MR Pleiotropy Residual Sum And Outlier Research Articles

Correlation between diabetic retinopathy and diabetic nephropathy: a two-sample Mendelian randomization study.

A causal relationship concerning diabetic retinopathy (DR) and diabetic nephropathy (DN) has been studied in many epidemiological observational studies. We conducted a two-sample mendelian randomization study from the perspective of genetics to assess these associations. 20 independent single nucleotide polymorphisms (SNPs) associated with diabetic retinopathy were selected from the FinnGen consortium. Summary-level data for diabetic nephropathy were obtained from the publicly available genome-wide association studies (GWAS) database, FinnGen and CKDGen consortium. Inverse variance weighted (IVW) was selected as the primary analysis. MR-Egger, weighted median (WM), simple mode and weighted mode were used as complementary methods to examine causality. Additionally, sensitivity analyses including Cochran's Q test, MR-Egger, MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO), and leave-one-out analyses were conducted to guarantee the accuracy and robustness of our MR analysis. Our current study demonstrated positive associations of genetically predicted diabetic retinopathy with diabetic nephropathy (OR=1.32; P=3.72E-11), type 1 diabetes with renal complications (OR=1.96; P= 7.11E-11), and type 2 diabetes with renal complications (OR=1.26, P=3.58E-04). Further subtype analysis and multivariate mendelian randomization (MVMR) also reached the same conclusion. A significant casualty with DN was demonstrated both in non-proliferative DR (OR=1.07, P=0.000396) and proliferative DR (OR=1.67, P=3.699068E-14). All the findings were robust across several sensitivity analyses. Consistent with previous clinical studies, our findings revealed a positive correlation between DR and DN, providing genetic evidence for the non-invasive nature of DR in predicting DN.

Mendelian randomization study on the causal effect of serum IgA levels on H7N9 avian influenza A virus susceptibility.

Avian influenza A viruses (IAVs) that cross the species barrier to infect humans have the potential to initiate a new pandemic. However, the host factors influencing avian IAV infection remain poorly understood. To address this knowledge gap, we conducted a two-sample Mendelian randomization (MR) analysis by integrating our in-house genome-wide association study (GWAS) of avian IAV H7N9 susceptibility (with 217 cases and 116 controls) with the largest GWAS of serum IgA levels to date (sample size 41 263). Using the inverse-variance weighted (IVW) method, we discovered that genetically decreased serum IgA levels were associated with an increased risk of H7N9 infection (β = -2.528, 95% confidence interval [CI]: -4.572 to -0.484; p = 0.015). Consistent results were obtained from three other MR methods, including robust IVW estimation (β = -2.506, 95% CI: -4.109 to -0.902; p = 0.002), generalized summary-data-based MR (GSMR) (β = -2.238, 95% CI: -4.106 to -0.602; p = 0.019), and MR-pleiotropy residual sum and outlier (MR-PRESSO) (β = -2.528, 95% CI: -4.396 to -0.892; p = 0.026). In conclusion, our analysis provided compelling evidence support a causal relationship between genetically predicted serum IgA levels and avian IAV H7N9 susceptibility.

No evident causal association between Helicobacter pylori infection and colorectal cancer: a bidirectional mendelian randomization study

Observational studies have reported a correlation between Helicobacter pylori infection and colorectal cancer (CRC); however, the underlying cause has remained unclear. This research was aimed at determining whether there is a correlation between H. pylori infection and CRC by measuring the prevalence of H. pylori CagA antibodies and VacA antibodies. Using data from many genome-wide association studies (GWAS), we conducted a Mendelian randomization (MR) study with two sample GWAS. Then, we used bidirectional MR to evaluate the association between H. pylori infection and CRC for identifying causation. The most common method of analysis was the inverse variance-weighted technique. In addition, we performed supplementary analyses using the weighted median technique and MR-Egger regression. Horizontal pleiotropic outliers were identified and corrected using the MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) method. Genetically predicted anti-H. pylori IgG seropositivity was not causally associated with CRC [odds ratio (OR): 1.12; 95% confidence interval (CI): 0.98–1.27, P = 0.08] and neither were H. pylori VacA antibody levels (OR = 0.96, 95% CI: 0.90–1.02, P = 0.25) or H. pylori CagA antibody levels (OR = 1.00, 95% CI: 0.93–1.07, P = 0.92). Furthermore, reverse MR analysis did not reveal evidence for a causal effect of CRC on H. pylori infection. The weighted median, the MR-Egger method, and MR-PRESSO yielded identical results. Using genetic data, MR analysis showed there was no evidence for a causal association between seroprevalence of H. pylori infection and CRC. The relationship between H. pylori infection and CRC requires further research.

