Two-sample Mendelian Randomization Analysis Research Articles

Inherited Genetic Variation in Parkinson's Disease: Convergence on Impaired Autophagosome-Lysosome Fusion Through the Altered Expression of mRNA Isoforms.

Parkinson's disease (PD) pathogenesis involves complex interactions between genetic factors. We employed two-sample Mendelian randomization (MR) integrating tissue-specific gene regulatory networks to identify causal genes and regulatory elements modulating PD risk. Two-sample MR analysis identified 79 putative causal genes for PD. A subset of the 79 causal genes was enriched within chr17q21.31 and chr16p11.2 cytobands that have been previously linked to neurodevelopmental disorders. Functional enrichment analysis of the 79 genes revealed autophagosome-lysosome fusion as a key process. Ten genes (ELOVL7, HSD3B7, PLEKHM1, PRSS53, SNCA, STX1B, STX4, ZSWIM7, LINC02210, and RP11-1072 A3.3) showed causal associations with tissue-specific expression patterns driving risk or protection for PD. Further investigation into their tissue-specific isoform expression profile revealed isoform-specific contributions to disease risk (or protection). These findings highlight the critical role of isoform-specific expression of causal genes in modulating PD risk, particularly relating to autophagosome-lysosome fusion. While our findings provide new insights into PD susceptibility, we acknowledge that the observed isoform-specific changes may, in part, reflect sample selection bias. Therefore, further experimental verification is needed to confirm the importance of incorporating tissue-specific gene isoform profiles in understanding PD causal mechanisms.

Causal link between gut microbiota and obsessive-compulsive disorder: A two-sample Mendelian randomization analysis.

Causal link between gut microbiota and obsessive-compulsive disorder: A two-sample Mendelian randomization analysis.

Genetic associations of sex hormones with cerebral aneurysm formation and subarachnoid hemorrhage: A two-sample Mendelian randomization analysis.

Genetic associations of sex hormones with cerebral aneurysm formation and subarachnoid hemorrhage: A two-sample Mendelian randomization analysis.

Thyroid Dysfunction and Oral Lichen Planus: Evidence From Two-Sample Mendelian Randomization Analysis.

Thyroid Dysfunction and Oral Lichen Planus: Evidence From Two-Sample Mendelian Randomization Analysis.

The interplay between systemic inflammation and myopia: A bidirectional Mendelian randomization and experimental validation study.

The interplay between systemic inflammation and myopia: A bidirectional Mendelian randomization and experimental validation study.

Synergistic impact of 25-hydroxyvitamin D and physical activity on incident depression: Evidence from a prospective cohort and genome-wide data.

Synergistic impact of 25-hydroxyvitamin D and physical activity on incident depression: Evidence from a prospective cohort and genome-wide data.

Association of Immune Cell Phenotypes With Oral Cancer: A Two-Sample Mendelian Randomisation Study.

Association of Immune Cell Phenotypes With Oral Cancer: A Two-Sample Mendelian Randomisation Study.

Nutritional interventions for preventing cognitive decline in patients with mild cognitive impairment and Alzheimer's disease: A comprehensive network meta-analysis and Mendelian Randomization study.

Nutritional interventions for preventing cognitive decline in patients with mild cognitive impairment and Alzheimer's disease: A comprehensive network meta-analysis and Mendelian Randomization study.

Obstructive sleep apnea and osteoporosis: A bidirectional two-sample mendelian randomization analysis.

Obstructive sleep apnea and osteoporosis: A bidirectional two-sample mendelian randomization analysis.

The connection between 91 inflammatory cytokines and frailty mediated by 1400 metabolites: An exploratory two-step Mendelian randomization analysis.

The connection between 91 inflammatory cytokines and frailty mediated by 1400 metabolites: An exploratory two-step Mendelian randomization analysis.

Autoimmune thyroid disease is a risk factor for mood disorders, a Mendelian randomization study.

Autoimmune thyroid disease is a risk factor for mood disorders, a Mendelian randomization study.

