Mendelian Randomization Egger Regression Research Articles

Revealing the link between gut microbiota and brain tumor risk: a new perspective from Mendelian randomization

BackgroundRecent studies have shown that gut microbiota may be related to the occurrence of brain tumors, but direct evidence is lacking. This study used the Mendelian randomization study (MR) method to explore the potential causal link between gut microbiota and brain tumors.MethodWe analyzed the genome-wide association data between 211 gut microbiota taxa and brain tumors, using the largest existing gut microbiota Genome-Wide Association Studies meta-analysis data (n=13266) and combining it with brain tumor data in the IEU OpenGWAS database. We use inverse-variance weighted analysis, supplemented by methods such as Mendelian randomization-Egger regression, weighted median estimator, simple mode, and weighted mode, to assess causality. In addition, we also conducted the Mendelian randomization-Egger intercept test, Cochran’s Q test, and Mendelian randomization Steiger directionality test to ensure the accuracy of the analysis. Quality control includes sensitivity analysis, horizontal gene pleiotropy test, heterogeneity test, and MR Steiger directionality test.ResultOur study found that specific gut microbial taxa, such as order Lactobacillales and family Clostridiaceae1, were positively correlated with the occurrence of brain tumors, while genus Defluviitaleaceae UCG011 and genus Flavonifractor were negatively correlated with the occurrence of brain tumors. The Mendelian randomization-Egger intercept test showed that our analysis was not affected by pleiotropy (P>0.05).ConclusionThis study reveals for the first time the potential causal relationship between gut microbiota and brain tumors, providing a new perspective for the prevention and treatment of early brain tumors. These findings may help develop new clinical intervention strategies and point the way for future research.

Bidirectional two-sample Mendelian randomization analysis identifies causal associations between migraine and five psychiatric disorders

BackgroundThe question of whether a correlation exists between migraine and five psychiatric disorders, including posttraumatic stress disorder (PTSD), major depressive disorder (MDD), anorexia nervosa (AN), bipolar disorder (BIP), and schizophrenia (SCZ), remains a matter of controversy. Hence, this research aims to investigate whether there is a possible association between migraine and five psychiatric disorders.MethodsWe performed a bidirectional 2-sample Mendelian randomization (MR) analysis to assess the causality between migraine and five psychiatric disorders. Genetic associations of PTSD, MDD, AN, BIP, and SCZ were obtained from the Psychiatric Genomics Consortium (PGC) database and genetic associations of migraine with aura and migraine without aura were obtained from the FinnGen dataset. We used the inverse-variance weighted (IVW), weighted median, weighted mode, MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and MR Egger regression methods to evaluate the association of genetically predicted exposure with the risk of outcome.ResultsMR demonstrated that MDD was associated with a high risk of migraine without aura (OR = 1.930578, 95% confidence interview (CI): 1.224510, 3.043550, p < 0.05), but BIP was related to a low risk of migraine without aura (OR = 0.758650, 95%CI: 0.639601, 0.899858, p < 0.05). According to the results of reverse MR, migraine with aura was associated with a high risk of BIP (OR = 1.019100, 95%CI: 1.002538, 1.035935, p < 0.05), and migraine without aura was associated with an increased risk of AN (OR = 1.055634, 95%CI: 1.023859, 1.088394, p < 0.05).ConclusionOur results provide evidence of the potential causal association between migraine and some psychiatric disorders. It may contribute to the prevention of migraine and some psychiatric disorders.

Sjögren's syndrome and Parkinson's disease: a bidirectional Mendelian randomization study.