Ankylosing spondylitis and psychiatric disorders in European population: a Mendelian randomization study.

Epidemiologic evidence has demonstrated a correlation between ankylosing spondylitis and psychiatric disorders. However, little is known about the common genetics and causality of this association. This study aimed to investigate the common genetics and causality between ankylosing spondylitis (AS) and psychiatric disorders. A two-sample Mendelian Randomization (MR) analysis was carried out to confirm causal relationships between ankylosing spondylitis and five mental health conditions including major depressive disorder (MDD), anxiety disorder (AXD), schizophrenia (SCZ), bipolar disorder (BIP), and anorexia nervosa (AN). Genetic instrumental variables associated with exposures and outcomes were derived from the largest available summary statistics of genome-wide association studies (GWAS). Bidirectional causal estimation of MR was primarily obtained using the inverse variance weighting (IVW) method. Other MR methods include MR-Egger regression, Weighted Median Estimator (WME), Weighted Mode, Simple Mode, and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO). Sensitivity analyses are conducted to estimate the robustness of MR results. The findings suggest that AS may be causally responsible for the risk of developing SCZ (OR = 1.18, 95% confidence interval = (1.06, 1.31), P = 2.58 × 10-3) and AN (OR = 1.32, 95% confidence interval = (1.07, 1.64), P = 9.43 × 10-3). In addition, MDD, AXD, SCZ, AN, and BIP were not inversely causally related to AS (all p > 0.05). Our study provides fresh insights into the relationship between AS and psychiatric disorders (SCZ and AN). Furthermore, it may provide new clues for risk management and preventive interventions for mental disorders in patients with AS.

Unveiling the intricate causal nexus between pancreatic cancer and peripheral metabolites through a comprehensive bidirectional two-sample Mendelian randomization analysis.

Aim: Pancreatic cancer (PC) is a devastating malignancy characterized by its aggressive nature and poor prognosis. However, the relationship of PC with peripheral metabolites remains not fully investigated. The study aimed to explore the causal linkage between PC and peripheral metabolite profiles. Methods: Employing publicly accessible genome-wide association studies (GWAS) data, we conducted a bidirectional two-sample Mendelian randomization (MR) analysis. The primary analysis employed the inverse-variance weighted (IVW) method. To address potential concerns about horizontal pleiotropy, we also employed supplementary methods such as maximum likelihood, weighted median, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO). Results: We ascertained 20 genetically determined peripheral metabolites with causal linkages to PC while high-density lipoprotein (HDL) and very low-density lipoprotein (VLDL) particles accounted for the vast majority. Specifically, HDL particles exhibited an elevated PC risk while VLDL particles displayed an opposing pattern. The converse MR analysis underscored a notable alteration in 17 peripheral metabolites due to PC, including branch chain amino acids and derivatives of glycerophospholipid. Cross-referencing the bidirectional MR results revealed a reciprocal causation of PC and X-02269 which might form a self-perpetuating loop in PC development. Additionally, 1-arachidonoylglycerophosphocholine indicated a reduced PC risk and an increase under PC influence, possibly serving as a negative feedback regulator. Conclusion: Our findings suggest a complex interplay between pancreatic cancer and peripheral metabolites, with potential implications for understanding the etiology of pancreatic cancer and identifying novel early diagnosis and therapeutic targets. Moreover, X-02269 may hold a pivotal role in PC onset and progression.

Causal effects of gut microbiota on erectile dysfunction: a two-sample Mendelian randomization study.

