MR-BOIL: Causal inference in one-sample Mendelian randomization for binary outcome with integrated likelihood method.

Mendelian randomization is a statistical method for inferring the causal relationship between exposures and outcomes using an economics-derived instrumental variable approach. The research results are relatively complete when both exposures and outcomes are continuous variables. However, due to the noncollapsing nature of the logistic model, the existing methods inherited from the linear model for exploring binary outcome cannot take the effect of confounding factors into account, which leads to biased estimate of the causal effect. In this article, we propose an integrated likelihood method MR-BOIL to investigate causal relationships for binary outcomes by treating confounders as latent variables in one-sample Mendelian randomization. Under the assumption of a joint normal distribution of the confounders, we use expectation maximization algorithm to estimate the causal effect. Extensive simulations demonstrate that the estimator of MR-BOIL is asymptotically unbiased and that our method improves statistical power without inflating type I error rate. We then apply this method to analyze the data from Atherosclerosis Risk in Communications Study. The results show that MR-BOIL can better identify plausible causal relationships with high reliability, compared with the unreliable results of existing methods. MR-BOIL is implemented in R and the corresponding R code is provided for free download.

The immune factors have complex causal regulation effects on kidney stone disease: a mendelian randomization study.

PURPOSE: Previous studies have reported the potential impact of immune cells on kidney stone disease (KSD), but definitive causal relationships have yet to be established. The purpose of this paper is to elucidate the potential causal association between immune cells and KSD by Mendelian randomization (MR) analysis. METHODS: In our study, a thorough two-sample Mendelian randomization (MR) analysis was performed by us to determine the potential causal relationship between immune cell traits and kidney stone disease. We included a total of four immune traits (median fluorescence intensity (MFI), relative cellular (RC), absolute cellular (AC), and morphological parameters (MP)), which are publicly available data. GWAS summary data related to KSD (9713 cases and 366,693 controls) were obtained from the FinnGen consortium. The primary MR analysis method was Inverse variance weighted. Cochran's Q test, MR Egger, and MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) were used to assess the stability of the results. RESULTS: After FDR correction, the CD8 on HLA DR + CD8br (OR = 0.95, 95% CI = 0.93-0.98, p-value = 7.20 × 10- 4, q-value = 0.088) was determined to be distinctly associated with KSD, and we also found other 25 suggestive associations between immune cells and KSD, of which 13 associations were suggested as protective factors and 12 associations were suggested as risk factors. There was no horizontal pleiotropy or significant heterogeneity in our MR analysis, as determined by the p-value results of our Cochrane Q-test, MR Egger's intercept test, and MR-PRESSO, which were all > 0.05. CONCLUSIONS: Our study has explored the potential causal connection between immune cells and KSD by Mendelian randomization analysis, thus providing some insights for future clinical studies.

Assessing the causal relationship between immune cells and prostatitis: evidence from bidirectional mendelian randomization analysis.

Prostatitis represents a common disease of the male genitourinary system, significantly impacting the physical and mental health of male patients. While numerous studies have suggested a potential link between immune cell activity and prostatitis, the exact causal role of immune cells in prostatitis remains uncertain. This study aims to explore the causal relationship between immune cell characteristics and prostatitis using a bidirectional Mendelian randomization approach. This study utilizes data from the public GWAS database and employs bidirectional Mendelian randomization analysis to investigate the causal relationship between immune cells and prostatitis. The causal relationship between 731 immune cell features and prostatitis was primarily investigated through inverse variance weighting (IVW), complemented by MR-Egger regression, a simple model, the weighted median method, and a weighted model. Ultimately, the results underwent sensitivity analysis to assess the heterogeneity, horizontal pleiotropy, and stability of Single Nucleotide Polymorphisms (SNPs) in immune cells and prostatitis. MR analysis revealed 17 immune cells exhibiting significant causal effects on prostatitis. In contrast, findings from reverse MR indicated a significant causal relationship between prostatitis and 13 immune cells. Our study utilizes bidirectional Mendelian Randomization to establish causal relationships between specific immune cell phenotypes and prostatitis, highlighting the reciprocal influence between immune system behavior and the disease. Our findings suggest targeted therapeutic approaches and the importance of including diverse populations for broader validation and personalized treatment strategies.

Large-scale genome-wide association studies reveal the genetic causal etiology between air pollutants and autoimmune diseases.