Previous epidemiological studies have reported an association between Sjögren's syndrome (SS) and Parkinson's disease (PD); however, the causality and direction of this relationship remain unclear. In this study, we aimed to investigate the causal relationship between genetically determined SS and the risk of PD using bidirectional Mendelian randomization (MR). Summary statistics for Sjögren's syndrome used as exposure were obtained from the FinnGen database, comprising 1,290 cases and 213,145 controls. The outcome dataset for PD was derived from the United Kingdom Biobank database, including 6,998 cases and 415,466 controls. Various MR methods, such as inverse variance weighted (IVW), Mendelian randomization Egger regression (MR-Egger), weighted median (WM), simple mode, weighted mode, MR-pleiotropy residual sum and outlier (MR-PRESSO), and robust adjusted profile score (RAPS), were employed to investigate the causal effects of SS on PD. Instrumental variable strength evaluation and sensitivity analyses were conducted to ensure the reliability of the results. In addition, reverse MR analysis was performed to examine the causal effects of PD on SS. The WM, IVW, RAPS and MR-PRESSO methods demonstrated a significant association between genetically predicted SS and reduced risk of PD (odds ratio ORWM = 0.9988, ORIVW = 0.9987, ORRAPS = 0.9987, ORMR-PRESSO = 0.9987, respectively, P < 0.05). None of the MR analyses showed evidence of horizontal pleiotropy (P > 0.05) based on the MR-Egger and MR-PRESSO tests, and there was no statistical heterogeneity in the test results of the MR-Egger and IVW methods. The leave-one-out sensitivity analysis confirmed the robustness of the causal relationship between SS and PD. Furthermore, reverse MR analysis did not support any causal effects of PD on SS. Our MR study supports a potential causal association between SS and a reduced risk of PD. Further extensive clinical investigations and comprehensive fundamental research are warranted to elucidate the underlying mechanisms linking SS and PD.

Relationship between Sjogren's syndrome and gastroesophageal reflux: A bidirectional Mendelian randomization study

The clinical incidence of sjogren's syndrome combined with gastroesophageal reflux disease is high. Existing observational studies have shown inconsistent results in the association between gastroesophageal reflux disease (GERD) and Sjogren's syndrome (SS).We observed that the symptoms of SS patients also improved after receiving GERD-related treatment. Therefore, we aimed to investigate the relationship between GERD and SS through a bidirectional two-sample Mendelian randomization (MR) study. Independent SNPs associated with GERD and SS were selected from a genome-wide association study (GWAS) as instrumental variables to conduct a bidirectional two-sample Mendelian analysis of GERD and SS. Genetic data were obtained from two databases for the following two outcomes: Gastroesophageal reflux (IEU Open GWAS) [sample size = 602,604 (patients = 129,080; nonpatients = 473,524)] and SS (FinnGen) [sample size = 392,423 (patients = 2,495; nonpatients = 389,928)]. Statistical methods for the MR analysis included the inverse-variance weighting method, weighted median, simple mode and weighted mode, as well as heterogeneity and sensitivity analyses using the Cochran Q statistic, MR‒Egger regression, outlier detection methods (MR-PRESSO). In addition, Steiger Test was conducted to test the direction of causality. MR analysis showed a positive correlation between GERD and SS risk [odds ratio (OR) = 1.3279 (95% confidence interval 1.0312–1.7099, P = 0.0280)]. However, in contrast, no significant causal effect of SS on GERD was observed [OR = 1.0024 (95% CI 0.9651–1.0412; P = 0.8995)]. This bidirectional two-sample Mendelian randomization study confirmed a causal relationship between SS and GERD, and suggested that GERD is a risk factor for SS, while SS does not affect GERD.

Causal effects of hypertensive disorders of pregnancy on structural changes in specific brain regions: a Mendelian randomization study.

This study utilized Mendelian randomization to explore the impact of hypertensive disorders of pregnancy and their subtypes on brain structures, using genome-wide association study data from the FinnGen consortium for hypertensive disorders of pregnancy exposure and brain structure data from the ENIGMA consortium as outcomes. The inverse-variance weighted method, along with Cochran's Q test, Mendelian randomization-Egger regression, Mendelian randomization-PRESSO global test, and the leave-one-out approach, were applied to infer causality and assess heterogeneity and pleiotropy. Findings indicate hypertensive disorders of pregnancy are associated with structural brain alterations, including reduced cortical thickness in areas like the insula, isthmus cingulate gyrus, superior temporal gyrus, temporal pole, and transverse temporal gyrus, and an increased surface area in the superior frontal gyrus. Specific associations were found for hypertensive disorders of pregnancy subtypes: chronic hypertension with superimposed preeclampsia increased cortical thickness in the supramarginal gyrus; preeclampsia/eclampsia led to thinner cortex in the lingual gyrus and larger hippocampal volume and superior parietal lobule surface area. Chronic hypertension was associated with reduced cortical thickness in the caudal and rostral anterior cingulate and increased surface area of the cuneus and thickness of the pars orbitalis cortex. Gestational hypertension showed no significant brain region changes. These insights clarify hypertensive disorders of pregnancies' neurological and cognitive effects by identifying affected brain regions.