Several observational studies have reported the correlation between gut microbiota and the risk of erectile dysfunction (ED). However, the causal association between them remained unestablished owing to intrinsic limitations, confounding factors, and reverse causality. Therefore, the two-sample Mendelian randomization (MR) study was performed to determine the causal effect of gut microbiota on the risk of ED. The MR analysis utilized the publicly available genome-wide association study (GWAS) summary-level data to explore the causal associations between gut microbiota and ED. The gut microbiota data were extracted from the MiBioGen study (N = 18,340), and the ED data were extracted from the IEU Open GWAS (6,175 ED cases and 217,630 controls). The single nucleotide polymorphisms (SNPs) served as instrumental variables (IVs) by two thresholds of P-values, the first P-value setting as <1e-05 (locus-wide significance level) and the second P-value setting as <5e-08 (genome-wide significance level). The inverse variance weighted approach was used as the primary approach for MR analysis, supplemented with the other methods. In addition, sensitivity analyses were performed to evaluate the robustness of the MR results, including Cochran's Q test for heterogeneity, the MR-Egger intercept test for horizontal pleiotropy, the Mendelian randomization pleiotropy residual sum, and outlier (MR-PRESSO) global test for outliers, and the forest test and leave-one-out test for strong influence SNPs. Our results presented that the increased abundance of Lachnospiraceae at family level (OR: 1.265, 95% CI: 1.054-1.519), Senegalimassilia (OR: 1.320, 95% CI: 1.064-1.638), Lachnospiraceae NC2004 group (OR: 1.197, 95% CI: 1.018-1.407), Tyzzerella3 (OR: 1.138, 95% CI: 1.017-1.273), and Oscillibacter (OR: 1.201, 95% CI: 1.035-1.393) at genus level may be risk factors for ED, while the increased abundance of Ruminococcaceae UCG013 (OR: 0.770, 95% CI: 0.615-0.965) at genus level may have a protective effect on ED. No heterogeneity or pleiotropy was found based on the previously described set of sensitivity analyses. Our MR analysis demonstrated that the gut microbiota had inducing and protective effects on the risk of ED. The results provide clinicians with novel insights into the treatment and prevention of ED in the future. Furthermore, our study also displays novel insights into the pathogenesis of microbiota-mediated ED.

Depression and risk of sarcopenia: a national cohort and Mendelian randomization study.

Depression and the increased risk of sarcopenia are prevalent among the elderly population. However, the causal associations between these factors remain unclear. To investigate the potential association between depression and the risk of sarcopenia in older adults, this study was performed. In the baseline survey, a total of 14,258 individuals aged 40 and above from the China Health and Retirement Longitudinal Study (2015) participated. We initially described the baseline prevalence of the disease. Then, logistic regression and restricted cubic spline (RCS) regression were conducted to assess the relationship between depression and sarcopenia. Subgroup analysis was performed to validate the robustness of the findings. Additionally, we conducted Mendelian randomization analysis using the inverse variance weighting estimator to assess the causal relationship between depression and sarcopenia. Furthermore, we adopted six methods, including MR-Egger, simple median, weighted median, maximum likelihood, robust adjusted profile score (RAPS), and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO), for sensitivity analyses. Depression patients exhibited higher risks of sarcopenia in all five models adjusting for different covariates (P < 0.05). The RCS analysis demonstrated a linear relationship between depression and sarcopenia (P < 0.05). In the subgroup analysis, increased risk was observed among participants aged 60-70, married or cohabiting individuals, non-smokers, non-drinkers, those with less than 8 h of sleep, BMI below 24, and individuals with hypertension (all P < 0.05). Mendelian randomization results revealed that genetically proxied depression led to a reduction in appendicular skeletal muscle mass (all P < 0.05). Our study provides observational and causal evidences that depression can lead to sarcopenia. This finding emphasizes the importance of timely identification and management of depression, as well as implementing targeted educational programs as part of comprehensive strategies to prevent sarcopenia.

Causal association of circulating cytokines with sepsis: a Mendelian randomization study.