BACKGROUND: Epidemiological evidence links a close correlation between long-term exposure to air pollutants and autoimmune diseases, while the causality remained unknown. METHODS: Two-sample Mendelian randomization (TSMR) was used to investigate the role of PM10, PM2.5, NO2, and NOX (N = 423,796-456,380) in 15 autoimmune diseases (N = 14,890-314,995) using data from large European GWASs including UKB, FINNGEN, IMSGC, and IPSCSG. Multivariable Mendelian randomization (MVMR) was conducted to investigate the direct effect of each air pollutant and the mediating role of common factors, including body mass index (BMI), alcohol consumption, smoking status, and household income. Transcriptome-wide association studies (TWAS), two-step MR, and colocalization analyses were performed to explore underlying mechanisms between air pollution and autoimmune diseases. RESULTS: In TSMR, after correction of multiple testing, hypothyroidism was causally associated with higher exposure to NO2 [odds ratio (OR): 1.37, p = 9.08 × 10-4] and NOX [OR: 1.34, p = 2.86 × 10-3], ulcerative colitis (UC) was causally associated with higher exposure to NOX [OR: 2.24, p = 1.23 × 10-2] and PM2.5 [OR: 2.60, p = 5.96 × 10-3], rheumatoid arthritis was causally associated with higher exposure to NOX [OR: 1.72, p = 1.50 × 10-2], systemic lupus erythematosus was causally associated with higher exposure to NOX [OR: 4.92, p = 6.89 × 10-3], celiac disease was causally associated with lower exposure to NOX [OR: 0.14, p = 6.74 × 10-4] and PM2.5 [OR: 0.17, p = 3.18 × 10-3]. The risky effects of PM2.5 on UC remained significant in MVMR analyses after adjusting for other air pollutants. MVMR revealed several common mediators between air pollutants and autoimmune diseases. Transcriptional analysis identified specific gene transcripts and pathways interconnecting air pollutants and autoimmune diseases. Two-step MR revealed that POR, HSPA1B, and BRD2 might mediate from air pollutants to autoimmune diseases. POR pQTL (rs59882870, PPH4=1.00) strongly colocalized with autoimmune diseases. CONCLUSION: This research underscores the necessity of rigorous air pollutant surveillance within public health studies to curb the prevalence of autoimmune diseases.

Genetic evidence of the causal relationship between chronic liver diseases and musculoskeletal disorders.

BACKGROUND: Chronic liver diseases constitute a major global public health burden, posing a substantial threat to patients' daily lives and even survival due to the potential development of musculoskeletal disorders. Although the relationship between chronic liver diseases and musculoskeletal disorders has received extensive attention, their causal relationship has not been comprehensively and systematically investigated. METHODS: This study aimed to assess the causal relationships between viral hepatitis, primary biliary cholangitis, primary sclerosing cholangitis (PSC), liver cirrhosis, and hepatocellular carcinoma (HCC) with osteoporosis, osteoarthritis, and sarcopenia through bidirectional Mendelian randomization (MR) research. The traits related to osteoporosis and osteoarthritis included both overall and site-specific phenotypes, and the traits linked to sarcopenia involved indicators of muscle mass and function. Random-effect inverse-variance weighted (IVW), weighted median, MR-Egger, and Causal Analysis Using the Summary Effect Estimates were used to evaluate causal effects, with IVW being the main analysis method. To enhance robustness, sensitivity analyses were performed using Cochran's Q test, MR-Egger intercept, MR-PRESSO global test, funnel plots, leave-one-out analyses, and latent causal variable model. RESULTS: The forward MR analysis indicated that PSC can reduce forearm bone mineral density (beta = - 0.0454, 95% CI - 0.0798 to - 0.0110; P = 0.0098) and increase the risk of overall osteoarthritis (OR = 1.012, 95% CI 1.002-1.022; P = 0.0247), while HCC can decrease grip strength (beta = - 0.0053, 95% CI - 0.008 to - 0.0025; P = 0.0002). The reverse MR analysis did not find significant causal effects of musculoskeletal disorders on chronic liver diseases. Additionally, no heterogeneity or pleiotropy was detected. CONCLUSIONS: These findings corroborate the causal effects of PSC on osteoporosis and osteoarthritis, as well as the causal impact of HCC on sarcopenia. Thus, the implementation of comprehensive preventive measures is imperative for PSC and HCC patients to mitigate the risk of musculoskeletal disorders, ultimately improving their quality of life.

The relationship between sex hormone-binding protein and non-alcoholic fatty liver disease using Mendelian randomisation.