Peripheral blood leukocyte Telomere length and endometriosis: A Mendelian randomization study

BackgroundThe link between peripheral blood leukocyte telomere length (LTL) and endometriosis has remained uncertain. In order to investigate this association, a two-sample Mendelian randomization(MR) analysis was performed. MethodsWe extracted Single-nucleotide polymorphisms (SNPs) associated with LTL from a published genome-wide association study (GWAS) comprising 472,174 individuals. Data on endometriosis, including its seven subtypes, were sourced from the iue open gwas project. Four methods were employed for MR: Inverse-variance weighted analysis (IVW), Mendelian randomization-Egger regression (MR Egger), weighted-median analysis, and Weighted Mode. ResultsGenetically determined LTL was identified as a factor that can promote the occurrence of endometriosis. With every 1-SD increase in LTL, the risk of endometriosis increased by 26 % (OR = 1.260, 95 % CI = 1.073 to 1.479; P = 0.005). Genetically determined LTL also contributed to endometriosis subtypes: intestine (OR = 3.584, 95 % CI = 1.597 to 8.041; P = 0.002), ovary (OR = 1.308, 95 % CI = 1.033 to 1.655; P = 0.026), rectovaginal septum and vagina (OR = 1.360, 95 % CI = 1.000 to 1.851; P = 0.049). There was no observed causal relationship between LTL and the other four subtypes. ConclusionThis study, utilizing genetic data, offers evidence that longer LTL may cause increased risks of endometriosis, specifically endometriosis of the intestine, ovary, rectovaginal septum and vagina. These findings not only suggest that LTL may serve as a predictive factor for assessing the prevalence of three endometriosis subtypes but also provide new insights into the study of endometriosis pathogenesis.

Exploring causal effects of gut microbiota and metabolites on body fat percentage using two-sample Mendelian randomization.

The relationship between the gut microbiota, metabolites and body fat percentage (BFP) remains unexplored. We systematically assessed the causal relationships between gut microbiota, metabolites and BFP using Mendelian randomization analysis. Single nucleotide polymorphisms associated with gut microbiota, blood metabolites and BFP were screened via a genome-wide association study enrolling individuals of European descent. Summary data from genome-wide association studies were extracted from the MiBioGen consortium and the UK Biobank. The inverse variance-weighted model was the primary method used to estimate these causal relationships. Sensitivity analyses were performed using pleiotropy, Mendelian randomization-Egger regression, heterogeneity tests and leave-one-out tests. In the aspect of phyla, classes, orders, families and genera, we observed that o_Bifidobacteriales [β = -0.05; 95% confidence interval (CI): -0.07 to -0.03; false discovery rate (FDR) = 2.76 × 10-3], f_Bifidobacteriaceae (β = -0.05; 95% CI: -0.07 to -0.07; FDR = 2.76 × 10-3), p_Actinobacteria (β = -0.06; 95% CI: -0.09 to -0.03; FDR = 6.36 × 10-3), c_Actinobacteria (β = -0.05; 95% CI: -0.08 to -0.02; FDR = 1.06 × 10-2), g_Bifidobacterium (β = -0.05; 95% CI: -0.07 to -0.02; FDR = 1.85 × 10-2), g_Ruminiclostridium9 (β = -0.03; 95% CI: -0.06 to -0.01; FDR = 4.81 × 10-2) were negatively associated with BFP. G_Olsenella (β = 0.02; 95% CI: 0.01-0.03; FDR = 2.16 × 10-2) was positively associated with BFP. Among the gut microbiotas, f_Bifidobacteriales, o_Bifidobacteriales, c_Actinobacteria and p_Actinobacteria were shown to be significantly associated with BFP in the validated dataset. In the aspect of metabolites, we only observed that valine (β = 0.77; 95% CI: 0.5-1.04; FDR = 8.65 × 10-6) was associated with BFP. Multiple gut microbiota and metabolites were strongly associated with an increased BFP. Further studies are required to elucidate the mechanisms underlying this putative causality. In addition, BFP, a key indicator of obesity, suggests that obesity-related interventions can be developed from gut microbiota and metabolite perspectives.

Stroke and frailty index: a two-sample Mendelian randomisation study.