Observational studies have reported an association between circulating cytokines and sepsis. However, the precise causal relationship between these factors remains unclear. The objective of this study was to explore the causal link between circulating cytokines and sepsis using genetic data within the framework of Mendelian Randomization (MR). We performed a two-sample MR analysis to investigate this causality relationship in individuals of European ancestry. The publicly available genome-wide association studies (GWAS) statistics were used. We selected eligible instrumental single nucleotide polymorphisms (SNPs) that were significantly related to the circulating cytokines. Multiple MR analysis approaches were carried out, which included inverse variance weighted (IVW), Weighted Median, MR-Egger, Weighted Mode, Simple Mode, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods. We found evidence to support the causal role of genetically predicted circulating levels on decreased risk of sepsis, including RANTES (OR = 0.920, 95% CI: 0.849-0.997, P = 0.041) and basic fibroblast growth factor (basic-FGF) (OR = 0.869, 95% CI: 0.766-0.986, P = 0.029). Additionally, MR analysis positive causal association of between beta-nerve growth factor (β-NGF) and sepsis (OR = 1.120, 95% CI: 1.037-1.211, P = 0.004). The results of MR-Egger, Weighted Median, Weighted Mode, and Simple Mode methods were consistent with the IVW estimates. Sensitivity analysis showed no horizontal pleiotropy to bias the causal estimates. This MR study provides first novel evidence that genetically predicted causal association of circulating levels of RANTES, basic-FGF, and β-NGF with altered sepsis risk. The findings shed light on the potential involvement of these cytokines in sepsis pathogenesis. Although requiring additional confirmation, the results contribute new insights into cytokine mediators in sepsis and suggest promising future research directions.

Genetically predicted gut microbiome and risk of oral cancer.

Mounting evidence suggests a possible link between gut microbiome and oral cancer, pointing to some potential modifiable targets for disease prevention. In the present study, Mendelian randomization (MR) was used to explore whether there was a causal link between gut microbiome and oral cancer. The single nucleotide polymorphisms (SNPs) significantly associated with gut microbiome were served as instrumental variables. MR analyses were performed using genetic approaches such as inverse variance weighting (IVW), MR Egger and weighted median, with IVW as the primary approach, supplemented by MR Egger and weighted median. Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and MR-Egger regression were used to detect the presence of horizontal pleiotropy and identify outlier SNPs. Causal effect estimates indicated that genetically predicted abundance of Prevotellaceae was associated with higher risk of oral cancer (odds ratio (OR) 1.80, 95% confidence interval (CI) 1.16-2.81, p = 0.009). There was no evidence of notable heterogeneity and horizontal pleiotropy. Genetically derived estimates suggest that Prevotellaceae may be associated with the risk of oral cancer. Such robust evidence should be given priority in future studies and explore the underlying mechanisms.

THU628 Causal Relationship Between The Menstrual Cycle Length And Basal Metabolic Rate: A Two-sample Mendelian Randomization Study

Abstract Disclosure: M. Kazemi: None. S.A. Parry: None. Long or irregular menstrual cycles, as a hallmark reproductive trait in polycystic ovary syndrome (PCOS), have been associated with aberrant energy expenditure, obesity, and cardiometabolic comorbidities. However, current observational studies addressing the contributions of energy expenditure to menstrual cyclicity have generated conflicting results and have not utilized the full extent of known single nucleotide polymorphisms associated with basal energy expenditure. Whether the relationship is causal is uncertain. We conducted a two-sample Mendelian Randomization study to interrogate the causal relationships between basal metabolic rate and length of menstrual cycles. The (MR) analyses were performed using publicly released genome-wide association studies (GWAS) statistics from 2 separate European cohorts using the UK Biobank database. The inverse-variance weighted (IVW) method was used as the primary analysis. We applied four complementary methods, including weighted median, weighted mode, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO), to detect and correct the effect of horizontal pleiotropy. The result of the IVM method revealed that genetically determined basal metabolic rate has an inverse causal effect on the length of the menstrual cycle (β, -0.13, SE, 0.03; P=2.17 E-05). The results of MR-Egger regression, weighted median, and weighted mode methods were consistent with those of the IVW method. Sensitivity analyses revealed that horizontal pleiotropy was unlikely to distort the causal estimates. Collectively, our MR analysis revealed that basal metabolic rate appears to be causally affecting the length of menstrual cycles. Our findings reflect novel insights into the role of energy metabolism on menstrual disturbances. However, the molecular mechanisms should be investigated. Future MR analysis is warranted to confirm our findings by controlling for potentially relevant confounders, including obesity and age. Nevertheless, our findings have perturbations to elucidate causal pathways explaining obesity in relevant conditions, including PCOS. Presentation: Thursday, June 15, 2023

Causality of occupational exposure on rheumatoid arthritis and ankylosing spondylitis: a two-sample mendelian randomization study.

