, we conducted a bidirectional Mendelian randomization (MR) study to investigate the causal relationship between frailty, as measured by the frailty index (FI), and chronic obstructive pulmonary disease (COPD) or asthma. MethodsThe latest meta-analysis of genome-wide association studies for FI, which included individuals of European ancestry from UK Biobank and TwinGene (N = 175,226), yielded the genetic instruments for frailty and outcome summary statistics. The genetic instrument for COPD and asthma, as well as the outcome summary data, were derived from the GWAS conducted on individuals of European ancestry from the FinnGen, with a sample size of 16,410 cases and 283,589 controls for COPD, and 37,253 cases and 187,112 controls for asthma. The analysis of MR was conducted employing the inverse-variance weighted (IVW) method, complemented by the weighted median method, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO) test. ResultsOur results showed that genetically predicted higher FI was significantly associated with increased risk of COPD (odds ratio [OR] 1.75, 95 % confidence interval [CI] 1.29–2.36) and asthma (OR 2.10, 95 % CI 1.44–3.16). In the reverse direction analysis, genetic liability to both COPD (beta 0.06, 95 % CI 0.01–0.10) and asthma (beta 0.08, 95 % CI 0.06–0.11) showed significant associations with a higher FI. ConclusionsOur research has reinforced the existing evidence supporting a reciprocal causal relationship between frailty and obstructive lung diseases. A deeper comprehension of this interconnection is imperative for the prevention and treatment of obstructive lung diseases.

Gamma-glutamyl transferase and calculus of kidney incidence: a Mendelian randomization study

Elevated Gamma-glutamyl transferase (GGT) levels are often suggestive of cholelithiasis, and previous studies have indicated that GGT is highly expressed in the urinary system. Therefore, we hypothesized that there may be an association between GGT levels and calculus of kidney (CK) incidence. To investigate this potential causal relationship, we employed Mendelian randomization (MR) analysis. Additionally, we analyzed the levels of other liver enzymes, including alanine transaminase (ALT) and alkaline phosphatase (ALP). The relationship between GGT levels and CK incidence was analyzed using two-sample Mendelian randomization. Summary Genome-Wide Association Studies data were utilized for this analysis. 33 single nucleotide polymorphisms known to be associated with GGT levels were employed as instrumental variables. We employed several MR methods including IVW (inverse variance weighting), MR-Egger, weighted median, weighted mode, and MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier). Furthermore, we conducted tests for horizontal multivariate validity, heterogeneity, and performed leave-one-out analysis to ensure the stability of the results. Overall, several MR methods yielded statistically significant results with a p-value < 0.05. The results from the IVW analysis yielded an odds ratio (OR) of 1.0062 with a 95% confidence interval (CI) of 1.0016–1.0109 (p = 0.0077). Additional MR methods provided supplementary results: MR-Egger (OR 1.0167, 95% CI 1.0070–1.0266, p = 0.0040); weighted median (OR 1.0058, 95% CI 1.0002–1.0115, p = 0.0423); and weighted mode (OR 1.0083, 95% CI 1.0020–1.0146, p- = 0.0188). Sensitivity analyses did not reveal heterogeneity or outliers. Although potential horizontal pleiotropy emerged, we speculate that this could be attributed to inadequate test efficacy. However, subsequent use of MR-PRESSO did not provide evidence of pleiotropy. Our analysis suggests a positive association between elevated GGT levels and CK incidence, indicating an increased risk of CK development. However, no causal relationship was observed between levels of ALP or ALT and CK incidence.

Periodontitis causally affects the brain cortical structure: A Mendelian randomization study.