Previous observational studies have found an increased risk of frailty in patients with stroke. However, evidence of a causal relationship between stroke and frailty is scarce. The aim of this study was to investigate the potential causal relationship between stroke and frailty index (FI). Pooled data on stroke and debility were obtained from genome-wide association studies (GWAS).The MEGASTROKE Consortium provided data on stroke (N = 40,585), ischemic stroke (IS,N = 34,217), large-vessel atherosclerotic stroke (LAS,N = 4373), and cardioembolic stroke (CES,N = 7 193).Summary statistics for the FI were obtained from the most recent GWAS meta-analysis of UK BioBank participants and Swedish TwinGene participants of European ancestry (N = 175,226).Two-sample Mendelian randomization (MR) analyses were performed by inverse variance weighting (IVW), weighted median, MR-Egger regression, Simple mode, and Weighted mode, and heterogeneity and horizontal multiplicity of results were assessed using Cochran's Q test and MR-Egger regression intercept term test. The results of the current MR study showed a significant correlation between stroke gene prediction and FI (odds ratio 1.104, 95% confidence interval 1.064 - 1.144, P < 0.001). In terms of stroke subtypes, IS (odds ratio 1.081, 95% confidence interval 1.044 - 1.120, P < 0.001) and LAS (odds ratio 1.037, 95% confidence interval 1.012 - 1.062, P = 0.005). There was no causal relationship between gene-predicted CES and FI. Horizontal multidimensionality was not found in the intercept test for MR Egger regression (P > 0.05), nor in the heterogeneity test (P > 0.05). This study provides evidence for a causal relationship between stroke and FI and offers new insights into the genetic study of FI.

Juvenile idiopathic arthritis and primary ovarian failure: a two-sample Mendelian randomization analysis in a mixed-gender cohort.

The causal relationship between juvenile idiopathic arthritis (JIA) and primary ovarian failure (POF) remains uncertain. To elucidate this relationship, we employed a two-sample Mendelian randomization analysis. The single nucleotide polymorphisms (SNPs) associated with JIA were obtained from a previously published genome-wide association study (GWAS), while the pooled data for POF originated from the FinnGen consortium. The study populations consisted exclusively of individuals of European descent. In our Mendelian randomization analysis, we performed inverse-variance weighted analysis, weighted-median analysis, weighted-mode analysis and Mendelian randomization-Egger regression analysis, supplemented by sensitivity analyses to validate the accuracy and robustness of the findings. The IVW (OR = 1.23, 95% CI 1.06-1.43; P = 0.007) and weighted median (OR = 1.25, 95% CI 1.06-1.47; P = 0.009), along with sensitivity analysis validation, provide compelling evidence of a significant causal association between JIA and POF. The study revealed a significant causal association between genetically predicted JIA and POF, indicating that JIA significantly elevates the risk of developing POF. Therefore, it is recommended to implement screening for premature ovarian failure in women diagnosed with JIA.

Investigation of the causal association between Parkinson's disease and autoimmune disorders: a bidirectional Mendelian randomization study.

To date, an increasing number of epidemiological evidence has pointed to potential relationships between Parkinson's disease (PD) and various autoimmune diseases (AIDs), however, no definitive conclusions has been drawn about whether PD is causally related to AIDs risk. By employing summary statistics from the latest and most extensive genome-wide association studies (GWAS), we performed a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the causal associations between PD and a variety of 17 AIDs, encompassing multiple sclerosis, neuromyelitis optica spectrum disorder, myasthenia gravis, asthma, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, celiac disease, primary biliary cirrhosis, primary sclerosing cholangitis, type 1 diabetes, ankylosing spondylitis, rheumatoid arthritis, systemic lupus erythematosus, psoriasis and vitiligo. Inverse-variance weighted (IVW) was adopted as the main statistical approach to obtain the causal estimates of PD on different AIDs, supplemented by a series of complementary analyses (weighted median, MR Egger regression, and MR-PRESSO) for further strengthening the robustness of results. Our MR findings suggested that genetically predicted higher liability to PD was causally associated with a decreased risk of irritable bowel syndrome (OR = 0.98; 95% CI: 0.96-0.99; P = 0.032). On the contrary, IVW analysis showed a potential positive correlation between genetically determined PD and the incidence of type 1 diabetes (OR = 1.10; 95%CI: 1.02-1.19; P = 0.010). Subsequent MR tests ended up in similar results, confirming our findings were reliable. Additionally, in the reverse MR analyses, we did not identify any evidence to support the causal relationship of genetic predisposition to AIDs with PD susceptibility. In general, a bifunctional role that PD exerted on the risk of developing AIDs was detected in our studies, both protecting against irritable bowel syndrome occurrence and raising the incidence of type 1 diabetes. Future studies, including population-based observational studies and molecular experiments in vitro and in vivo, are warranted to validate the results of our MR analyses and refine the underlying pathological mechanisms involved in PD-AIDs associations.

