MR Pleiotropy Residual Sum And Outlier Research Articles

Gut microbiota and intervertebral disc degeneration: a bidirectional two-sample Mendelian randomization study

BackgroundAlthough previous studies have suggested a close association between gut microbiota (GM) and intervertebral disc degeneration (IVDD), the causal relationship between them remains unclear. Hence, we thoroughly investigate their causal relationship by means of a two-sample Mendelian randomization (MR) study, aiming to determine the impact of gut microbiota on the risk of developing intervertebral disc degeneration.MethodsSummary data from genome-wide association studies of GM (the MiBioGen) and IVDD (the FinnGen biobank) have been acquired. The inverse variance weighted (IVW) method was utilized as the primary MR analysis approach. Weighted median, MR-Egger regression, weighted mode, and simple mode were used as supplements. The Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and MR-Egger regression were performed to assess horizontal pleiotropy. Cochran's Q test evaluated heterogeneity. Leave-one-out sensitivity analysis was further conducted to determine the reliability of the causal relationship. A reverse MR analysis was conducted to assess potential reverse causation.ResultsWe identified nine gut microbial taxa that were causally associated with IVDD (P < 0.05). Following the Benjamini–Hochberg corrected test, the association between the phylum Bacteroidetes and a higher risk of IVDD remained significant (IVW FDR-corrected P = 0.0365). The results of the Cochrane Q test did not indicate heterogeneity (P > 0.05). Additionally, both the MR-Egger intercept test and the MR-PRESSO global test revealed that our results were not influenced by horizontal pleiotropy (P > 0.05). Furthermore, the leave-one-out analysis substantiated the reliability of the causal relationship. In the reverse analysis, no evidence was found to suggest that IVDD has an impact on the gut microbiota.ConclusionOur results validate the potential causal impact of particular GM taxa on IVDD, thus providing fresh insights into the gut microbiota-mediated mechanism of IVDD and laying the groundwork for further research into targeted preventive measures.

Causal effects between atrial fibrillation and heart failure: evidence from a bidirectional Mendelian randomization study

BackgroundObservational studies have suggested a close association between atrial fibrillation (AF) and heart failure (HF), yet the causal effect remains uncertain. In this study, we employed a bidirectional Mendelian randomization analysis to investigate the causal effect of one disease on the other.MethodsGenetic instrumental variables were obtained from large-scale summary-level genome-wide association studies of AF (n = 1,030,836) and HF(n = 1,665,481), respectively. Two-sample Mendelian randomization was conducted to establish causal inferences. Inverse-variance weighted (IVW) was the primary estimate, while additional analyses including MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO), MR-Egger, and Weighted median were performed to validate robustness and identify pleiotropy.ResultsAfter accounting for confounding variables, MR analysis suggested a potential causal relationship between AF and HF. An augmented genetic predisposition to atrial fibrillation was associated with an elevated risk of heart failure (odds ratio (OR) = 1.18, 95% confidence interval (CI):1.14–1.22). Likewise, genetically determined heart failure also increased the risk of heart failure (OR = 1.44, 95%CI:1.23–1.68). The robustness of the findings was corroborated through MR sensitivity analyses, and the causal estimates remained consistent when the instrument P-value threshold was tightened.ConclusionsOur bidirectional Mendelian randomization study supports a reciprocal causal relationship between AF and HF. The shared genetic profile of these conditions may provide crucial insights into potential therapeutic targets for the prevention and progression of both disorders. These findings underscore the necessity for further investigation into the underlying molecular mechanisms linking AF and HF, as well as the potential for personalized treatment strategies grounded in genetic profiling.

Noncausal effects between tea intake and migraine risk: a Mendelian randomization study

Observational studies have yielded conflicting results regarding the relationship between tea intake and migraine risk. Residual confounders and potential reverse causality are unavoidable in traditional observational studies. To provide evidence for establishing viable disease screening and prevention strategies, a Mendelian randomization study (MR) was conducted to determine the causal inference between tea intake and migraine. We obtained 28 single-nucleotide polymorphisms (SNPs) for any migraine (AM), 25 SNPs for migraine with aura (MA), and 27 SNPs for migraine without aura (MO) associated with tea intake derived from a large genome-wide association study (GWAS) of the UK Biobank (UKBB) (containing 447,485 samples). The largest migraine GWAS performed by the International Headache Genetics Consortium (IHGC), including 29,209 cases and 172,931 controls, provided data on migraines and their subtypes (MA and MO). We used the method of inverse variance weighting (IVW) with fixed effects as the first-string MR selection. Sensitivity analysis and MR-pleiotropy residual sum and outlier (MR-PRESSO) method further assessed the robustness of the findings. Based on the conclusion of IVW in the fixed effects model, we found that tea intake had no causal relationship with AM risk (odds ratio (OR), 0.94; 95% confidence interval (CI), 0.70–1.25; P = 0.65), MA risk (OR, 0.93; 95% CI, 0.51–1.72; P = 0.83), or MO risk (OR, 0.90; 95% CI, 0.52–1.54; P = 0.69). Sensitivity analyses and MR-PRESSO showed no directional pleiotropy or heterogeneity. Our two-sample MR investigation found no causality between tea intake and migraine risk in European populations, implying that attempts to change tea drinking habits may not lead to a reduced risk of migraine.

