Two-sample Mendelian Randomization Research Articles

Evaluating the causal association between circulating plasma proteins, 731 immune cell phenotypes, and atopic dermatitis: A mediation Mendelian randomization study.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by eczematous lesions and severe itching. However, its pathogenesis has not yet been fully elucidated. The aim of this study was to investigate the causal relationship between plasma proteins and AD, as well as to identify and quantify the potential roles of immune cell phenotypes as mediators. We utilized summary-level data from genome-wide association studies and conducted a two-sample Mendelian randomization (MR) analysis involving 4907 circulating plasma proteins, 731 immune cell phenotypes, and AD. Initially, we conducted bidirectional univariate MR analyses to forecast causal effects linking circulating plasma proteins and AD. Subsequently, we employed a two-step MR analysis to scrutinize the immune cell phenotypes that could mediate these effects. The inverse variance weighted was the main method employed for MR analysis, while the Cochran's Q test and MR-Egger intercept test were used to assess the presence of heterogeneity and pleiotropy, respectively. We then determined whether our results could be influenced by individual single-nucleotide polymorphisms using the "leave-one-out" test. Positive correlations were observed between KRT1, IL18R1, and SEMA6A and the risk of AD, whereas BDH2, ADAMTS3, ANKRD1, TIAM1, MID2, and IFNA16 all showed negative correlations with the risk of AD. Mediation analysis indicated that CD8 on CM CD8br cells acted as a mediator between IFNA16 and AD, with a mediation effect proportion of 11.2%. In addition, sensitivity analyses did not reveal significant heterogeneity or level pleiotropy. Our findings indicated the presence of a one-way causal relationship between the circulating plasma protein IFNA16 and AD. This study also explored immune cell phenotypes that may serve as mediators, offering novel insights into the etiology, pathogenesis, and potential clinical interventions in AD. Nevertheless, these findings need to be validated by clinical and laboratory studies.

Brain structures as potential mediators of the causal effect of COVID 19 on migraine risk.

Migraine is a common neurological disorder observed after coronavirus disease 2019 (COVID 19) infection. However, the intricate relationship between COVID 19 and migraine, particularly the potential mediating role of brain imaging-derived phenotypes (BIPs), remains unclear. This study used linkage disequilibrium score regression (LDSC), a bidirectional two-sample Mendelian randomization (MR) approach, and two-step MR analysis to investigate potential causal links. The robustness of the MR findings was corroborated through generalized summary-data-based Mendelian randomization (GSMR) and MR-Steiger methods. The results of the LDSC analysis revealed that the genetic correlation coefficient between COVID 19 traits and migraine was 0.0277 for infection (P = 0.0051), 0.1690 for hospitalization (P = 0.0016), and 0.1147 for severity (P = 0.0330). The genetic correlation coefficients between COVID 19 infection, hospitalization, severity and migraine and migraine with aura (MA) were 0.2654 (P = 0.0012), 0.2065 (P = 0.0043), and 0.1537 (P = 0.0230), respectively. Two-sample MR analysis revealed a significant causal association of COVID 19 infection (odds ratio [OR] 1.2502, P = 0.0083; OR 1.4956, P = 0.0084), hospitalization (OR 1.0689, P = 0.0138; OR 1.0919, P = 0.0208), and severity (OR 1.0644, P = 0.0072; OR 1.0844, P = 0.0098) with increased risk of migraine and migraine with aura (MA). Cortical thickness (CT), total surface area (TSA), and fractional anisotropy (FA) were identified as BIP intermediaries in the risk trajectory from COVID 19 to migraine. The TSA exhibited a more pronounced mediating effect than did CT. This study revealed that genetically predicted COVID 19 is associated with an increased risk of migraine and MA, and BIPs act as potential mediators of these causal relationships, offering insights into the neurobiological underpinnings of migraine in the context of COVID 19.