The gut microbiota-constipation connection: Insights from a two sample bidirectional Mendelian randomization study

ObjectiveThe dysbiosis of the gut microbiota has been implicated in various maladies. Research has identified an association between the dysbiosis of the gut microbiota and the risk of constipation, prompting this study to elucidate the potential causal relationship between gut microbiota imbalance with constipation through a two sample bidirectional Mendelian randomization (MR) study, shedding light on the genetic mechanisms underlying the connection between gut microbiota and constipation. MethodsThe forward MR analysis aimed to scrutinize whether alterations in the composition and abundance of gut microbiota impact the risk of constipation, while the reverse MR analysis explored whether the genetic predisposition to constipation influences the abundance of gut microbiota. Genomic correlation data for the gut microbiota were sourced from the comprehensive statistics of the MiBioGen consortium. Genomic correlation data for constipation were obtained from the IEU database, encoded as the dataset ebi-a-GCST90018829. The correlation was assessed using various analytical techniques, including inverse variance weighting (IVW), Mendelian randomization-Egger regression (MR-Egger), and weighted median and mode methodologies. To ensure the robustness of the results, a meticulous sensitivity analysis was conducted, incorporating Cochran's Q test, MR-Egger intercept test, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and a Leave-one-out analysis. ResultsIn the forward Mendelian randomization analyses, a negative correlation was discerned between the abundance of Coprococcus in the gut microbiota and the occurrence of constipation (IVW: OR = 0.74, 95 % CI = 0.64–0.86, p = 0.0001), whereas a positive correlation was observed between the abundance of Bacteroidetes in the gut microbiota and constipation (IVW: OR = 1.22, 95 % CI = 1.00–1.50, p = 0.04). In the forward Mendelian randomization analyses, we were unsuccessful in obtaining valid instrumental variables for scrutiny, and we deemed that constipation exerts no influence on the composition of the gut microbiota. ConclusionGenetic predisposition towards increased abundance of Coprococcus and decreased abundance of Bacteroidetes is correlated with a diminished susceptibility to constipation. This investigation showed that alterations in the gut microbiota precipitated the onset of constipation, rather than constipation inducing modifications in the microbial flora.

No bidirectional relationship between sleep phenotypes and risk of proliferative diabetic retinopathy: a two-sample Mendelian randomization study

This study aimed to investigate the probable existence of a causal relationship between sleep phenotypes and proliferative diabetic retinopathy (PDR). Single nucleotide polymorphisms associated with sleep phenotypes were selected as instrumental variables at the genome-wide significance threshold (P < 5 × 10−8). Inverse‐variance weighted was applied as the primary Mendelian randomization (MR) analysis method, and MR Egger regression, weighted median, simple mode, and weighted mode methods were used as complementary analysis methods to estimate the causal association between sleep phenotypes and PDR. Results indicated that genetically predicted sleep phenotypes had no causal effects on PDR risk after Bonferroni correction (P = 0.05/10) [Chronotype: P = 0.143; Daytime napping: P = 0.691; Daytime sleepiness: P = 0.473; Insomnia: P = 0.181; Long sleep duration: P = 0.671; Morning person:P = 0.113; Short sleep duration: P = 0.517; Obstructive sleep apnea: P = 0.091; Sleep duration: P = 0.216; and snoring: P = 0.014]. Meanwhile, there are no reverse causality for genetically predicted PDR on sleep phenotypes [Chronotype: P = 0.100; Daytime napping: P = 0.146; Daytime sleepiness: P = 0.469; Insomnia: P = 0.571; Long sleep duration: P = 0.779; Morning person: P = 0.040; Short sleep duration: P = 0.875; Obstructive sleep apnea: P = 0.628; Sleep duration: P = 0.896; and snoring: P = 0.047]. This study’s findings did not support the causal effect of between sleep phenotypes and PDR. Whereas, longitudinal studies can further verify results validation.

Genetically supported causality between gut microbiota and frailty: a two-sample Mendelian randomization study.