Genetically predicted circulating levels of cytokines and the risk of depression: a bidirectional Mendelian-randomization study.

Objective: Inflammatory cytokines disturbance is the main result of immune dysregulation, which is widely described in major depressive disorder (MDD). However, the potential causal relationship between these two factors has not been discovered. Therefore, the purpose of this study was to investigate the causal relationship between inflammatory cytokines and MDD risk by using the two-sample Mendelian randomization (MR) analysis. Method: Two genetic instruments obtained from publicly available gene profile data were utilized for the analysis. We obtained the genetic variation data of 41 inflammatory cytokines from genome-wide association studies (GWAS) meta-analysis of 8293 individuals of Finnish descent. The MDD data, including 135,458 MDD cases and 344,901 controls, were obtained from the Psychiatric Genomics Consortium Database. For the Mendelian randomization (MR) estimation, several methods were employed, namely, MR-Egger regression, inverse-variance weighted (IVW), weighted median, and MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) methods. Result: A causal relationship was identified between the genetically proxied levels of Interleukin (IL) -18, IL-1β, and Regulated upon activation normal T cell expressed and secreted (RANTES) and the risk of MDD (OR = 0.968, 95%CI = 0.938, 0.998, p = 0.036; OR = 0.875, 95%CI = 0.787, 0.971, p = 0.012; OR = 0.947, 95%CI = 0.902, 0.995, p = 0.03; respectively). However, our Mendelian randomization (MR) estimates provided no causality of MDD on inflammatory cytokines. Conclusion: Our study elucidates the connection between inflammatory cytokines and MDD by using MR analysis, thereby enhancing our comprehension of the potential mechanisms. By identifying these associations, our findings hold substantial implications for the development of more effective treatments aimed at improving patient outcomes. However, further investigation is required to fully comprehend the exact biological mechanisms involved.

No evidence of genetic causal association between sex hormone-related traits and systemic lupus erythematosus: A two-sample Mendelian randomization study.

Previous studies have demonstrated an association between sex hormone-related traits and systemic lupus erythematosus (SLE). However, because of the difficulties in determining sequential temporality, the causal association remains elusive. In this study, we used two-sample Mendelian randomization (MR) to explore the genetic causal associations between sex hormone-related traits and SLE. We used a two-sample MR to explore the causal association between sex hormone-related traits and SLE. The summarized data for sex hormone-related traits (including testosterone, estradiol (E2), sex hormone-binding globulin (SHBG), and bioavailable testosterone (BT)) originated from large genome-wide association studies (GWASs) of European descent. Aggregated data for SLE were derived from the FinnGen consortium (835 cases and 300,162 controls). Random-effects inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, weighted mode, and fixed-effects IVW methods were used for the MR analysis. Random-effects IVW was the primary method used to analyze the genetic causal association between sex hormone-related traits and SLE. Heterogeneity of the MR results was detected using the IVW Cochran's Q estimates. The pleiotropy of MR results was detected using MR-Egger regression and the MR pleiotropy residual sum and outlier (MR-PRESSO) test. Finally, leave-one-out analysis was performed to determine whether MR results were affected by a single single-nucleotide polymorphism (SNP). Random-effects IVW as the primary method showed that testosterone (odds ratio (OR), 0.87; 95% confidence interval (CI), 0.41-1.82; P = 0.705), E2 (OR, 0.95; 95% CI, 0.73-1.23; P = 0.693), SHBG (OR, 1.25; 95% CI, 0.74-2.13; P = 0.400), and BT (OR, 0.99; 95% CI, 0.67-1.47; P = 0.959) had no potential causal association with SLE. The MR-Egger, weighted median, simple mode, weighted mode, and fixed-effects IVW methods all indicated consistent results. The results of the MR-Egger regression showed that there was no pleiotropy in our MR analysis (P > 0.05). The IVW Cochran's Q estimates showed that the MR analysis results of E2, SHBG, and BT on SLE had no heterogeneity (P > 0.05), but testosterone and SLE had heterogeneity (P < 0.05). The leave-one-out analysis confirmed that a single SNP did not affect the MR results. Our MR analysis demonstrated that genetically predicted testosterone, E2, SHBG, and BT levels were not associated with SLE risk, but the roles of other non-genetic pathways cannot be ruled out. Key Points • This is the first MR study to explore the causal association of sex hormone-related traits with SLE. • No evidence to support causal associations between sex hormone-related traits and SLE. • Our MR analysis may provide novel insights into the causal association between sex hormone-related traits and SLE risk.