BACKGROUND: The incidence of non-alcohol fatty liver disease (NAFLD) has been increasing annually with the improvement of living standards. Numerous epidemiological observations have linked sex hormone-binding protein (SHBG) levels to NAFLD. However, evidence of the causal role of SHBG in the development and progression of NAFLD is still absent. Therefore, a systematic assessment of the causal relationship is needed. METHOD: A two-sample Mendelian randomisation (MR) analysis was conducted. Genome-wide association study (GWAS) data for SHBG were obtained online from the IEU database (ebi-a-GCST90012111) as exposure. GWAS data from the NAFLD of the Finngen consortium were used for preliminary analysis, while NAFLD data from another GWAS involving 8434 participants were used for replication and meta-analyses. Causal effects were investigated with inverse variance weighted (IVW), weighted median and MR-Egger regression. Sensitivity analyses including Cochran's Q test, leave-one-out analysis and MR-Egger intercept analysis were simultaneously conducted to assess heterogeneity and pleiotropy. RESULTS: After rigorous selection, 179 single-nucleotide polymorphisms (SNPs) were identified as strongly correlated instrumental variables. Preliminary analysis suggested a significant causal relationship between genetically determined serum SHBG levels and NAFLD [odds ratio (OR) IVW = .54, 95% confidence interval (CI) = .30-.98, p = .043], supported by the results of the replication analysis (ORIVW = .61, 95% CI = .46-.81, p = .0006) and further meta-analysis (OR = .59, 95% CI = .46-.77, p < .0001). CONCLUSION: The genetic tendency to high levels of SHBG was causally correlated with a reduced risk of NAFLD, indicating that circulating high levels of SHBG was a protective factor for NAFLD.

Causal relationship between gut microbiota and tuberculosis: a bidirectional two-sample Mendelian randomization analysis.

BACKGROUND: Growing evidence from observational studies and clinical trials suggests that the gut microbiota is associated with tuberculosis (TB). However, it is unclear whether any causal relationship exists between them and whether causality is bidirectional. METHODS: A bidirectional two-sample Mendelian randomization (MR) analysis was performed. The genome-wide association study (GWAS) summary statistics of gut microbiota were obtained from the MiBioGen consortium, while the GWAS summary statistics of TB and its specific phenotypes [respiratory tuberculosis (RTB) and extrapulmonary tuberculosis (EPTB)] were retrieved from the UK Biobank and the FinnGen consortium. And 195 bacterial taxa from phylum to genus were analyzed. Inverse variance weighted (IVW), MR-Egger regression, maximum likelihood (ML), weighted median, and weighted mode methods were applied to the MR analysis. The robustness of causal estimation was tested using the heterogeneity test, horizontal pleiotropy test, and leave-one-out method. RESULTS: In the UK Biobank database, we found that 11 bacterial taxa had potential causal effects on TB. Three bacterial taxa genus.Akkermansia, family.Verrucomicrobiacea, order.Verrucomicrobiales were validated in the FinnGen database. Based on the results in the FinnGen database, the present study found significant differences in the characteristics of gut microbial distribution between RTB and EPTB. Four bacterial taxa genus.LachnospiraceaeUCG010, genus.Parabacteroides, genus.RuminococcaceaeUCG011, and order.Bacillales were common traits in relation to both RTB and TB, among which order.Bacillales showed a protective effect. Additionally, family.Bacteroidacea and genus.Bacteroides were identified as common traits in relation to both EPTB and TB, positively associating with a higher risk of EPTB. In reverse MR analysis, no causal association was identified. No significant heterogeneity of instrumental variables (IVs) or horizontal pleiotropy was found. CONCLUSION: Our study supports a one-way causal relationship between gut microbiota and TB, with gut microbiota having a causal effect on TB. The identification of characteristic gut microbiota provides scientific insights for the potential application of the gut microbiota as a preventive, diagnostic, and therapeutic tool for TB.

Causal relationship between psoriasis vulgaris and dementia: Insights from Mendelian randomization analysis.

Many clinical studies have demonstrated a correlation between psoriasis vulgaris and dementia, yet this correlation remains controversial. Our study employed the Mendelian randomization (MR) method to investigate the causal relationship between psoriasis vulgaris and dementia. Data were obtained from the summary statistics of the genome-wide association studies from IEU-OpenGWAS project database. In univariate Mendelian randomization (UVMR) analysis, psoriasis vulgaris was used as exposure. Alzheimer disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD) and frontotemporal dementia (FTD) served as the outcomes. In multivariate Mendelian randomization (MVMR) analysis, VaD served as the outcome. The first MVMR analysis used psoriasis vulgaris, mean platelet volume (MPV), platelet distribution width (PDW) and platelet count (PLT) as exposures. The second MVMR analysis used psoriasis vulgaris, vitamin D level and 25 hydroxyvitamin D level as exposures. The main analysis employed the inverse variance weighted method, and the outcomes were evaluated by odds ratio (OR) and 95% confidence interval (95% CI). In UVMR analysis, the results depicted that psoriasis vulgaris was associated with VaD (OR: 0.903, 95% CI: 0.818-0.996, p = 0.041). The results revealed insignificant associations between psoriasis vulgaris and other dementia types. After adjusting the effects of MPV, PDW and PLT in MVMR analysis, the association between psoriasis vulgaris and VaD was no longer significant (p = 0.164). Similarly, after adjusting the effects of vitamin D level and 25 hydroxyvitamin D level in MVMR analysis, the association between psoriasis vulgaris and VaD was also no longer significant (p = 0.533). Our study suggests that psoriasis vulgaris may potentially decrease VaD incidence. However, the causal association between psoriasis vulgaris and VaD may be impeded by platelet-related indices, vitamin D level and 25 hydroxyvitamin D level.