Causal relationship between immune cells and Guillain-Barré syndrome: a Mendelian randomization study

ObjectiveThe aim of this study was to investigate the causal effect of immune cell phenotype on GBS using two-sample Mendelian randomization (MR) approach.MethodsThis study used MR to investigate the causal relationship between 731 immune cell phenotypes and GBS. We used Inverse variance weighted, Weighted median, MR Egger, Simple mode, Weighted mode for MR analysis. We also used the Cochran Q test, MR-Egger intercept test, IVW regression and MR-PRESSO, leave-one-out analysis to assess the presence of horizontal pleiotropy, heterogeneity and stability, respectively.ResultsOur study revealed a causal relationship between 33 immune cell phenotypes and GBS. Twenty immunophenotypes were observed to be associated with GBS as risk factors. For example, CD20 on IgD+ CD38dim in the B cell group (OR = 1.313, 95%CI:1.042–1.654, p = 0.021), CD3 on CD4 Treg in Treg cell group (OR = 1.395, 95%CI:1.069–1.819, p = 0.014), CD3 on TD CD8br in Maturation stages of T cell group (OR = 1.486, 95%CI:1.025–2.154, p = 0.037), CD16 on CD14+ CD16+ monocyte in Monocyte group (OR = 1.285, 95%CI:1.018–1.621, p = 0.035), CD33dim HLA DR+ CD11b + %CD33dim HLA DR+ in Myeloid cell group (OR = 1.262, 95%CI:1.020–1.561, p = 0.032), HLA DR+ NK AC in TBNK cell group (OR = 1.568, 95%CI:1.100–2.237, p = 0.013). Thirteen immune phenotypes are associated with GBS as protective factors. For example, CD19 on PB/PC in the B cell group (OR = 0.577, 95%CI:0.370–0.902, p = 0.016), CD4 Treg AC in Treg cell group (OR = 0.727, 95%CI:0.538–0.983, p = 0.038), CD11c + monocyte %monocyte in cDC group (OR = 0.704, 95%CI:0.514–0.966, p = 0.030), CX3CR1 on CD14+ CD16− monocyte in Monocyte group (OR = 0.717, 95%CI:0.548–0.939, p = 0.016), Mo MDSC AC in Myeloid cell group (OR = 0.763, 95%CI:0.619–0.939, p = 0.011), CD45 on granulocyte in TBNK group (OR = 0.621, 95%CI:0.391–0.984, p = 0.042).ConclusionThe findings suggest that certain specific immune cell phenotypes, particularly B cell and Treg cell subpopulations, are causally associated with GBS, providing potential targets for the clinical treatment of GBS.

Effect of the Intake of Solid Block Dairy Products Like Cheese on Serum Uric Acid in Children: A Preliminary Mechanistic Investigation

Objective: This study aimed to investigate the relationship between the intake of solid block dairy products like cheese and serum uric acid levels, along with its potential physiological mechanisms. Methods: Data for our study were obtained from the Chinese Children and Lactating Women Nutrition and Health Surveillance. Generalized linear models and restricted cubic splines were employed to analyze the relationship between the intake of solid block dairy products like cheese and serum uric acid levels. Two-sample Mendelian randomization (TSMR) analysis was conducted to infer causality, based on a large sample size and robust methodology. Gene Ontology (GO) enrichment analysis was also performed to identify potential biological pathways. Results: Among all types of dairy products, a significant negative association with serum uric acid levels was observed only for the intake of solid block dairy products like cheese, regardless of covariate adjustment (β = −0.182, p < 0.001). TSMR results supported a negative causal relationship between cheese intake and serum uric acid levels (β = −0.103, 95% CI: −0.149 to −0.057; p = 0.002). The JAK-STAT signaling pathway and autophagy regulation were identified as potential physiological mechanisms underlying this relationship. Conclusions: The intake of solid block dairy products like cheese was found to result in decreased levels of serum uric acid, with potential mechanisms involving the JAK-STAT signaling pathway and the regulation of autophagy.