Causal effect of vitamin D on myasthenia gravis: a two-sample Mendelian randomization study.

Observational studies suggest that vitamin D supplementation may be effective in preventing myasthenia gravis (MG). However, the causal relationship between circulating vitamin D levels and MG remains unclear. This study aimed to examine the genetic causality of circulating vitamin D and MG using data from large population-based genome-wide association studies (GWAS). SNPs (single nucleotide polymorphisms) strongly associated with exposure were selected. Two-sample Mendelian Randomization (MR) was performed with inverse variance weighting (IVW), MR-Egger (Mendelian randomization-Egger), weight median and MR-PRESSO (Mendelian randomization pleiotropy residual sum and outlier) methods. Heterogeneity was tested via IVW and MR-Egger. Pleiotropy was tested using MR-Egger intercept test and MR-PRESSO method. MR-PRESSO was also used to detect outliers. Leave-one-out analysis was used to identify SNPs with potential effect. Reverse MR analysis was also performed. In IVW, circulating vitamin D levels had no causal effect on MG [OR = 0.91 (0.67-1.22), p = 0.532] and MG had no causal effect on circulating vitamin D [OR = 1.01 (099-1.02), p = 0.663]. No heterogeneity or pleiotropy was observed (p > 0.05). Other MR methods also agreed with IVW results. This study provides the causal relationship between genetically predicted circulating vitamin D levels and MG and provides new insights into the genetics of MG.

Assessing causal relationships between gut microbiota and asthma: evidence from two sample Mendelian randomization analysis.

Accumulating evidence has suggested that gut microbiota dysbiosis is commonly observed in asthmatics. However, it remains unclear whether dysbiosis is a cause or consequence of asthma. We aimed to examine the genetic causal relationships of gut microbiota with asthma and its three phenotypes, including adult-onset asthma, childhood-onset asthma, and moderate-severe asthma. To elucidate the causality of gut microbiota with asthma, we applied two sample Mendelian randomization (MR) based on the largest publicly available genome-wide association study (GWAS) summary statistics. Inverse variance weighting meta-analysis (IVW) was used to obtain the main estimates; and Weighted median, MR-Egger, Robust Adjusted Profile Score (MR-RAPS), Maximum likelihood method (ML), and MR pleiotropy residual sum and outlier (MR-PRESSO) methods were applied in sensitivity analyses. Finally, a reverse MR analysis was performed to evaluate the possibility of reverse causation. In the absence of heterogeneity and horizontal pleiotropy, the IVW method revealed that genetically predicted Barnesiella and RuminococcaceaeUCG014 were positively correlated with the risk of asthma, while the association between genetically predicted CandidatusSoleaferrea and asthma was negative. And for the three phenotypes of asthma, genetically predicted Akkermansia reduced the risk of adult-onset asthma, Collinsella and RuminococcaceaeUCG014 increased the risk of childhood-onset asthma, and FamilyXIIIAD3011group, Eisenbergiella, and Ruminiclostridium6 were correlated with the risk of moderate-severe asthma (all P<0.05). The reverse MR analysis didn't find evidence supporting the reverse causality from asthma and its three phenotypes to the gut microbiota genus. This study suggested that microbial genera were causally associated with asthma as well as its three phenotypes. The findings deepened our understanding of the role of gut microbiota in the pathology of asthma, which emphasizes the potential of opening up a new vista for the prevention and diagnosis of asthma.

Inflammatory bowel disease and prostate cancer risk: a two-sample Mendelian randomization analysis.

Previous epidemiological observational studies have reported an association between inflammatory bowel disease (IBD) and prostate cancer (PCa), but the causality is inconclusive. The purpose of this study was to evaluate the causality of IBD on PCa using the mendelian randomization (MR) analysis. We performed a two-sample MR analysis with public genome-wide association studies (GWAS) data. Eligible instrumental variables (IVs) were selected according to the three assumptions of MR analysis. The inverse-variance weighted (IVW) method was the main method. Complementary methods included the MR-Egger regression, the Weighted Median, the Simple Mode, the Weighted Mode and MR pleiotropy residual sum and outlier (MR-PRESSO) methods. Genetically determined IBD did not have a causal effect on PCa (IVW P > 0.05). Additionally, there was no causal effect of Crohn's disease (CD) and ulcerative colitis (UC) on PCa in the MR analysis (IVW P > 0.05). Results of complementary methods were consistent with those of the IVW method. This study does not support a causal association of IBD on PCa, which is in contrast to most observational studies.