Investigating causal associations between pneumonia and lung cancer using a bidirectional mendelian randomization framework.

BACKGROUND: Pneumonia and lung cancer are both major respiratory diseases, and observational studies have explored the association between their susceptibility. However, due to the presence of potential confounders and reverse causality, the comprehensive causal relationships between pneumonia and lung cancer require further exploration. METHODS: Genome-wide association study (GWAS) summary-level data were obtained from the hitherto latest FinnGen database, COVID-19 Host Genetics Initiative resource, and International Lung Cancer Consortium. We implemented a bidirectional Mendelian randomization (MR) framework to evaluate the causal relationships between several specific types of pneumonia and lung cancer. The causal estimates were mainly calculated by inverse-variance weighted (IVW) approach. Additionally, sensitivity analyses were also conducted to validate the robustness of the causalty. RESULTS: In the MR analyses, overall pneumonia demonstrated a suggestive but modest association with overall lung cancer risk (Odds ratio [OR]: 1.21, 95% confidence interval [CI]: 1.01 - 1.44, P = 0.037). The correlations between specific pneumonia types and overall lung cancer were not as significant, including bacterial pneumonia (OR: 1.07, 95% CI: 0.91 - 1.26, P = 0.386), viral pneumonia (OR: 1.00, 95% CI: 0.95 - 1.06, P = 0.891), asthma-related pneumonia (OR: 1.18, 95% CI: 0.92 - 1.52, P = 0.181), and COVID-19 (OR: 1.01, 95% CI: 0.78 - 1.30, P = 0.952). Reversely, with lung cancer as the exposure, we observed that overall lung cancer had statistically crucial associations with bacterial pneumonia (OR: 1.08, 95% CI: 1.03 - 1.13, P = 0.001) and viral pneumonia (OR: 1.09, 95% CI: 1.01 - 1.19, P = 0.037). Sensitivity analysis also confirmed the robustness of these findings. CONCLUSION: This study has presented a systematic investigation into the causal relationships between pneumonia and lung cancer subtypes. Further prospective study is warranted to verify these findings.

New evidence: Metformin unsuitable as routine adjuvant for breast cancer: a drug-target mendelian randomization analysis.

PURPOSE: The potential efficacy of metformin in breast cancer (BC) has been hotly discussed but never conclusive. This genetics-based study aimed to evaluate the relationships between metformin targets and BC risk. METHODS: Metformin targets from DrugBank and genome-wide association study (GWAS) data from IEU OpenGWAS and FinnGen were used to investigate the breast cancer (BC)-metformin causal link with various Mendelian Randomization (MR) methods (e.g., inverse-variance-weighting). The genetic association between type 2 diabetes (T2D) and the drug target of metformin was also analyzed as a positive control. Sensitivity and pleiotropic tests ensured reliability. RESULTS: The primary targets of metformin are PRKAB1, ETFDH and GPD1L. We found a causal association between PRKAB1 and T2D (odds ratio [OR] 0.959, P = 0.002), but no causal relationship was observed between metformin targets and overall BC risk (PRKAB1: OR 0.990, P = 0.530; ETFDH: OR 0.986, P = 0.592; GPD1L: OR 1.002, P = 0.806). A noteworthy causal relationship was observed between ETFDH and estrogen receptor (ER)-positive BC (OR 0.867, P = 0.018), and between GPD1L and human epidermal growth factor receptor 2 (HER2)-negative BC (OR 0.966, P = 0.040). Other group analyses did not yield positive results. CONCLUSION: The star target of metformin, PRKAB1, does not exhibit a substantial causal association with the risk of BC. Conversely, metformin, acting as an inhibitor of ETFDH and GPD1L, may potentially elevate the likelihood of developing ER-positive BC and HER2-negative BC. Consequently, it is not advisable to employ metformin as a standard supplementary therapy for BC patients without T2D.

Association between gynecologic cancer and Alzheimer's disease: a bidirectional mendelian randomization study.