A systematic Mendelian randomized study of the effects of the gut microbiome and immune cells on pancreatic neuroendocrine tumors

Pancreatic neuroendocrine tumors (pNETs) are a rare subset of pancreatic cancers often diagnosed late and characterized by complex behaviors. Recent evidence suggests the gut microbiome (GM) significantly influences various diseases by modulating the immune system. This study utilized a Mendelian randomization (MR) approach to investigate the causal relationship between GM and pNETs, using single nucleotide polymorphism data as instrumental variables. Two-sample MR analysis identified significant correlations between GM and immune cell types. The study found eight specific GMs affecting pNETs risk: the family Sutterellaceae (OR: 1.52, 95% CI 1.10–2.10, p = 0.01), the genus Paraprevotella (OR: 1.34, 95% CI 1.05–1.72, p = 0.02), the species Paraprevotella unclassified (OR: 1.40, 95% CI 1.08–1.81, p = 0.01), and the species Ruminococcus torques (OR: 1.45, 95% CI 1.12–1.89, p = 0.01) increased risk, while the class Gammaproteobacteria (OR: 0.75, 95% CI 0.57–0.98, p = 0.04), the family Acidaminococcaceae (OR: 0.70, 95% CI 0.52–0.94, p = 0.02), the species Paraprevotella xylaniphila (OR: 0.72, 95% CI 0.54–0.96, p = 0.03), and the species Bacteroides finegoldii (OR: 0.68, 95% CI 0.51–0.91, p = 0.01) decreased it. Mediation analysis indicated the species Ruminococcus torques mediated the effect of CD25 on CD45RA+ CD4 non-regulatory T cells on pNETs, accounting for 3.6% of the total effect. This study provides evidence suggestive of a potential causal role of specific GM compositions in pNETs progression and their mediation through immune cell signatures. However, mechanistic studies are required to further validate this relationship.Graphical abstract

Identifying causal genes for prostatitis through drug-targeted Mendelian randomization

Prostatitis is a common condition in andrology and urology that significantly impacts the quality of life of affected individuals. Current treatments often fail to provide lasting benefits. To identify novel therapeutic targets, we conducted a drug-targeted Mendelian randomization (MR) study. Using cis-expression quantitative trait loci (cis-eQTL) data from the eQTLGen Consortium combined with Genome-Wide Association Studies (GWAS) data on prostatitis from FinnGen, we performed a two-sample MR analysis. This analysis identified nine potential causal genes: ANXA1, CRY2, DSTYK, FKBP1A, LAMA5, NENF, PTGIR, STK39, and TGFA. Following heterogeneity testing, horizontal pleiotropy assessment, and bidirectional MR, CRY2 and PTGIR were validated in the Genotype-Tissue Expression (GTEx) portal replication phase. Bayesian colocalization analysis and genetic correlation analysis investigations provided strong evidence of shared causal variants with prostatitis and negative genetic correlations for these genes. PheWAS indicated negligible horizontal pleiotropy, and drug prediction analysis identified potential targeting agents for CRY2 and PTGIR. This study highlights CRY2 and PTGIR as promising therapeutic targets for prostatitis, providing new insights into its genetic underpinnings and offering potential pathways for developing effective treatments.

Causal associations between gut microbiota and rheumatoid arthritis: A two-sample Mendelian randomization study.

The gut microbiota has been implicated in the development of rheumatoid arthritis (RA), but whether these associations reflect causal relationships remains unclear. We conducted a two-sample Mendelian randomization analysis to investigate the potential causal effects of gut microbial taxa on RA risk. Summary-level data from the MiBioGen consortium (n = 13,266) and a large RA genome-wide association study (n = 97,173) were used. Multiple Mendelian randomization methods and sensitivity analyses were applied to ensure robustness. Four microbial taxa showed nominal associations with RA. Increased abundance of Catenibacterium, Desulfovibrio, and Ruminiclostridium 6 was associated with a higher risk of RA, while Lachnospiraceae (UCG008) appeared to have a protective effect. Although these associations did not meet Bonferroni-corrected significance, results were consistent across analytical methods with no evidence of pleiotropy or heterogeneity. This study provides genetic evidence supporting a potential causal link between specific gut microbes and RA risk. The findings highlight host immune modulation as a possible pathway connecting the gut microbiome to RA and identify candidate taxa for future mechanistic and therapeutic research.

Association of glucagon-like peptide-1 receptor agonists with atrial fibrillation, cardiac arrest, and ventricular fibrillation: Casual evidence from a drug target Mendelian randomization

BackgroundGlucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown benefits for cardiorenal outcomes in patients with type 2 diabetes mellitus. Although some observational studies suggest that GLP-1RAs protect against arrhythmias, the evidence remains inconclusive.MethodsThis study aimed to assess the causal relationship between GLP-1RAs and arrhythmias, including atrial fibrillation (AF), cardiac arrest, and ventricular fibrillation. We performed a two-sample Mendelian randomization (MR) analysis to examine the associations between genetically proxied GLP-1RAs and the risk of arrhythmias. Genetic instruments for GLP-1RAs were obtained from the cis-expression quantitative trait loci of the GLP1R gene, on the basis of data from the eQTLGen Consortium. Genome-wide association study (GWAS) data for AF were sourced from FinnGen10, whereas data for cardiac arrest and ventricular fibrillation came from the GWAS Catalog. Bayesian colocalization and multivariable Mendelian randomization (MVMR) analyses were conducted as supplementary analyses.ResultsTwelve independent single nucleotide polymorphisms were identified as genetic instruments for GLP-1RAs. MR analysis indicated that genetically proxied GLP-1RAs were associated with a reduced risk of AF (odds ratio [OR] = 0.78, 95% confidence interval [CI] = 0.71–0.85, p = 4.45E-08, posterior probability of hypothesis 4 [PP.H4] = 0.007) and a lower risk of cardiac arrest and ventricular fibrillation (OR = 0.60, 95% CI = 0.42–0.85, p = 0.0039, PP.H4 = 0.018). Bayesian colocalization analysis revealed that genetically proxied GLP-1RAs did not share genetic variation with arrhythmias. MVMR analysis revealed that, after adjusting for body mass index and type 2 diabetes mellitus, genetically proxied GLP-1RAs did not have a significant effect on the risk of arrhythmias.ConclusionsOur findings suggest that genetically proxied GLP-1RAs are causally associated with a reduced risk of AF, cardiac arrest, and ventricular fibrillation. Further randomized controlled trials are needed to confirm these results.

Common sleep characteristics and the risk of common perinatal complications and adverse outcomes: a multi-sample, bidirectional Mendelian randomization study

BackgroundImproving maternal and child health has been a global priority since the early 2000s, with a focus on reducing perinatal complications and improving overall maternal well-being. Sleep characteristics influence various health outcomes, yet their role in perinatal complications and adverse outcomes remains poorly understood.MethodsA Mendelian randomization analysis was conducted, using seven common sleep characteristics (sleeplessness, sleep duration, getting up in the morning, daytime napping, morning/evening person, narcolepsy, snoring) as exposure factors and twelve common perinatal complications and adverse outcomes (preterm birth, polyhydramnios, slow fetal growth and fetal malnutrition, dystocia, umbilical cord-related complications, postpartum hemorrhage, fetal distress, gestational diabetes, pregnancy hypertension, eclampsia, abruptio placentae, placenta previa) as outcomes. A two-sample Mendelian randomization analysis was performed to infer causal effects.ResultsThe inverse variance weighted (IVW) analysis showed that sleeplessness was associated with preterm birth, sleep duration with gestational diabetes, and narcolepsy with pregnancy hypertension and eclampsia. These results were consistently supported by other methods, suggesting that sleep characteristics are causal risk factors for perinatal complications and adverse outcomes.ConclusionThis study found that sleeplessness is associated with preterm birth, sleep duration with gestational diabetes, and narcolepsy with pregnancy hypertension and eclampsia. These findings contribute to a better understanding of the impact of sleep characteristics on common perinatal complications and adverse outcomes. Targeting sleep interventions, such as improving sleep duration and addressing sleep disorders like sleeplessness and narcolepsy, may reduce the incidence of preterm birth, gestational diabetes, and pregnancy hypertension, offering effective strategies to improve maternal and infant health outcomes.

Decoding the impact of glucose-dependent insulinotropic polypeptide receptor (GIPR) agonist on cardiometabolic health: inflammatory mediators at the focus

BackgroundThe Glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR) are well-established drug targets for the treatment of diabetes and obesity. Studies have linked GLP-1R agonist to cardiometabolic diseases (CMDs), while the therapeutic potential of the GIPR agonist remains a topic of debate.MethodsUsing genetic variants as instrumental variables, we performed a two-sample Mendelian randomization (MR) analysis to investigate causal relationships between genetically proxied GIPR agonist and 23 CMD outcomes, and a two-step mediation analysis to identify mediating inflammatory biomarkers. The inverse variance weighted (IVW) method served as the primary analytical approach, supplemented by sensitivity analyses to validate robustness.ResultsThe genetic mimicry of GIPR enhancement showed significant protective associations with 14 CMDs. Mediation analysis revealed that Fms-related tyrosine kinase 3 ligand (Flt3L) partially mediated the effects of GIPR agonist on angina (OR 0.997 [0.995–0.999], P = 0.0048) and myocardial infarction(MI) (OR 0.998 [0.996–0.999], P = 0.0077), accounting for 15.49% and 16.71% of the total risk reduction, respectively.ConclusionOur study revealed that GIPR agonist lowers the risk of 14 CMDs. Flt3L is pinpointed as a key mediating factor in reducing angina and MI risk, suggesting a new therapeutic avenue.

The Mediating Role of Plasma Inflammatory Proteins in Gut Microbiota-Driven Valvular Heart Disease: A Mendelian Randomization Study.