Association Between Rheumatoid Arthritis and Osteoporosis in Japanese Populations: A Mendelian Randomization Study.

The positive association between rheumatoid arthritis (RA) and osteoporosis has been reported in previous observational studies, but the causal relationship remains unclear. This study was undertaken to investigate whether RA was causally associated with osteoporosis in Japanese populations using Mendelian randomization (MR) analyses. Publicly available summarized data from genome-wide association studies (GWAS) on RA (4,199 cases and 208,254 controls) and osteoporosis (7,788 cases and 204,665 controls) were obtained from BioBank Japan. Eleven RA-related single-nucleotide polymorphisms (P < 5×10-8 ) were selected as instrumental variables. We used the inverse variance-weighted method as the primary method to calculate the odds ratios (ORs) and 95% confidence intervals (95% CIs). We also used the MR-Egger's method, weighted median, and weighted mode to determine the robustness of the main results. To partially test the horizontal pleiotropy, we used the MR-Egger's intercept test and the Mendelian randomization pleiotropy residual sum and outlier (MRPRESSO) test. Using the inverse variance-weighted method, we showed that genetically predicted RA was positively associated with osteoporosis (OR 1.10, 95% CI 1.06-1.14, P < 0.001). The positive association was robust when we tested the results using the MR-Egger's method (OR 1.09, 95% CI 1.03-1.16, P = 0.023), weighted median (OR 1.09, 95% CI 1.04-1.15, P < 0.001), and weighted mode (OR 1.08, 95% CI 1.03-1.13, P = 0.012). Horizontal pleiotropy was not detected (P = 0.737) by the MR-Egger's intercept test or the MRPRESSO test. Our results show a potential causal association between genetically predicted RA and osteoporosis. The finding was consistent when we used different MR methods and the sensitivity analysis. Further MR studies are needed when GWAS with more details of RA and osteoporosis performed in other East Asian/Japanese populations are available.

A bidirectional Mendelian randomization study about the role of morning plasma cortisol in attention deficit hyperactivity disorder.

Cortisol, a hormone regulated by the hypothalamic-pituitary-adrenal (HPA) axis, has been linked to attention deficit hyperactivity disorder (ADHD). The nature of the relationship between cortisol and ADHD, and whether it is causal or explained by reverse causality, remains a matter of debate. This study aims to evaluate the bidirectional causal relationship between morning plasma cortisol levels and ADHD. This study used a bidirectional 2-sample Mendelian randomization (MR) design to analyze the association between morning plasma cortisol levels and ADHD using genetic information from the authoritative Psychiatric Genomics Collaboration (PGC) database (n = 55,347) and the ADHD Working Group of the CORtisol NETwork (CORNET) Consortium (n = 12,597). MR analyses were employed: inverse variance weighting (IVW), MR-Egger regression, and weighted medians. OR values and 95% CI were used to evaluate whether there was a causal association between morning plasma cortisol levels on ADHD and ADHD on morning plasma cortisol levels. The Egger-intercept method was employed to test for level pleiotropy. Sensitivity analysis was performed using the "leave-one-out" method, MR pleiotropy residual sum, and MR pleiotropy residual sum and outlier (MR-PRESSO). Findings from bidirectional MR demonstrated that lower morning plasma cortisol levels were associated with ADHD (ADHD-cortisol OR = 0.857; 95% CI, 0.755-0.974; P = 0.018), suggesting there is a reverse causal relationship between cortisol and ADHD. However, morning plasma cortisol levels were not found to have a causal effect on the risk of ADHD (OR = 1.006; 95% CI, 0.909-1.113; P = 0.907), despite the lack of genetic evidence. The MR-Egger method revealed intercepts close to zero, indicating that the selected instrumental variables had no horizontal multiplicity. The "leave-one-out" sensitivity analysis revealed stable results, with no instrumental variables significantly affecting the results. Heterogeneity tests were insignificant, and MR-PRESSO did not detect any significant outliers. The selected single-nucleotide polymorphisms (SNPs) F were all >10, indicating no weak instrumental variables. Thus, the overall MR analysis results were reliable. The study findings suggest a reverse causal relationship between morning plasma cortisol levels and ADHD, with low cortisol levels associated with ADHD. No genetic evidence was found to support a causal relationship between morning plasma cortisol levels and the risk of ADHD. These results suggest that ADHD may lead to a significant reduction in morning plasma cortisol secretion.