BACKGROUND: Alzheimer's disease (AD) manifests with a higher rate of occurrence in women. Previous epidemiological studies have suggested a potential association between AD and gynecological cancers, but the causal relationship between them remains unclear. This study aims to explore the causal link between 12 types of gynecological cancers and AD using a bidirectional Mendelian randomization (MR) approach. METHODS: We obtained genetic correlation tools for AD using data from the most extensive genome-wide association study. Genetic correlation data for 12 types of gynecological cancers were also sourced from the Finnish Biobank. These cancers include breast cancer (BC), cervical adenocarcinoma (CA), cervical squamous cell carcinoma (CSCC), cervical cancer (CC), endometrial cancer (EC), ovarian endometrioid carcinoma (OEC), ovarian cancer (OC), ovarian serous carcinoma (OSC), breast carcinoma in situ (BCIS), cervical carcinoma in situ (CCIS), endometrial carcinoma in situ (ECIS), and vulvar carcinoma in situ (VCIS). We used the inverse-variance weighted (IVW) model for causal analysis and conducted horizontal pleiotropy tests, heterogeneity tests, MR-PRESSO tests, and leave-one-out analyses to ensure the robustness of our results. We also applied replication analysis and meta-analysis to further validate our experimental results. RESULTS: The study found that EC (P_IVW =0.037, OR [95% CI] = 1.032 [1.002, 1.064]) and CCIS (P_IVW = 0.046, OR [95% CI] = 1.032 [1.011, 1.064]) increase the risk of AD, whereas OC was negatively correlated with AD (P_IVW = 0.016, OR [95% CI] = 0.974[0.954, 0.995]). In reverse MR analysis, AD increased the risk of CC (P_IVW = 0.039, OR [95% CI] = 1.395 [1.017, 1.914]) and VCIS (P_IVW = 0.041, OR [95% CI] = 1.761 [1.027, 2.021]), but was negatively correlated with OEC (P_IVW = 0.034, OR [95% CI] = 0.634 [0.417, 0.966]). Sensitivity analysis results demonstrated robustness. These findings were further substantiated through replication and meta-analyses. CONCLUSIONS: Our MR study supports a causal relationship between AD and gynecological cancers. This encourages further research into the incidence of gynecological cancers in female Alzheimer's patients and the active prevention of AD.

Genetic contribution of reproductive traits to risk of uterine leiomyomata: a large-scale, genome-wide, cross-trait analysis.

BACKGROUND: Although phenotypic associations between female reproductive characteristics and uterine leiomyomata have long been observed in epidemiologic investigations, the shared genetic architecture underlying these complex phenotypes remains unclear. OBJECTIVE: We aimed to investigate the shared genetic basis, pleiotropic effects, and potential causal relationships underlying reproductive traits (age at menarche, age at natural menopause, and age at first birth) and uterine leiomyomata. STUDY DESIGN: With the use of large-scale, genome-wide association studies conducted among women of European ancestry for age at menarche (n=329,345), age at natural menopause (n=201,323), age at first birth (n=418,758), and uterine leiomyomata (ncases/ncontrols=35,474/267,505), we performed a comprehensive, genome-wide, cross-trait analysis to examine systematically the common genetic influences between reproductive traits and uterine leiomyomata. RESULTS: Significant global genetic correlations were identified between uterine leiomyomata and age at menarche (rg, -0.17; P=3.65×10-10), age at natural menopause (rg, 0.23; P=3.26×10-07), and age at first birth (rg, -0.16; P=1.96×10-06). Thirteen genomic regions were further revealed as contributing significant local correlations (P<.05/2353) to age at natural menopause and uterine leiomyomata. A cross-trait meta-analysis identified 23 shared loci, 3 of which were novel. A transcriptome-wide association study found 15 shared genes that target tissues of the digestive, exo- or endocrine, nervous, and cardiovascular systems. Mendelian randomization suggested causal relationships between a genetically predicted older age at menarche (odds ratio, 0.88; 95% confidence interval, 0.85-0.92; P=1.50×10-10) or older age at first birth (odds ratio, 0.95; 95% confidence interval, 0.90-0.99; P=.02) and a reduced risk for uterine leiomyomata and between a genetically predicted older age at natural menopause and an increased risk for uterine leiomyomata (odds ratio, 1.08; 95% confidence interval, 1.06-1.09; P=2.30×10-27). No causal association in the reverse direction was found. CONCLUSION: Our work highlights that there are substantial shared genetic influences and putative causal links that underlie reproductive traits and uterine leiomyomata. The findings suggest that early identification of female reproductive risk factors may facilitate the initiation of strategies to modify potential uterine leiomyomata risk.