Depression and the risk of fibromyalgia syndrome: a two-sample Mendelian randomization study

BackgroundFibromyalgia (FM) is a common illness with a wide range of symptoms, mainly manifested by unexplained chronic systemic musculoskeletal pain, sleep disorders and fatigue, sometimes accompanied by cognitive impairment, psychiatric symptoms and autonomic dysfunction. Previous studies have indicated a correlation between depression and the risk of FM; however, it remains uncertain whether this association reflects a causal relationship.MethodsWe evaluated the etiological association between the genetically predicted depression and the risk of developing FM by conducting a two-sample Mendelian Randomization (MR) study. The data on single nucleotide polymorphisms (SNPs) related to depression were obtained from the UK Biobank (UKB) and the Psychiatric Genomics Consortium (PGC) of White British European ancestry, and the data for FM were from the 5th release of the FinnGen study. We adopted the Inverse Variance Weighted (IVW) approach as the principal standard. In order to detect the existence of horizontal pleiotropy and heterogeneity, we adopted the MR-Egger approach as the sensitivity analysis.ResultsIn our MR analysis, 42 depression-related variants were identified as valid instrumental variables (IVs). The IVW approach’s results manifest that there is no etiologic causality between genetically predicted depression and the risk of FM (odds ratio [OR]: 1.673, 95% confidence interval [CI]: 0.852—3.287, P = 0.135). The study did not find any significant heterogeneities or horizontal pleiotropies (P > 0.05).ConclusionsOur results suggest that there is no significant genetic evidence linking depression to an increased risk of FM. However, further research is necessary to investigate the potential relationship and underlying mechanisms between depression and the risk of FM.

Abstract 4145812: Cardiovascular MRI-Derived Cardiac Age Acceleration is Associated with Shortened Leukocyte Telomere Length But Not Clonal Hematopoiesis of Indeterminate Potential

Introduction: Cardiac structure and function typically decline with age. Abnormal acceleration of this decline, known as cardiac age acceleration, can be estimated from MRI using deep learning. Both general and cardiac-specific mechanisms may contribute to cardiac aging. Longer telomere length in circulating leukocytes, which indicates greater cellular capacity for replication, has been associated with a lower risk of heart failure and more favorable cardiac structure and function Recent data have also suggested that longer telomeres contribute to risk of clonal hematopoiesis of indeterminate potential (CHIP), which has been linked to increased risk of atherosclerosis, heart failure and arrhythmia. Here we studied whether telomere length or CHIP status are associated with deep learning derived cardiac age acceleration. Methods: We developed a deep learning model to estimate cardiac age acceleration in 70,805 UK Biobank participants from the cardiovascular MRI (four-chamber long axis view). Of these, we identified leukocyte telomere length (LTL) in 61,554 and were able to evaluate CHIP in 61,636. In an additional 372,465 participants unrelated to those with imaging, a genome-wide association study (GWAS) was conducted for LTL, and a GWAS of cardiac age acceleration was conducted in those with imaging; using these, a two-sample Mendelian randomization (MR) was performed to identify putatively causal relationships. Results: In the 61,636 participants with both CHIP and cardiac age acceleration measurements, CHIP was not associated with cardiac age acceleration regardless of driver gene (p=0.79). In contrast, cardiac age acceleration was associated with a shorter LTL (Beta=-0.025 SD, p=5.4E-10). Shorter LTL was causally associated with cardiac age acceleration (Beta=-0.10, p=0.047). Conclusions: These data suggest that general aging mechanisms conferred by shortening telomeres may contribute to the age-associated structural and functional decline of the heart as observed with MRI. In comparison, the relationship between CHIP and cardiovascular risk may not manifest in ways that cause apparent cardiac age acceleration.