This study aimed to explore the potential causal link between three specific types of occupational exposure on rheumatoid arthritis (RA) and ankylosing spondylitis (AS). A Two-sample Mendelian randomization (TSMR) analysis, comprising univariate MR (UVMR) and multivariate MR (MVMR) analyses, was performed to investigate the potential causal association between three types of occupational exposures, jobs involving mainly walking or standing (JWS), jobs involving heavy manual or physical work (JMP), and jobs involving shift work(JSW) on RA and AS. Genetic variants for genome-wide association studies (GWAS) of occupational exposure and AS were obtained from the UK Biobank. GWAS summary data for RA were obtained from FinnGen Biobank analysis. For UVMR, six methods of Inverse Variance Weighted (IVW), MR-Egger, Weighted Mode, Weighted Median, Simple Mode, MR pleiotropy residual sum, and outlier (MR-PRESSO) were used for the analysis. The MVMR was analyzed using the IVW model as well as the MR-Egger model. The UVMR suggested no causal relationship between the three occupational exposure and RA [IVW: P=0.59,0.21,0.63] or AS [IVW: P=0.43,0.57,0.04], as did the bidirectional MR [IVW: P=0.73,0.70,0.16], [IVW: P=0.65,0.68,0.74]. Although unadjusted MVMR suggested a causal relationship between JMP and AS [IVW: OR = 1.01, 95% CI = 1.00- 1.02, p = 0.02], the adjusted MVMR denied this relationship and concluded that there was no causal relationship between the other occupational exposure and either RA or AS. Our MR analysis did not establish a direct causal relationship between certain occupational exposures and either RA or AS.

Unravelling the liver-brain connection: A two-sample Mendelian randomization study investigating the causal relationship between NAFLD and cortical structure

BackgroundNon-alcoholic fatty liver disease (NAFLD) has been linked to cognitive decline and neuropsychiatric conditions, implying a potential connection between NAFLD and brain health. However, the causal association between NAFLD and cortical changes remains uncertain. This study aimed to examine the causal impact of NAFLD on cortical structures using a two-sample Mendelian randomization (MR) approach. MethodsSummary data from genome-wide association studies (GWAS) for NAFLD were gathered from large-scale cohorts. Surface area (SA) and cortical thickness (TH) measurements were derived from Enhancing Neuro Imaging Genetics through Meta-Analysis (ENIGMA) Consortium magnetic resonance imaging (MRI) data of 33,992 participants. Inverse-variance weighted (IVW) served as the primary method. Additional sensitivity analyses, including MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), MR-Egger, and weighted median procedures, were conducted to detect heterogeneity and pleiotropy. ResultsOur MR analysis revealed that NAFLD led to notable alterations in cortical structures, particularly in the pars orbitalis gyrus. Specifically, genetically predicted NAFLD was linked to a decrease in TH (β = -0.008 mm, 95 % CI: −0.013 mm to −0.004 mm, P = 3.00 × 10−4) within this region. No significant heterogeneity and pleiotropy were identified. ConclusionThe two-sample MR study supports the existence of a liver-brain axis by demonstrating a causal association between NAFLD and changes in cortical structures. These findings emphasize the potential association between NAFLD and brain health, which could have implications for preventing and treating cognitive deficits and neuropsychiatric conditions in patients with NAFLD.

The causal relationship between gut microbiota and inflammatory dermatoses: a Mendelian randomization study.

Observational studies have shown that gut microbiota is closely associated with inflammatory dermatoses such as psoriasis, rosacea, and atopic dermatitis (AD). However, the causal relationship between gut microbiota and inflammatory dermatosis remains unclear. Based on Maximum Likelihood (ML), MR-Egger regression, Inverse Variance Weighted (IVW), MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), Weighted Mode, and Weighted Median Estimator (WME) methods, we performed a bidirectional two-sample Mendelian randomization (MR) analysis to explore the causal relationship between gut microbiota and inflammatory dermatosis. The genome-wide association study (GWAS) summary data of gut microbiota came from the MiBioGen consortium, while the GWAS summary data of inflammatory dermatosis (including psoriasis, AD, rosacea, vitiligo, acne, and eczema) came from the FinnGen consortium and IEU Open GWAS project. Cochran's IVW Q test tested the heterogeneity among instrumental variables (IVs). The horizontal pleiotropy was tested by MR-Egger regression intercept analysis and MR-PRESSO analysis. Eventually, the results indicated that 5, 16, 17, 11, 15, and 12 gut microbiota had significant causal effects on psoriasis, rosacea, AD, vitiligo, acne, and eczema, respectively, including 42 protective and 34 risk causal relationships. Especially, Lactobacilli and Bifidobacteria at the Family and Genus Level, as common probiotics, were identified as protective factors for the corresponding inflammatory dermatoses. The results of reverse MR analysis suggested a bidirectional causal effect between AD and genus Eubacterium brachy group, vitiligo and genus Ruminococcaceae UCG004. The causal relationship between gut microbiota and psoriasis, rosacea, acne, and eczema is unidirectional. There was no significant heterogeneity among these IVs. In conclusion, this bidirectional two-sample MR study identified 76 causal relationships between the gut microbiome and six inflammatory dermatoses, which may be helpful for the clinical prevention and treatment of inflammatory dermatoses.