Causal relationship of inflammatory cytokines and serum metabolites in cerebral small vessel disease: a two-step Mendelian randomization study.

BACKGROUND AND PURPOSE: The aim was to investigate the causal relationships of inflammatory cytokines and serum metabolites in cerebral small vessel disease (CSVD). METHODS: Bidirectional Mendelian randomization was first conducted to screen inflammatory cytokines and serum metabolites that were associated with imaging features of CSVD, including white matter hyperintensities, recent small subcortical infarcts, cortical cerebral microinfarcts, cerebral microbleeds, lacunes and enlarged perivascular spaces. Sensitivity analyses were performed to evaluate the robustness and pleiotropy of these results. Subsequently, inflammatory cytokines and serum metabolites that were associated with CSVD were subjected to functional enrichment. Finally, mediation analysis was employed to investigate whether inflammatory cytokines or serum metabolites acted as an intermediary for the other in their causal relationship with CSVD. RESULTS: Of the inflammatory cytokines, five were risk factors (e.g., tumour-necrosis-factor-related apoptosis-inducing ligand) and five (e.g., fibroblast growth factor 19) were protective factors for CSVD. Eleven serum metabolites that increased CSVD risk and 13 metabolites that decreased CSVD risk were also identified. The majority of these markers of CSVD susceptibility were lipid metabolites. Natural killer cell receptor sub-type 2B4 was determined to act as a mediating factor of an unidentified metabolite for the enlargement of perivascular spaces. CONCLUSION: Several inflammatory cytokines and serum metabolites had causal relationships with imaging features of CSVD. A natural killer cell receptor mediated in part the promotional effect of a metabolite on perivascular space enlargement.

Association between autoimmune liver diseases and chronic hepatitis B: A multivariable Mendelian randomization study in European population.

BACKGROUND: Observational studies have indicated a link between autoimmune liver diseases (AILD) and chronic hepatitis B (CHB) through observational studies. The association between AILD and CHB remains indeterminate. METHODS: A two-sample Mendelian randomization (MR) analysis was conducted to scrutinize the causal nexus between AILD and CHB utilizing summary statistics derived from extensive genome-wide association studies (GWASs) in European populations. The primary statistical methodology employed was the inverse variance-weighted (IVW) method to deduce the causal connection of AILD on CHB. This study incorporated primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) as subtypes of AILD. Additionally, we conducted a multivariable MR (MVMR) analysis to account for the potential confounding effects of smoking, alcohol consumption, body mass index (BMI), and some autoimmune diseases. RESULTS: Our MR investigation encompassed a cohort of 725,816 individuals. The MR analysis revealed that genetically predicted PSC significantly correlated with a reduced risk of CHB (IVW OR = 0.857; 95%CI: 0.770-0.953, P = 0.005). Conversely, the reverse MR analysis suggested that genetic susceptibility to PSC might not modify the risk of CHB (IVW OR = 1.004; 95% CI: 0.958-1.053, P = 0.866). Genetically proxied PBC and AIH exhibited no discernible causal association with CHB in the MR analysis using the IVW method (P = 0.583; P = 0.425). The MVMR analysis still indicated a decreased risk of CHB associated with PSC (OR = 0.853, P = 0.003). CONCLUSION: Our study elucidates a causal relationship between PSC and a diminished risk of CHB.

Genetically predicted gut microbiota mediate the association between plasma lipidomics and primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a complex disease with pathogenic mechanisms that remain to be elucidated. Previous observational studies with small sample sizes have reported associations between PSC, dyslipidemia, and gut microbiota dysbiosis. However, the causality of these associations is uncertain, and there has been no systematic analysis to date. METHODS: The datasets comprise data on PSC, 179 lipid species, and 412 gut microbiota species. PSC data (n = 14,890) were sourced from the International PSC Study Group, while the dataset pertaining to plasma lipidomics originated from a study involving 7174 Finnish individuals. Data on gut microbiota species were derived from the Dutch Microbiome Project study, which conducted a genome-wide association study involving 7738 participants. Furthermore, we employed a two-step Mendelian randomization (MR) analysis to quantify the proportion of the effect of gut microbiota-mediated lipidomics on PSC. RESULTS: Following a rigorous screening process, our MR analysis revealed a causal relationship between higher levels of gene-predicted Phosphatidylcholine (O-16:1_18:1) (PC O-16:1_18:1) and an increased risk of developing PSC (inverse variance-weighted method, odds ratio (OR) 1.30, 95% confidence interval (CI) 1.03-1.63). There is insufficient evidence to suggest that gene-predicted PSC impacts the levels of PC O-16:1_18:1 (OR 1.01, 95% CI 0.98-1.05). When incorporating gut microbiota data into the analysis, we found that Eubacterium rectale-mediated genetic prediction explains 17.59% of the variance in PC O-16:1_18:1 levels. CONCLUSION: Our study revealed a causal association between PC O-16:1_18:1 levels and PSC, with a minor portion of the effect mediated by Eubacterium rectale. This study aims to further explore the pathogenesis of PSC and identify promising therapeutic targets. For patients with PSC who lack effective treatment options, the results are encouraging.