A mounting body of evidence suggests a strong connection between gut microbiota and the risk of frailty. However, the question of causality remains unanswered. In this study, we employed a Mendelian randomization (MR) approach to assess potential causal relationships between gut microbiota and the risk of frailty. Summary statistics for the gut microbiome were obtained from a genome wide association study (GWAS) meta-analysis of the MiBioGen consortium (N = 18,340). Summary statistics for frailty were obtained from a GWAS meta-analysis, including the UK Biobank and TwinGene (N = 175,226). Our primary analysis utilized the inverse variance weighted (IVW) method. To enhance the robustness of our results, we also applied weighted median methods, MR Egger regression, and MR pleiotropy residual sum and outlier test. Finally, we conducted reverse MR analysis to investigate the potential for reverse causality. IVW method identified 7 bacterial taxa nominally associated with the risk of FI. Class Bacteroidia (p = 0.033) and genus Eubacterium ruminantium group (p = 0.028) were protective against FI. In addition, class Betaproteobacteria (p = 0.042), genus Allisonella (p = 0.012), genus Bifidobacterium (p = 0.013), genus Clostridium innocuum group (p = 0.036) and genus Eubacterium coprostanoligenes group (p = 0.003) were associated with a higher risk of FI. No pleiotropy or heterogeneity were found. The MR analysis indicates a causal relationship between specific gut microbiota and FI, offering new insights into the mechanisms underlying FI mediated by gut microbiota.

Association of major depression, schizophrenia and bipolar disorder with thyroid cancer: a bidirectional two-sample mendelian randomized study

BackgroundMajor depressive disease (MDD), schizophrenia (SCZ), and bipolar disorder (BD) are common psychiatric disorders, and their relationship with thyroid cancer has been of great interest. This study aimed to investigate the potential causal effects of MDD, SCZ, BD, and thyroid cancer.MethodsWe used publicly available summary statistics from large-scale genome-wide association studies to select genetic variant loci associated with MDD, SCZ, BD, and thyroid cancer as instrumental variables (IVs), which were quality controlled and clustered. Additionally, we used three Mendelian randomization (MR) methods, inverse variance weighted (IVW), MR–Egger regression and weighted median estimator (WME) methods, to estimate the bidirectional causal relationship between psychiatric disorders and thyroid cancer. In addition, we performed heterogeneity and multivariate tests to verify the validity of the IVs.ResultsWe used two-sample bidirectional MR analysis to determine whether there was a positive causal association between MDD and thyroid cancer risk. The results of the IVW analysis (OR = 3.956 95% CI = 1.177–13.299; P = 0.026) and the WME method (OR = 5.563 95% CI = 0.998–31.008; P = 0.050) confirmed that MDD may increase the risk of thyroid cancer. Additionally, our study revealed a correlation between genetic susceptibility to SCZ and thyroid cancer (OR = 1.532 95% CI = 1.123–2.088; P = 0.007). The results of the WME method analysis based on the median estimate (OR = 1.599 95% CI = 1.014–2.521; P = 0.043) also suggested that SCZ may increase the risk of thyroid cancer. Furthermore, our study did not find a causal relationship between BD and thyroid cancer incidence. In addition, the results of reverse MR analysis showed no significant causal relationships between thyroid cancer and MDD, SCZ, or BD (P > 0.05), ruling out the possibility of reverse causality.ConclusionsThis MR method analysis provides new evidence that MDD and SCZ may be positively associated with thyroid cancer risk while also revealing a correlation between BD and thyroid cancer. These results may have important implications for public health policy and clinical practice. Future studies will help elucidate the biological mechanisms of these associations and potential confounders.

Genetic prediction of causal association between serum bilirubin and hematologic malignancies: a two-sample Mendelian randomized and bioinformatics study.

An increasing number of cohort studies have shown a correlation between serum bilirubin and tumors, but no definitive causal relationship has been established between serum bilirubin and hematological malignancies.Therefore, the aim of the present study was to assess the causal relationship of serum bilirubin, including total bilirubin (TBIL) and direct bilirubin (DBIL), with hematological malignancies, including leukemia, lymphoma, and myeloma. We used a genome-wide association study (GWAS) collection of TBIL, DBIL, and hematological malignancies data. Using two-sample Mendelian randomization(MR), we assessed the impact of TBIL and DBIL on hematological malignancies. For this study, the inverse variance weighting method (IVW) was the primary method of MR analysis. In the sensitivity analysis, the weighted median method, MR Egger regression, and MR-PRESSO test were used. To understand the mechanisms behind TBIL and DBIL, we used three different approaches based on screening single nucleotide polymorphisms (SNPs) and their associated genes, followed by bioinformatics analysis. The IVW test results showed evidence of effects of TBIL (odds ratio [OR]: 4.47, 95% confidence interval [CI]: 1.58-12.62) and DBIL (OR: 3.31, 95% CI: 1.08-10.18) on the risk of acute myeloid leukemia (AML).The findings from bioinformatics indicated that TBIL could potentially undergo xenobiotic metabolism through cytochrome P450 and contribute to chemical carcinogenesis. In this study, two-sample MR analysis revealed a causal relationship between TBIL, DBIL, and AML.