Cigarette smoking and thyroid cancer risk: A Mendelian randomization study.

The association between cigarette smoking and thyroid cancer has been reported in prospective cohort studies, but the relationship remains controversial. To investigate this potential correlation further, we employed Mendelian randomization methodology to evaluate the causative impact of smoking on thyroid cancer incidence. From the genome-wide association study and Sequencing Consortium of Alcohol and Nicotine use, we obtained genetic variants associated with smoking initiation and cigarettes per day (1.2 million individuals). We also extracted genetic variants associated with past tobacco smoking from the UK Biobank (424,960 individuals). Thyroid cancer outcomes were selected from the FinnGen GWAS (989 thyroid cancer cases and 217,803 control cases). Sensitivity analyses employing various approaches such as weighted median, MR-Egger, and MR-pleiotropy residual sum and outlier (MR-PRESSO) have been executed, as well as leave-one-out analysis to identify pleiotropy. Using the IVW approach, we did not find evidence that any of the three smoking phenotypes were related to thyroid cancer (smoking initiation: odds ratio (OR) = 1.56, p = 0.61; cigarettes per day: OR = 0.85, p = 0.51; past tobacco smoking: OR = 0.80, p = 0.78). The heterogeneity (p > 0.05) and pleiotropy (p > 0.05) testing provided confirmatory evidence for the validity of our MR estimates. The MR analysis revealed that there may not exist a causative link between smoking exposure and elevated incidence rates of thyroid malignancies.

Genetic Evidence Supporting a Causal Association Between mTOR-Dependent EIF-4E Circulating Protein Level and Osteoporosis.

The mechanistic target of rapamycin (mTOR) regulates bone homeostasis, a crucial factor in osteoporosis (OP) development. However, most research is based on observational studies, and the causality remains uncertain. Therefore, we analyzed two samples of mendelian randomization (MR) to determine whether there is a causal relationship between mTOR-dependent circulating proteins and OP. Mendelian weighting (weighted median [WM], inverse variance weighting [IVW], and MR-Egger regression) were applied to analyze the causality between bone phenotypes (bone mineral density [BMD] in forearm, femoral neck, lumbar spine, and heel) and mTOR-dependent circulating proteins (RP-S6K, 4EBP, EIF-4E, EIF-4A, and EIF-4G). Horizontal pleiotropy and heterogeneities were detected using Cochran's Q test, MR-Pleiotropy RE-Sidual Sum and Outlier (MR-PRESSO), and "leave-one-out" analysis. The proteomics-GWAS INTERVAL study was used to select the instrumental variables (IVs) for mTOR proteins. As phenotypes for OP, estimations of BMD were taken in four different sites: forearm (FA) (n = 8143), femoral neck (FN) (n = 32,735), lumbar spine (LS) (n = 28,498), and heel (eBMD) (n = 426,824). Based on IVW analysis, EIF4E is causally related to FA-BMD (OR = 0.938, 95% CI 0.887, 0.991, p = 0.024) but not to BMD elsewhere. MR analysis revealed a causal relationship between EIF-4E and FA-BMD, which may provide new insights into the underlying pathogenesis of OP and a new therapeutic target for OP.

Association between gut microbiota and benign prostatic hyperplasia: a two-sample mendelian randomization study.