Correlation between obstructive sleep apnea and cerebral small vessel disease: a mendelian randomization study.

Whether obstructive sleep apnea (OSA) is causally associated with an increased risk of cerebral small vessel disease (CSVD) remains controversial. We conducted a two-sample Mendelian randomization (MR) study to clarify the causal relationship between OSA and CSVD risk. Single-nucleotide polymorphisms associated with OSA at the genome-wide significance level (P < 5 × 10- 8) in the FinnGen consortium were selected as instrumental variables. Summary-level data for white matter hyperintensities (WMHs), lacunar infarctions (LIs), cerebral microbleeds (CMBs), fractional anisotropy (FA), and mean diffusivity (MD) were obtained from three meta-analyses of genome-wide association studies (GWASs). The random-effects inverse-variance weighted (IVW) method was selected for the major analysis. Weighted-median, MR-Egger, MR pleiotropy residual sum and outlier (MR-PRESSO), and leave-one-out analysis methods were implemented for the sensitivity analyses. Genetically predicted OSA was not associated with LIs (odds ratio [OR] = 1.10, 95% confidence interval [CI] = 0.86-1.40), WMHs (OR = 0.94, 95% CI = 0.83-1.07), FA (OR = 1.33, 95% CI = 0.75-2.33), MD (OR = 0.93, 95% CI = 0.58-1.47), CMBs (OR = 1.29, 95% CI = 0.86-1.94), mixed CMBs (OR = 1.17, 95% CI = 0.63-2.17), and lobar CMBs (OR = 1.15, 95% CI = 0.75-1.76) in IVW method. The results of the sensitivity analyses were generally consistent with the major analyses. This MR study does not support causal associations between OSA and the risk of CSVD in individuals of European ancestry. These findings need to be further validated in randomized controlled trials, larger cohort studies, and MR studies based on larger GWASs.

Investigating the causal relationship between ankylosing spondylitis and osteoporosis in the European population: a bidirectional Mendelian randomization study.

Ankylosing Spondylitis (AS) is an inflammatory condition affecting the spine, which may lead to complications such as osteoporosis (OP). Many observational studies have demonstrated a close relationship with strong evidence between OP and AS. The combination of AS and OP is already an indisputable fact, but the exact mechanism of AS complicated with OP is unclear. To better prevent and treat OP in patients with AS, it is necessary to understand the specific mechanism of OP in these patients. In addition, there is a study showing that OP is a risk factor for AS, but the causal relationship between them is not yet clear. Therefore, we conducted a bidirectional Mendelian randomization (MR) analysis to determine whether there is a direct causal effect between AS and OP and to investigate the co-inherited genetic information between the two. Bone mineral density (BMD) was used as a phenotype for OP. The AS dataset was taken from the IGAS consortium and included people of European ancestry (9,069 cases and 13,578 controls). BMD datasets were obtained from the GEFOS consortium, a large GWAS meta-analysis study, and the UK Biobank and were categorized based on site (total body (TB): 56,284 cases; lumbar spine (LS): 28,498 cases; femoral neck (FN): 32,735 cases; forearm (FA): 8,143 cases; and heel: 265,627 cases) and age (0-15: 11,807 cases; 15-30: 4,180 cases; 30-45: 10,062 cases; 45-60: 18,062 cases; and over 60: 22,504 cases).To obtain the casual estimates, the inverse variant weighted (IVW) method was mainly used due to its good statistical power and robustness. The presence of heterogeneity was evaluated using Cochran's Q test. Pleiotropy was assessed utilizing MR-Egger regression and MR-pleiotropy residual sum and outlier (MR-PRESSO). Generally, there were no significant causal associations between genetically predicted AS and decreased BMD levels. The results of MR-Egger regression, Weighted Median, and Weighted Mode methods were consistent with those of the IVW method. However, there was a sign of a connection between genetically elevated BMD levels and a decreased risk of AS (Heel-BMD: OR = 0.879, 95% CI: 0.795-0.971, P = 0.012; Total-BMD: OR = 0.948, 95% CI: 0.907-0.990, P = 0.017; LS-BMD: OR = 0.919, 95% CI: 0.861-0.980, P = 0.010). The results were confirmed to be reliable by sensitivity analysis. This MR study found that the causal association between genetic liability to AS and the risk of OP or lower BMD in the European population was not evident, which highlights the second effect (e.g., mechanical reasons such as limited movement) of AS on OP. However, genetically predicted decreased BMD/OP is a risk factor for AS with a causal relationship, implying that patients with OP should be aware of the potential risk of developing AS. Moreover, OP and AS share similar pathogenesis and pathways.