Genetic association between smoking and DLCO in idiopathic pulmonary fibrosis patients

BackgroundObservational studies have shown that smoking is related to the diffusing capacity of the lungs for carbon monoxide (DLCO) in individuals with idiopathic pulmonary fibrosis (IPF). Nevertheless, further investigation is needed to determine the causal effect between these two variables. Therefore, we conducted a study to investigate the causal relationship between smoking and DLCO in IPF patients using two-sample Mendelian randomization (MR) analysis.MethodsLarge-scale genome-wide association study (GWAS) datasets from individuals of European descent were analysed. These datasets included published lifetime smoking index (LSI) data for 462,690 participants and DLCO data for 975 IPF patients. The inverse-variance weighting (IVW) method was the main method used in our analysis. Sensitivity analyses were performed by MR‒Egger regression, Cochran’s Q test, the leave-one-out test and the MR-PRESSO global test.ResultsA genetically predicted increase in LSI was associated with a decrease in DLCO in IPF patients [ORIVW = 0.54; 95% CI 0.32–0.93; P = 0.02].ConclusionsOur study suggested that smoking is associated with a decrease in DLCO. Patients diagnosed with IPF should adopt an active and healthy lifestyle, especially by quitting smoking, which may be effective at slowing the progression of IPF.

CSF N-acylethanolamine acid amidase level and Parkinson's disease risk: A mendelian randomization study

BackgroundNeuroinflammation is involved in the progression of Parkinson's disease (PD), and N-acylethanolamine acid amidase (NAAA) is involved in regulating inflammation by hydrolyzing bioactive lipid mediators called N-acylethanolamines (NAEs). However, the causal relationship between cerebrospinal fluid (CSF) NAAA protein levels and the risk of PD remains unclear. This study aimed to explore the causal effect of CSF NAAA levels on PD risk through Mendelian randomization (MR) analysis. MethodGenome-wide association study (GWAS) summary statistics for CSF NAAA protein quantitative trait loci (pQTL) and GWAS summary statistics for PD were obtained from publicly available databases. Inverse-variance weighted (IVW) was the main causal estimation method for MR analysis. In addition, the maximum likelihood, MR Egger regression, and weighted median were used to supplement the IVW results. Finally, various sensitivity tests were performed to verify the reliability of the MR findings. ResultsIn the initial MR analysis, the IVW showed that CSF NAAA protein levels significantly increased PD risk (odds ratio [OR] = 1.17, 95% confidence interval [CI]: 1.01–1.35, P = 0.031). This finding was further validated in a replicate MR analysis (OR = 1.20, 95% CI: 1.02–1.41, P = 0.027). Sensitivity analysis showed that MR results were stable and not affected by heterogeneity and horizontal pleiotropy. ConclusionThe present MR study supports a causal relationship between elevated CSF NAAA protein levels and increased PD risk.

Causal association between thyroid dysfunction and sepsis: a two-sample mendelian randomization study.