To estimate whether genetically proxied periodontitis causally impacts the brain cortical structure using Mendelian randomization (MR). Periodontitis is one of the most prevalent inflammatory conditions globally, and emerging evidence has indicated its influences on distal organs, including the brain, whose disorders are always accompanied by magnetic resonance imaging (MRI)-identified brain cortical changes. However, to date, no available evidence has revealed the association between periodontitis and brain cortical structures. The instrumental variables (IVs) were adopted from previous genome-wide association study (GWAS) studies and meta-analyses of GWAS studies of periodontitis from 1844 to 5266 cases and 8255 to 12 515 controls. IVs were linked to GWAS summary data of 51 665 patients from the ENIGMA Consortium, assessing the impacts of genetically proxied periodontitis on the surficial area (SA) or the cortical thickness (TH) of the global and 34 MRI-identified functional regions of the brain. Inverse-variance weighted was used as the primary estimate; the MR pleiotropy residual sum and outlier (MR-PRESSO), the MR-Egger intercept test, and leave-one-out analyses were used to examine the potential horizontal pleiotropy. Genetically proxied periodontitis affects the SA of the medial orbitofrontal cortex, the lateral orbitofrontal cortex, the inferior temporal cortex, the entorhinal cortex, and the temporal pole, as well as the TH of the entorhinal. No pleiotropy was detected. Periodontitis causally influences the brain cortical structures, implying the existence of a periodontal tissue-brain axis.

Effects of childhood obesity on heart failure and its associated risk factors in the European population: A Mendelian randomization study

Background and aimsObservational studies have shown that obesity considerably affects the cardiovascular system. Thus we conducted this Mendelian randomization (MR) analysis to evaluate the causal effect of childhood obesity on heart failure (HF) and its risk factors. Methods and resultsWe obtained genetic instruments from genome-wide association studies (GWAS) that investigated childhood obesity, HF, type 2 diabetes mellitus (T2DM), atrial fibrillation (AF), coronary artery disease (CAD), myocardial infarction (MI), chronic kidney disease (CKD), valvular heart disease, myocarditis, hypertrophic cardiomyopathy, and hyperthyroidism. Inverse variance weighting (IVW), weighted median analysis, MR-Egger, and MR-pleiotropy residual sum and outlier (MR-PRESSO) were employed for MR analyses. In addition, the leave-one-out sensitivity test, MR-PRESSO global test, and Cochran’s Q test were used for sensitivity analyses. Genetic evaluations showed that childhood obesity increases the risk of HF (odds ratio [OR] = 1.11, 95%CI: 1.05–1.17, p = 1.26 × 10−4), T2DM (OR = 1.17, 95%CI: 1.12–1.23, p = 8.80 × 10−12), AF (OR = 1.08, 95%CI: 1.05–1.12, p = 2.66 × 10−7), MI (OR = 1.08, 95%CI: 1.04–1.13, p = 3.35 × 10−4), and CAD (OR = 1.08, 95%CI: 1.03–1.13, p = 1.48 × 10−3). We found no association between childhood obesity and CKD, valvular heart disease, myocarditis, hypertrophic cardiomyopathy, or hyperthyroidism. Sensitivity analysis and Bonferroni’s correction showed consistent results. ConclusionsOur study provides new evidence for the relationship between childhood obesity and HF and its risk factors. The results indicate that individuals with a history of childhood obesity require more clinical attention to prevent the development of HF.

Causal association between circulating angiopoietin‐1 levels and the risk of Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD), characterized by cognitive decline and memory loss, is the most common neurodegenerative disorder. Angiopoietin‐1 is a protein that plays a role in the formation and maintenance of blood vessels and has been suggested to be involved in the development of AD. However, the causal relationship between angiopoietin‐1 and AD is not well understood.MethodTo investigate the causal relationship between angiopoietin‐1 levels and AD risk, we performed a Mendelian randomization (MR) analysis using instrumental variables (IV) identified from genome‐wide association studies (GWAS) summary statistics on blood angiopoietin‐1 levels (N = 3,301) and AD (N = 63,926). Seven different methods, including inverse variance weighted (IVW), MR‐Egger, weighted median, simple median, maximum likelihood, simple mode, and weighted mode, were applied to calculate the causal estimate. Pleiotropic test and heterogeneity analysis were also assessed to evaluate the stability of the estimates.ResultUsing the IVW method, genetically determined human blood angiopoietin‐1 levels were causally associated with a decreased risk of AD (odds ratio [OR] = 0.86, 95%CI = 0.78‐0.94, P = 0.001), which was further validated using other approaches (Figure 1A). The leave‐one‐out analysis plot showed that there was no significant outlier driving the overall causal estimate between angiopoietin‐1 levels and AD (Figure 1B). The results of MR‐PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier) global, MR‐Egger intercept test, and Cochran’s Q test showed that there were no obvious directional horizontal pleiotropy and heterogeneity, indicating good stability of the present MR study.ConclusionOur study provides evidence for a causal relationship between angiopoietin‐1 levels and a reduced risk of AD. However, further validation and replication of these findings are needed to confirm our results.