The Causal Effect of Dietary Composition on the Risk of Breast Cancer: A Mendelian Randomization Study.

Breast cancer has become the most common malignancy among women, posing a severe health risk to women worldwide and creating a heavy social burden. Based on current observational studies, the dietary factor may have a causal relationship with breast cancer. Therefore, exploring how dietary composition affects breast cancer incidence will provide nutrition strategies for clinicians and women. We performed a two-sample Mendelian randomization (MR) analysis to find the causal effect of four kinds of relative macronutrient intake (protein, carbohydrate, sugar, and fat) on the risk of breast cancer and its subtypes [Luminal A, Luminal B, Luminal B HER2-negative, HER2-positive, Triple-negative, Estrogen receptor (ER) positive, and ER-negative breast cancer]. The Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test, MR-Egger intercept test, Cochran's Q statistic, funnel plot, and leave-one-out (Loo) analysis were all used in a sensitivity analysis to test the robustness of MR. Genetically, a higher relative protein intake was found as a protective factor for Luminal A and overall breast cancer, which was inconsistent with recent findings. A higher relative sugar intake could genetically promote the risk of Luminal B and HER2-positive breast cancer. Conclusions: A higher protein proportion in diet genetically reduces the risk of breast cancer, while higher relative sugar intake does the opposite.

Associations between high-altitude adaptation and risk of cardiovascular diseases: a bidirectional Mendelian randomization study.

High-altitude adaptation (HAA) was reported to be significantly associated with reduced risks for multiple cardiovascular diseases (CVDs). However, the causality and direction of the associations are largely uncharacterized. We aimed to examine the potential causal relationships between HAA and six types of CVD, including coronary artery disease (CAD), cerebral aneurysm, ischemic stroke, peripheral artery disease, arrhythmia and atrial fibrillation. We obtained the summary data from largest available genome-wide association study of HAA and six types of CVD. Two-sample bidirectional Mendelian randomization (MR) analyses were performed to infer the causality between them. In the sensitivity analyses, MR-Egger regression analyses and MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) global analyses were used to assess the pleiotropic effects; Cochran's Q tests were used to test the heterogeneity by inverse variance-weighted (IVW) and MR-Egger methods; and the leave-one-out analyses were used to examine whether some single nucleotide polymorphisms (SNPs) could influence the results independently. The MR main analyses showed that the genetically instrumented HAA was significantly causally associated with the reduced risks of CAD (odds ratio [OR] = 0.029; 95% confidence interval [CI] = 0.004-0.234; P = 8.64 × 10-4). In contrast, there was no statistically significant relationship between CVDs and HAA. Our findings provide evidence for the causal effects of HAA on the reduced risks of CAD. However, there is no causality of CVDs on HAA. These findings might be helpful in developing the prevention and intervention strategies for CAD.

Causal relationships between COVID-19 and osteoporosis: a two-sample Mendelian randomization study in European population.

The causal relationship between Coronavirus disease 2019 (COVID-19) and osteoporosis (OP) remains uncertain. We aimed to assess the effect of COVID-19 severity (severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, COVID-19 hospitalization, and severe COVID-19) on OP by a two-sample Mendelian randomization (MR) study. We conducted a two-sample MR analysis using publicly available genome-wide association study (GWAS) data. Inverse variance weighting (IVW) was used as the main analysis method. Four complementary methods were used for our MR analysis, which included the MR-Egger regression method, the weighted median method, the simple mode method, and the weighted mode method. We utilized the MR-Egger intercept test and MR pleiotropy residual sum and outlier (MR-PRESSO) global test to identify the presence of horizontal pleiotropy. Cochran's Q statistics were employed to assess the existence of instrument heterogeneity. We conducted a sensitivity analysis using the leave-one-out method. The primary results of IVW showed that COVID-19 severity was not statistically related to OP (SARS-CoV-2 infection: OR (95% CI) = 0.998 (0.995 ~ 1.001), p = 0.201403; COVID-19 hospitalization: OR (95% CI) =1.001 (0.999 ~ 1.003), p = 0.504735; severe COVID-19: OR (95% CI) = 1.000 (0.998 ~ 1.001), p = 0.965383). In addition, the MR-Egger regression, weighted median, simple mode and weighted mode methods showed consistent results. The results were robust under all sensitivity analyses. The results of the MR analysis provide preliminary evidence that a genetic causal link between the severity of COVID-19 and OP may be absent.

Investigating association between gut microbiota and sarcopenia-related traits: a Mendelian randomization study.