This study investigates the causal relationships between gut microbiota (GM), plasma inflammatory proteins (PIPs), and valvular heart disease (VHD) using two-sample Mendelian Randomization (MR) analysis. We also assess whether PIPs mediate the link between GM and VHD. We conducted bidirectional MR analyses to explore causal associations between GM, PIPs, and VHD, and used multivariable MR to test the independence of associations. Genome-wide association study (GWAS) data on 196 GM taxa, 91 PIPs, and VHD were analyzed. MR methods including inverse-variance weighted (IVW), MR-Egger regression, and weighted median approaches were applied. Sensitivity analyses ensured robustness. Actinobacteria and Defluviitaleaceae were associated with lower VHD risk, while Oxalobacteraceae increased risk. At the genus level, Intestinibacter, Lachnospiraceae NC2004 group, Oscillospira, and Ruminococcaceae UCG004 were protective, whereas Oscillibacter increased risk. Among PIPs, Interleukin-10, Interleukin-17C, Leukemia inhibitory factor receptor (LIFR), and monocyte chemoattractant protein 2 were protective, while TNF-beta elevated risk. Multivariable MR confirmed the independent roles of TNF-beta, LIFR, and MCP-2. Actinobacteria's protective effect appeared partially mediated through increased LIFR expression, accounting for 14% of the effect. Our findings suggest that modulating gut microbiota, particularly enhancing Actinobacteria, may serve as a novel strategy for VHD prevention and treatment.

Association Between ω-3, ω-6 Polyunsaturated Fatty Acid and Sleep Disorders: From Cross-Sectional to Mendelian Randomization Studies.

Sleep disorders are a common health problem affecting a significant proportion of the adult population. Emerging evidence suggests that dietary factors, particularly polyunsaturated fatty acid (PUFA) intake, may play a role in modulating sleep quality. This study aims to investigate the association between omega-3 (ω-3) and omega-6 (ω-6) PUFA and sleep disorders using cross-sectional survey data and data from genome-wide association studies (GWAS). Using data from the National Health and Nutrition Examination Survey (NHANES, 2005-2018), we analyzed a cohort of 31,920 participants, with the primary independent variables being intake of ω-3 and ω-6 PUFAs. Multivariate regression was used to assess associations, and restricted cubic spline analysis was used to explore potential non-linear dose-response relationships. Two-sample Mendelian randomization (MR) analyses were performed to evaluate the causal effects of levels of multiple fatty acids on the risk of sleep disorders. For analysis on NHANES data, the participants with sleep disorders had significantly lower ω-3 PUFA intake (1.71 ± 1.11 g) compared to those without sleep disorders (1.78 ± 1.14 g, p < 0.001). Regression analysis revealed that higher ω-3 PUFA intake was associated with a reduced risk of sleep disorders, while the MR analyses showed that a higher ratio of ω-6 to total fatty acid levels was causally associated with a lower risk of sleep disorders (IVW OR = 0.930, 95% CI: 0.880-0.983, p = 0.011). Our findings suggest that increased ω-3 FA intake and increased ratio of ω-6 to total fatty acid level may be associated with a lower risk of sleep disorders, highlighting the potential benefits of dietary modification for sleep health. Future research should further explore these associations and consider intervention studies to establish causality and optimal dietary recommendations to prevent sleep disorders.

Assessing the causal relationship between obesity and ankylosing spondylitis: A two-sample Mendelian randomization study.

This study aims to explore the potential causal relationship between obesity and ankylosing spondylitis (AS) using the Mendelian randomization (MR) approach. Data were derived from a comprehensive genome-wide association study dataset. Genetic loci that demonstrated significant, independent associations with both obesity and AS in populations of European ancestry were selected as instrumental variables. Multiple MR analyses, including MR-Egger, weighted median, and inverse variance weighting, were employed to assess the causal impact of obesity on AS risk. To ensure reliability, heterogeneity, and multiplicity tests were conducted, and the robustness of the findings was evaluated through sensitivity analyses using the "leave-one-out" method. The inverse variance weighting analysis revealed an odds ratio (OR) of 0.95 with a 95% confidence interval of 0.76 to 1.19 and a P value of .653. These results indicated no significant causal link between obesity and AS development. Additionally, the heterogeneity and multiplicity tests showed no significant findings, while sensitivity analyses reinforced the consistency and robustness of the conclusions. This research did not find evidence of a causal relationship between obesity and the development of AS based on two-sample MR analysis and genetic data evaluation. However, the current study's limitations, including sample size and study design, highlight the need for future research with larger cohorts to further explore the intricate relationship between obesity and AS.