The causal relationship between gut microbiota and constipation: a two-sample Mendelian randomization study.

BACKGROUND: Constipation is one of the most common gastrointestinal disorders afflicting the population, with recent observational studies implicating dysfunction of the gut microbiota in constipation. Despite observational studies indicating a relationship, a clear causality remains unclear. This study aims to use two-sample Mendelian randomization (MR) to establish a clearer causal relationship between the two. METHODS: A two-sample Mendelian randomization (MR) study was performed using the gut microbiota summary Genome-Wide Association Studies (GWAS) statistics from MiBioGen consortium (n = 13,266) and constipation GWAS summary statistics from the IEU OpenGWAS database. The causality between gut microbiota and constipation is primarily analyzed using the inverse-variance weighted (IVW) method and reinforced by an additional four methods, including MR-Egger, Weighted Median, Simple Mode, and Weighted Mode. Finally, funnel plot, heterogeneity test, horizontal pleiotropy test, and leave-one-out test were used to evaluate the reliability of MR results. RESULTS: IVW estimates suggested that the bacterial species Anaerotruncus, Butyricimonas, and Hungatella were causally associated with constipation. The odds ratio (OR) values of Anaerotruncus, Butyricimonas, and Hungatella were 1.08 (95% CI = 1.02-1.13; P = 0.007), 1.07 (95% CI = 1.01-1.13; P = 0.015), 1.03 (95% CI = 1.00-1.06; P = 0.037) respectively. Meanwhile, Ruminiclostridium 9 and Intestinibacter have been shown to be associated with a reduced risk of constipation. The OR of Ruminiclostridium 9 = 0.75(95% CI = 0.73-0.78, P < 0.001 and Intestinibacter of OR = 0.89 (95% CI = 0.86-0.93, P < 0.001). Furthermore, validation by funnel plot, heterogeneity test, and horizontal pleiotropy test showed that MR results were reliable. CONCLUSION: This is the first Mendelian randomization study to explore the causalities between specific gut microbiota taxa and constipation, and as such may be useful in providing insights into the unclear pathology of constipation which can in turn aid in the search for prevention and treatment.

Elucidating the causal landscape: Mendelian randomization analysis of lifestyle and physiological factors in stress urinary incontinence.

PURPOSE: To explore the potential causal links between obesity, type 2 diabetes (T2D), and lifestyle choices (such as smoking, alcohol and coffee consumption, and vigorous physical activity) on stress urinary incontinence (SUI), this study employs a Mendelian Randomization approach. This research aims to clarify these associations, which have been suggested but not conclusively established in prior observational studies. METHODS: Genetic instruments associated with the exposures at the genome-wide significance (p < 5 × 10-8) were selected from corresponding genome-wide association studies. Summary-level data for SUI, was obtained from the UK Biobank. A two-sample MR analysis was employed to estimate causal effects, utilizing the inverse-variance weighted (IVW) method as the primary analytical approach. Complementary sensitivity analyses including MR-PRESSO, MR-Egger, and weighted median methods were performed. The horizontal pleiotropy was detected by using MR-Egger intercept and MR-PRESSO methods, and the heterogeneity was assessed using Cochran's Q statistics. RESULTS: Our findings demonstrate a significant causal relationship between higher body mass index (BMI) and the risk of SUI, with increased abdominal adiposity (WHRadjBMI) similarly linked to SUI. Smoking initiation is also causally associated with an elevated risk. However, our analysis did not find definitive causal connections for other factors, including T2D, alcohol consumption, coffee intake, and vigorous physical activity. CONCLUSIONS: These findings provide valuable insights for clinical strategies targeting SUI, suggesting a need for heightened awareness and potential intervention in individuals with higher BMI, WHR, and smoking habits. Further research is warranted to explore the complex interplay between genetic predisposition and lifestyle choices in the pathogenesis of SUI.

Role of blood metabolites in mediating the effect of gut microbiome on the mutated-RAS/BRAF metastatic colorectal cancer-specific survival.