Observational studies have indicated a potential link between gut microbiota and sarcopenia. However, the underlying mechanisms and a causal relationship have not been established. Thus, the objective of this study is to examine the possible causal association between gut microbiota and sarcopenia-related traits, including low hand-grip strength and appendicular lean mass (ALM), to shed light on the gut-muscle axis. To investigate the potential impact of gut microbiota on low hand-grip strength and ALM, we utilized a two-sample Mendelian randomization (MR) approach. Summary statistics were obtained from genome-wide association studies of gut microbiota, low hand-grip strength, and ALM. The primary MR analysis employed the random-effects inverse-variance weighted (IVW) method. To assess the robustness, we conducted sensitivity analyses using the MR pleiotropy residual sum and outlier (MR-PRESSO) test to detect and correct for horizontal pleiotropy, as well as the MR-Egger intercept test and leave-one-out analysis. Alcaligenaceae, Family XIII, and Paraprevotella were positively associated with the risk of low hand-grip strength (P-values<0.05). Streptococcaceae were negatively associated with low hand-grip strength (P-values<0.05). Eight bacterial taxa (Actinomycetales, Actinomycetaceae, Bacteroidaceae, Porphyromonadaceae, Prevotellaceae, Bacteroides, Marvinbryantia, and Phascolarctobacterium) were associated with a higher risk of ALM (P-values<0.05). Eubacterium fissicatena group was negatively associated with ALM (P-values<0.05). We found several gut microbiota components causally associated with sarcopenia-related traits. Our findings provided insights into novel strategies for the prevention and treatment of sarcopenia through the regulation of the gut microbiota, contributing to a better understanding of the gut-muscle axis.

Inflammatory bowel disease is causally related to irritable bowel syndrome: a bidirectional two-sample Mendelian randomization study.

Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are lifelong digestive diseases that severely impact patients' quality of life. The existence of a causal association between IBS and IBD remains unclear. This study aimed to determine the direction of causality between IBD and IBS by quantifying their genome-wide genetic associations and performing bidirectional two-sample Mendelian randomization (MR) analyses. Genome-wide association studies (GWAS) among a predominantly European patient cohort identified independent genetic variants associated with IBS and IBD. Two separate databases (a large GWAS meta-analysis and the FinnGen cohort) for both IBS and IBD were consulted to retrieve statistics on instrument-outcome associations. MR analyses included inverse-variance-weighted, weighted-median, MR-Egger regression, MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) methods, and sensitivity analyses were performed. The MR analyses were carried out for each outcome data, followed by a fixed-effect meta-analysis. Genetically predicted IBD was associated with an increased risk of IBS. Odds ratios (95% confidence intervals) for samples of 211,551 (17,302 individuals with IBD), 192,789 (7,476 Crohn's disease cases), and 201,143 (10,293 ulcerative colitis cases) individuals were 1.20 (1.00, 1.04), 1.02 (1.01, 1.03), and 1.01 (0.99, 1.03), respectively. After outlier correction using MR-PRESSO, the odds ratio for ulcerative colitis was 1.03 (1.02, 1.05) (p = 0.001). However, an association between genetically influenced IBS and IBD was not identified. This study confirms that IBD is causally related to IBS, which may interfere with the diagnosis and treatment of both diseases.

Immune-mediated inflammatory diseases and leukocyte telomere length: A Mendelian randomization study.

Objective: To elucidate the potential causality of leukocyte telomere length (LTL) with immune-mediated inflammatory diseases (IMIDs), we conducted a Mendelian randomization (MR) study. Methods: The genetically predicted causation between LTL and IMIDs was evaluated using a two-sample MR method. We analyzed 16 major IMIDs, which included systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), ankylosing spondylitis (AS), sicca syndrome (SS), rheumatoid arthritis (RA), type 1 diabetes (T1D), primary sclerosing cholangitis (PSC), idiopathic pulmonary fibrosis (IPF), atopic dermatitis (AD), sarcoidosis, hypothyroidism, hyperthyroidism, psoriasis, and childhood asthma. The random-effects inverse-variance weighted (IVW) method was performed as the main analytical approach in MR. Various sensitivity analyses, including MR-Egger, MR robust adjusted profile score (MR-RAPS), weighted median, MR pleiotropy residual sum and outlier (MR-PRESSO) methods, weighted mode, radial plot, and radial regression, were used to guarantee the robustness of the results and detect horizontal pleiotropy. Cochran's Q value was calculated to check for heterogeneity, and the MR Steiger approach was used to test the causal direction. Results: The MR results indicated significant inverse associations of LTL with risks of psoriasis (OR: 0.77, 95% CI: 0.66-0.89, and p = 3.66 × 10-4), SS (OR: 0.75, CI: 0.58-0.98, and p = 0.03), RA (OR: 0.77, 95% CI: 0.68-0.88, and p = 9.85 × 10-5), hypothyroidism (OR: 0.84, 95% CI: 0.78-0.91, and p = 7,08 × 10-6), hyperthyroidism (OR: 0.60, 95% CI: 0.44-0.83, and p = 1.90 × 10-3), sarcoidosis (OR: 0.67, 95% CI: 0.54-0.83, and p = 2.60 × 10-4), and IPF (OR: 0.41, 95% CI: 0.29-0.58, and p = 4.11 × 10-7) in the FinnGen study. We observed that longer LTL was associated with an increased risk of AS susceptibility (OR: 1.51, 95% CI: 1.18-1.94, and p = 9.66 × 10-4). The results of the IVW method showed no causal relationship between TL and SLE (OR: 0.92, 95% CI: 0.62-1.38, and p = 0.69) in the FinnGen study; however, a significantly positive correlation was shown between LTL and SLE in another larger GWAS (OR: 1.87, 95% CI: 1.37-2.54, and p = 8.01 × 10-5). Conclusion: Our findings reveal that abnormal LTL has the potential to increase the risk of IMIDs. Therefore, it could be treated as a predictor and may provide new potential treatment targets for IMIDs. However, the change of LTL may not be the direct cause of IMIDs. Further studies should aim at the pathogenic mechanism or potential protective effects of LTL in IMIDs.