Recent researches have shown a correlation between the gut microbiota (GM) and various diseases. However, it remains uncertain whether the relationship between GM and benign prostatic hyperplasia (BPH) is causal. We carried out a two-sample Mendelian randomization (MR) analysis, utilizing data from the most extensive GM-focused genome-wide association study by the MiBioGen consortium, with a sample size of 13,266. Data for BPH, encompassing 26,358 cases and 110,070 controls, were obtained from the R8 release of the FinnGen consortium. We employed multiple techniques, such as inverse variance weighted (IVW), constrained maximum likelihood and model averaging methods, maximum likelihood, MR-Pleiotropy RESidual Sum and Outlier (MRPRESSO),MR-Egger, and weighted median methods, to investigate the causal relationship between GM and BPH. To evaluate the heterogeneity among the instrumental variables, Cochran's Q statistics were employed. Additionally, the presence of horizontal pleiotropy was assessed through the application of both MR-Egger and MR-PRESSO tests. The direction of causality was scrutinized for robustness using the MR-Steiger directionality test. A reverse MR analysis examined the GM previously linked to BPH through a causal relationship in the forward MR assessment. According to the analysis conducted using IVW,Eisenbergiella (odds ratio [OR]=0.92, 95% confidence interval [CI]: 0.85-0.99,P=0.022) and Ruminococcaceae (UCG009) (OR=0.88, 95% CI: 0.79-0.99, P=0.027) were found to reduce the risk of BPH, while Escherichia shigella (OR=1.19, 95% CI: 1.05-1.36, P=0.0082) appeared to increase it. The subsequent reverse MR analysis revealed that the three GM were not significantly influenced by BPH, and there was no noticeable heterogeneity or horizontal pleiotropy among the instrumental variables.Conclusion: These results indicated a causal relationship between Eisenbergiella, Ruminococcaceae (UCG009), and Escherichia shigella and BPH. Further randomized controlled trials are needed to explore more comprehensively the roles and operational mechanisms of these GM in relation to BPH.

Causal association between self-reported fatigue and coronary artery disease: a bidirectional two-sample Mendelian randomization analysis.

Observational studies have reported the association between fatigue and coronary artery disease (CAD), but the causal association between fatigue and CAD is unclear. We conducted a bidirectional Mendelian randomization (MR) study using publicly available genome-wide association studies (GWAS) data. The inverse-variance weighted (IVW) method was used as the primary analysis. We performed three complementary methods, including weighted median, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO) to evaluate the sensitivity and horizontal pleiotropy of the results. Self-reported fatigue had a causal effect on coronary artery atherosclerosis (CAA) (OR 1.047, 95%CI 1.033-1.062), myocardial infarction (MI) (OR 1.027 95%CI 1.014-1.039) and coronary heart disease (CHD) (OR 1.037, 95%CI 1.021-1.053). We did not find a significant reverse causality between self-reported fatigue and CAD. Given the heterogeneity revealed by MR-Egger regression, we employed the IVW random effect model. For the examination of fatigue on CHD and the reverse analysis of CAA, and MI on fatigue, the MR-PRESSO test found horizontal pleiotropy. No significant outliers were found. The MR analysis reveals a causal relationship between self-reported fatigue and CAD. The results should be interpreted with caution due to horizontal pleiotropy.

Effect of genetic liability to migraine and its subtypes on breast cancer: a mendelian randomization study

BackgroundThe relationship between migraine and breast cancer risk has generated conflicting findings. We attempted to assess the association between migraine and breast cancer risk using Mendelian randomization (MR) analysis.MethodsWe selected genetic instruments associated with migraine from a recently published genome-wide association studies (GWAS). Inverse variant weighted (IVW) analysis was adopted as the main method, and we also performed the weighted-median method and the MR‒Egger, MR pleiotropy residual sum and outlier (MR-PRESSO), and MR Robust Adjusted Profile Score (MR-RAPS) methods as supplements.ResultsOur MR suggested that any migraine (AM) was a risk factor for overall breast cancer (IVW: odds ratio (OR) = 1.072, 95% confidence intervals (CI) = 1.035–1.110, P = 8.78 × 10− 5, false discovery rate (FDR) = 7.36 × 10− 4) and estrogen receptor-positive (ER+) breast cancer (IVW: OR = 1.066, 95% CI = 1.023–1.111, P = 0.0024; FDR = 0.0108) but not estrogen receptor-negative (ER-) breast cancer. In its subtype analysis, women with a history of migraine without aura (MO) had an increased risk of ER- breast cancer (IVW: OR = 1.089, 95% CI = 1.019–1.163, P = 0.0118, FDR = 0.0354), and MO was suggestively associated with the risk of overall breast cancer (FDR > 0.05 and IVW P < 0.05). No significant heterogeneity or horizontal pleiotropy was found in the sensitivity analysis.ConclusionThis study suggested that women with AM have an increased risk of overall breast cancer and ER + breast cancer. MO was suggestively associated with the risk of overall breast cancer and ER- breast cancer.