BACKGROUND: Recent studies have linked alterations in the gut microbiome and metabolic disruptions to the invasive behavior and metastasis of colorectal cancer (CRC), thus affecting patient prognosis. However, the specific relationship among gut microbiome, metabolite profiles, and mutated-RAS/BRAF metastatic colorectal cancer (M-mCRC) remains unclear. Furthermore, the potential mechanisms and prognostic implications of metabolic changes induced by gut microbiome alterations in patients with M-mCRC still need to be better understood. METHODS: We conducted Mendelian randomization (MR) to evaluate the causal relationship of genetically predicted 196 gut microbiome features and 1400 plasma metabolites/metabolite ratios on M-mCRC-specific survival. Additionally, we identified significant gut microbiome-metabolites/metabolite ratio associations based on M-mCRC. Metabolite information was annotated, and functional annotation and pathway enrichment analyses were performed on shared proteins corresponding to significant metabolite ratios, aiming to reveal potential mechanisms by which gut microbiome influences M-mCRC prognosis via modulation of human metabolism. RESULTS: We identified 11 gut microbiome features and 49 known metabolites/metabolite ratios correlated with M-mCRC-specific survival. Furthermore, we identified 17 gut microbiome-metabolite/metabolite ratio associations specific to M-mCRC, involving eight lipid metabolites and three bilirubin degradation products. The shared proteins corresponding to significant metabolite ratios were predominantly localized within the integral component of the membrane and exhibited enzymatic activities such as glucuronosyltransferase and UDP-glucuronosyltransferase, crucial in processes such as glucuronidation, bile secretion, and lipid metabolism. Moreover, these proteins were significantly enriched in pathways related to ascorbate and aldarate metabolism, pentose and glucuronate interconversions, steroid hormone biosynthesis, and bile secretion. CONCLUSION: Our study offers novel insights into the potential mechanisms underlying the impact of the gut microbiome on the prognosis of M-mCRC. These findings serve as a meaningful reference for exploring potential therapeutic targets and strategies in the future.

Causal associations between blood lipids and brain structures: a Mendelian randomization study.

The potential causal association between dyslipidemia and brain structures remains unclear. Therefore, this study aimed to investigate whether circulating lipids are causally associated with brain structure alterations using Mendelian randomization analysis. Genome-wide association study summary statistics of blood lipids and brain structures were obtained from publicly available databases. Inverse-variance weighted method was used as the primary method to assess causality. In addition, four additional Mendelian randomization methods (MR-Egger, weighted median, simple mode, and weighted mode) were applied to supplement inverse-variance weighted. Furthermore, Cochrane's Q test, MR-Egger intercept test, MR-PRESSO global test, and leave-one-out analysis were performed for sensitivity analyses. After Bonferroni corrections, two causal associations were finally identified: elevated non-high-density lipoprotein cholesterol level leads to higher average cortical thickness (ß = 0.0066 mm, 95% confidence interval: 0.0045-0.0087 mm, P = 0.001); and elevated high-density lipoprotein cholesterol level leads to higher inferior temporal surface area (ß = 18.6077 mm2, 95% confidence interval: 11.9835-25.2320 mm2, P = 0.005). Four additional Mendelian randomization methods indicated parallel results. Sensitivity tests demonstrated the stability. Overall, the present study showed causal relationships between several lipid profiles and specific brain structures, providing new insights into the link between dyslipidemia and neurological disorders.

Long-term exposure to ambient ozone and adult-onset asthma: A prospective cohort study.

BACKGROUND: The association between long-term exposure to ozone (O3) and adult-onset asthma (AOA) remains inconclusive, and analysis of causality is lacking. OBJECTIVES: To examine the causal association between long-term O3 exposure and AOA. METHODS: A prospective cohort study of 362,098 participants was conducted using the UK Biobank study. Incident cases of AOA were identified using health administrative data of the National Health Services. O3 exposure at participants' residential addresses was estimated by a spatio-temporal model. Instrumental variable (IV) modelling was used to analyze the causal association between O3 exposure and AOA, by incorporating wind speed and planetary boundary layer height as IVs into time-dependent Cox model. Negative control outcome (accidental injury) was also used to additionally evaluate unmeasured confounding. RESULTS: During a mean follow-up of 11.38 years, a total of 10,973 incident AOA cases were identified. A U-shaped concentration-response relationship was observed between O3 exposure and AOA in the traditional Cox models with HR of 0.916 (95% CI: 0.888, 0.945) for O3 at low levels (<38.17 ppb), and 1.204 (95% CI: 1.168, 1.242) for O3 at high levels (≥38.17 ppb). However, in the IV analysis we only found a statistically significant association between high-level O3 exposure and AOA risk, but not for low-level O3 exposure. No significant associations between O3 exposure and accidental injury were observed. CONCLUSION: Our findings suggest a potential causal relationship between long-term exposure to high-level ambient O3 and increased risks of AOA.