The causal association between thyroid dysfunction (including hyperthyroidism and hypothyroidism) and sepsis is controversial in previous studies. Therefore, we used Mendelian randomization (MR) to explore the causal association between hyperthyroidism or hypothyroidism and the susceptibility to four distinct subtypes of sepsis (streptococcal sepsis, puerperal sepsis, asthma-associated pneumonia or sepsis, and other sepsis). In our research, we conducted two-sample Mendelian randomization (MR) analyses utilizing publicly available genome-wide association studies (GWAS) data from Sakaue etal. and the Finnish database to investigate the potential causal associations between hyperthyroidism, hypothyroidism, and each of the four distinct subtypes of sepsis, in addition to reverse MR analyses of the positive results to examine the existence of reverse causality. Genetic hypothyroidism was causally related to the development of asthma-associated pneumonia or sepsis (ORIVW: 1.097, 95% CI: 1.024 to 1.174, P = 0.008); hypothyroidism was significantly associated with the development of other sepsis (ORIVW: 1.070, 95% CI: 1.028 to 1.115, P < 0.001). In addition, sensitivity analysis substantiated the robustness of these two MR findings, with no evidence of horizontal pleiotropy observed (P > 0.05). MR Egger regression analysis demonstrated no heterogeneity between instrumental variables (IVs). Inverse MR results confirmed no reverse causality between hypothyroidism and asthma-associated pneumonia or sepsis, or between hypothyroidism and other sepsis. The findings of this study also unveiled that there is no evidence of a causal link between hypothyroidism and the development of streptococcal sepsis or puerperal sepsis. Additionally, the research provided evidence indicating the absence of a causal relationship between hyperthyroidism and streptococcal sepsis, puerperal sepsis, asthma-associated pneumonia or sepsis, and other sepsis. This study identified a causal link between hypothyroidism and the occurrence of asthma-associated pneumonia or sepsis, and other sepsis, but not with the development of streptococcal sepsis and puerperal sepsis. Moreover, our findings did not reveal any causal association between hyperthyroidism and streptococcal sepsis, puerperal sepsis, asthma-associated pneumonia or sepsis, and other sepsis.

Type 2 diabetes and inflammatory bowel disease: a bidirectional two-sample Mendelian randomization study

To investigate the association between T2DM and IBD by bidirectional two-sample Mendelian randomization (MR) to clarify the casual relationship. Independent genetic variants for T2DM and IBD were selected as instruments from published genome-wide association studies (GWAS), mainly in European ancestry. Instrumental variables (IVs) associated with T2DM and IBD were extracted separately from the largest GWAS meta-analysis. MR analyses included inverse variance weighting, weighted median estimator, MR Egger regression, and sensitivity analyses with Steiger filtering and MR PRESSO. In the data samples for Ulcerative colitis (UC) (6968 cases, 20,464 controls) and Crohn's disease (CD) (5956 cases, 14,927 controls), there was a negative causal relationship between T2DM and UC [IVW, OR/95%CI: 0.882/(0.826,0.942), p < 0.001]. However, the causal relationships between T2DM and CD, UC and T2DM, CD and T2DM were not significant, and the p value measured by the IVW method was ≥ 0.05. All SNPs showed no significant horizontal pleiotropy (p > 0.05). The results of the bidirectional MR Study suggest that T2DM has a negative causal effect on UC, which provides implications for clinical treatment decisions in IBD patients with T2DM. The findings do not support a causal relationship between T2DM and CD, UC and T2DM, or CD and T2DM, and the impact of IBD on T2DM needs further investigation.

Serum fetuin-a and risk of thoracic aortic aneurysms: a two-sample mendelian randomization study.

Recent studies have revealed a significant decrease in serum fetuin-A levels in atherosclerotic aneurysms, indicating that fetuin-A may play a protective role in the progression of arterial calcification. However, the specific mechanism behind this phenomenon remains unclear. We aimed to examine the association between fetuin-A levels in thoracic aortic aneurysms (TAAs) and risk of TAAs and to evaluate whether this association was causal. A total of 26 SNPs were selected as instrumental variables for fetuin-A in 9,055 participants of European ancestry from the CHARGE consortium, and their effects on thoracic aortic aneurysm and decreased descending thoracic aortic diameter were separately estimated in 353,049 and 39,688 individuals from FinnGen consortium. We used two-sample Mendelian randomization (MR) analysis to examine the causal association. At the same time, we employed various methods, including random-effects inverse variance weighting, weighted median, MR Egger regression, and MR PRESSO, to ensure the robustness of causal effects. We assessed heterogeneity using Cochran's Q value and examined horizontal pleiotropy through MR Egger regression and retention analysis. Fetuin-A level was associated with a significantly decreasing risk of thoracic aortic aneurysm (odds ratio (OR) 0.64, 95% CI 0.47 - 0.87, P = 0.0044). Genetically predicted fetuin-A was also correlated with the decreased descending thoracic aortic diameter (β = -0.086, standard error (SE) 0.036, P = 0.017). Serum fetuin-A level was negatively associated with risk of TTAs and correlated with the decreased descending thoracic aortic diameter. Mendelian randomization provides support for the potential causal relationship between fetuin-A and thoracic aortic aneurysm.