Causal relationship between addictive behaviors and epilepsy risk: A mendelian randomization study

BackgroundPrevious studies have reported inconsistent results regarding the potential relationships between addictive behaviors and the risk of epilepsy. ObjectiveTo assess whether genetically predicted addictive behaviors are causally associated with the risk of epilepsy outcomes. MethodsThe causation between five addictive behaviors (including cigarettes per day, alcoholic drinks per week, tea intake, coffee intake, and lifetime cannabis use) and epilepsy was evaluated by using a two-sample Mendelian Randomization (MR) analysis. The inverse-variance weighted (IVW) method was used as the primary outcome. The other MR analysis methods (MR Egger, weighted median, simulation extrapolation corrected MR-Egger, and Mendelian Randomization Pleiotropy Residual Sum and Outlier (MR-PRESSO)) were performed to complement IVW. In addition, the robustness of the MR analysis results was assessed by leave-one-out analysis. ResultsThe IVW analysis method indicated an approximately 20% increased risk of epilepsy per standard deviation increase in lifetime cannabis use (odds ratio [OR], 1.20; 95% confidence interval [CI]), 1.02–1.42, P = 0.028). However, there is no causal association between the other four addictive behaviors and the risk of epilepsy (cigarettes per day: OR, 1.04; 95% CI, 0.92–1.18, P = 0.53; alcoholic drinks per week: OR, 1.31; 95% CI, 0.93–1.84, P = 0.13; tea intake: OR, 1.15; 95% CI, 0.84–1.56, P = 0.39; coffee intake: OR, 0.86; 95% CI, 0.59–1.23, P = 0.41). The other MR analysis methods and further leave-one-out sensitivity analysis suggested the results were robust. ConclusionThis MR study indicated a potential genetically predicted causal association between lifetime cannabis use and higher risk of epilepsy. As for the other four addictive behaviors, no evidence of a causal relationship with the risk of epilepsy was found in this study.

Genetic Insights into Intestinal Microbiota and Risk of Infertility: A Mendelian Randomization Study.

The interaction between intestinal microbiota and infertility is less researched. This study was performed to investigate the causal association between gut microbiota and infertility. In this two-sample Mendelian randomization (MR) study, genetic variants of intestinal microbiota were obtained from the MiBioGen consortium, which included 18,340 individuals. Inverse variance weighting (IVW), MR-Egger, weighted median, maximum likelihood, MR Robust adjusted profile score, MR Pleiotropy residual sum, and outlier (MR-PRESSO) methods were used to explore the causal links between intestinal microbiota and infertility. The MR-Egger intercept term and the global test from the MR-PRESSO estimator were used to assess the horizontal pleiotropy. The Cochran Q test was applied to evaluate the heterogeneity of instrumental variables (IVs). As indicated by the IVW estimator, significantly protective effects of the Family XIII AD3011 group (OR = 0.87) and Ruminococcaceae NK4A214 group (OR = 0.85) were identified for female fertility, while Betaproteobacteria (OR = 1.18), Burkholderiales (OR = 1.18), Candidatus Soleaferrea (OR = 1.12), and Lentisphaerae (OR = 1.11) showed adverse effects on female fertility. Meanwhile, Bacteroidaceae (OR = 0.57), Bacteroides (OR = 0.57), and Ruminococcaceae NK4A214 group (OR = 0.61) revealed protective effects on male fertility, and a causal association between Anaerotruncus (OR = 1.81) and male infertility was detected. The effect sizes and directions remained consistent in the other five methods except for Candidatus Soleaferrea. No heterogeneity or pleiotropy were identified by Cochran's Q test, MR-Egger, and global test (all p > 0.05). This two-sample MR study revealed that genetically proxied intestinal microbiota had potentially causal effects on infertility. In all, the Ruminococcaceae NK4A214 group displayed protective effects against both male and female infertility. Further investigations are needed to establish the biological mechanisms linking gut microbiota and infertility.