Genetically supported causality between gut microbiota, gut metabolites and low back pain: a two-sample Mendelian randomization study.

Previous studies have implicated a vital association between gut microbiota/gut microbial metabolites and low back pain (LBP), but their causal relationship is still unclear. Therefore, we aim to comprehensively investigate their causal relationship and identify the effect of gut microbiota/gut microbial metabolites on risk of LBP using a two-sample Mendelian randomization (MR) study. Summary data from genome-wide association studies (GWAS) of gut microbiota (18,340 participants), gut microbial metabolites (2,076 participants) and LBP (FinnGen biobank) were separately obtained. The inverse variance-weighted (IVW) method was used as the main MR analysis. Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) and MR-Egger regression were conducted to evaluate the horizontal pleiotropy and to eliminate outlier single-nucleotide polymorphisms (SNPs). Cochran's Q-test was applied for heterogeneity detection. Besides, leave-one-out analysis was conducted to determine whether the causal association signals were driven by any single SNP. Finally, a reverse MR was performed to evaluate the possibility of reverse causation. We discovered that 20 gut microbial taxa and 2 gut microbial metabolites were causally related to LBP (p < 0.05). Among them, the lower level of family Ruminococcaceae (OR: 0.771, 95% CI: 0.652-0.913, FDR-corrected p = 0.045) and Lactobacillaceae (OR: 0.875, 95% CI: 0.801-0.955, FDR-corrected p = 0.045) retained a strong causal relationship with higher risk of LBP after the Benjamini-Hochberg Corrected test. The Cochrane's Q test revealed no Heterogeneity (p > 0.05). Besides, MR-Egger and MR-PRESSO tests showed no significant horizontal pleiotropy (p > 0.05). Furthermore, leave-one-out analysis confirmed the robustness of MR results. After adding BMI to the multivariate MR analysis, the 17 gut microbial taxa exposure-outcome effect were significantly attenuated and tended to be null. Our findings confirm the the potential causal effect of specific gut microbiota and gut microbial metabolites on LBP, which offers new insights into the gut microbiota-mediated mechanism of LBP and provides the theoretical basis for further explorations of targeted prevention strategies.

Celiac Disease Is a Risk Factor for Mature T and NK Cell Lymphoma: A Mendelian Randomization Study.

Celiac disease (CeD) is an immune-mediated disorder triggered by gluten ingestion that damages the small intestine. Although CeD has been associated with a higher risk for cancer, the role of CeD as a risk factor for specific malignancies, such as enteropathy-associated T-cell lymphoma (EATL), remains controversial. Using two-sample Mendelian randomization (2SMR) methods and the summarized results of large genome-wide association studies from public repositories, we addressed the causal relationship between CeD and eight different malignancies. Eleven non-HLA SNPs were selected as instrumental variables (IVs), and causality estimates were obtained using four 2SMR methods: random-effects inverse variance-weighted, weighted median estimation, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO). We identified a significant causal relationship between CeD and mature T/NK cell lymphomas. Under a multivariate Mendelian randomization model, we observed that the causal effect of CeD was not dependent on other known lymphoma risk factors. We found that the most instrumental IV was located in the TAGAP locus, suggesting that aberrant T cell activation might be relevant in the T/NK cell malignization process. Our findings provide new insights into the connection between immune imbalance and the development of severe comorbidities, such as EATL, in patients with CeD.