Systemic lupus erythematosus Association between Osteomyelitis: A two-sample Mendelian randomization study in European population

BackgroundSystemic lupus erythematosus (SLE) has been correlated with osteomyelitis (OM), yet the underlying causal relationship remains poorly understood. This study aims to investigate the causal association between SLE and OM using Mendelian randomization (MR) analysis. MethodsGenetic instrumental variables (IVs) correlated with SLE were extracted from a comprehensive genome-wide association study (GWAS) summary database (5201 cases and 9066 controls). OM was considered a SLE phenotype, and summary data from the fast GWA data portal were utilized for the analysis. Eligible IVs were extracted following rigorous quality control measures (P < 5 × 10-8, LD r2>0.001, distance 1 Mb, and F > 10). MR analysis was conducted using the Inverse Variance Weighted (IVW), MR-Egger, and Weighted Median (WM) methods after excluding potential confounders. Cochran's Q was applied for heterogeneity test. Pleiotropy was evaluated through MR-Egger intercept, MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) method, and Leave-one-SNP-out analysis. ResultA total of 40 eligible IVs were included for MR analysis. IVW results demonstrated a positive causal association between SLE and OM (P = 0.049, OR = 1.167). Heterogeneity analysis reveal no significant heterogeneity in the IVW analysis (P = 0.5503). Pleiotropy tests, including MR-PRESSO global test and MR-Egger intercept, indicated no evidence of pleiotropy in our findings (P > 0.05). Additionally, the Leave-one-SNP-out analysis showed no substantial deviations when removing individual SNPs, thus supporting the robustness of our results. ConclusionThis study establishes a genetic causal relationship between SLE and OM, indicating an increased risk of developing OM in individuals with SLE. Therefore, proactive management of SLE is advised to mitigate the risk of developing OM.

Causal effects of genetically predicted testosterone on Alzheimer's disease: a two-sample mendelian randomization study.

Although several studies have reported that testosterone may protect against Alzheimer's disease, no evidence of a causal relationship has been demonstrated. A Mendelian randomization (MR) study was performed to determine the causal role of testosterone in Alzheimer's disease. The study utilized public databases obtained from separately published genome-wide associationstudies (GWAS). Single-nucleotide polymorphisms (SNPs) for testosterone were extracted from the most recent and largest published GWAS meta-analysis (178,782 participants), and SNPs for Alzheimer's disease were extracted from UK Biobank (954 AD cases and 487,331 controls). The odds ratio (OR) of the inverse variance weighting (IVW) approach was the primary outcome, and the weighted median and MR Egger regression were used for sensitivity analysis. Through IVW, we observed a causal association between genetically predicted testosterone and the risk of Alzheimer's disease, with an OR of 0.99 (95% confidence interval [CI] = 0.998-0.999, p = 0.047). In the sensitivity analyses, the weighted median regression showed directionally similar estimates (OR = 0.99, 95% CI = 0.998-0.999, p = 0.048). The MR Egger regression showed similar estimates (OR = 0.99, 95% CI = 0.998-1.00, p = 0.35), but with lower precision. Funnel plots, MR Egger intercepts, and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) analysis indicated the absence of directional pleiotropy effects. In conclusion, our MR study provides evidence of a causal relationship between testosterone levels and Alzheimer's disease; however, this relationship must be validated in future studies with larger sample sizes. Early testosterone monitoring may enable the prevention of Alzheimer's and related diseases.