Abstract 4135307: Integrating genomics and proteomics to identify causal proteins and biologic pathways for incident atrial fibrillation in chronic kidney disease

Introduction/ Background: Individuals with chronic kidney disease (CKD) are at an increased risk for developing atrial fibrillation (AF). Research Objective: By integrating genomics and proteomics, we sought to identify proteins and biologic pathways causally linked to the development of AF in the CKD population. Methods / Approach: We measured 4638 unique plasma proteins using SomaScan v.4.0 in participants (ppts) with CKD and no prior AF from 2 cohorts: Chronic Renal Insufficiency Cohort (CRIC, n=2654) and Atherosclerosis Risk in Communities Cohort (ARIC, n=1326). Associations of individual proteins with incident AF were analyzed using Cox regression after adjustment for demographics, comorbidities, and kidney function. Among proteins independently associated with incident AF in both cohorts, we tested for causality using two-sample Mendelian Randomization (MR). Previously published genome wide association studies (GWAS) were used to identify both protein quantitative loci (cis-pQTL) and summary statistics for incident AF. We then used Ingenuity Pathway Analysis to compare proteins and pathways associated with both incident AF and an increase in left atrial (LA) size across serial echocardiograms in CRIC. Results / Data: Over the 5-year analytic period, incident AF occurred in 150 ppts from CRIC and 140 ppts from ARIC. Eight proteins were independently associated with AF in both cohorts: NT-proBNP, SVEP1, TAGLN, TFF3, WAP4, MMP-12, CILP2 and NELL-1. Of these, 3 were significant in MR analysis (Figure 1): CILP2 and MMP-12 maintain structural integrity of the extracellular matrix in the heart and modulate the fibrotic response; NELL-1 is responsible for cell signaling in kidney disease and cardiovascular development. In addition, leading biologic pathways implicated in both development of AF and increase in LA size included systemic fibrosis (p=1.7x10 -4 for AF and 2.3 x10 -4 for LA); regulation of insulin-like growth factor (p=2.3 x10 -4 for AF and p=4.3 x10 -7 for LA) and extracellular matrix degradation (p=5.5 x10 -4 for AF and p=4.2 x10 -4 for LA). Conclusions: Trans-omics analyses identified 3 proteins causally associated with developing AF in the CKD population. Also, several pathways involved with cardiac remodeling and fibrosis are common to the development of AF and LA remodeling.

Abstract 4116714: Macrophage Colony Stimulating Factor as a Causal Metabolic Mediator of Cardiovascular Disease: An Observational and Mendelian Randomization Analysis

Background: Macrophage biology plays a key role in the pathogenesis of atherosclerosis and circulating macrophage colony-stimulating factor (M-CSF) is a marker of macrophage activity. However, there is conflicting evidence regarding its role as a mediator of cardiovascular disease. Methods: We evaluated the association between plasma M-CSF concentration with myocardial infarction, stroke, heart failure and mortality in a large substudy involving 9992 participants drawn from 14 countries and followed for a median period of 9.8 years (Interquartile Range 8.9 years - 11.4 years) utilizing a nested case-cohort design in the Prospective Urban Rural Epidemiology (PURE) study. We then conducted a two-sample Mendelian randomization (MR) analysis to evaluate the upstream determinants (using genome wide association data from the PURE biobank and publicly available consortia) and downstream effects on clinical events.. Results: The strongest causal upstream determinant of M-CSF concentration was body mass index (BMI), which showed a positive association with plasma M-CSF concentration (Beta: 0.17 SD increase; 95% CI: 0.08 - 0.27). In a survival analysis, M-CSF was independently associated with increased incident myocardial infarction (HR: 1.25 per 1 SD M-CSF increase; 95% CI: 1.13-1.38), stroke (HR: 1.17; 95% CI:1.04-1.32), and heart failure (HR: 1.34; 95% CI: 1.15-1.56) and other cardiovascular disease risk factors. Circulating M-CSF concentration also showed a strong association with long-term risk of overall mortality (HR: 1.44; 95% CI: 1.39-1.60). Mendelian randomization analyses confirmed that increased M-CSF was associated with increased risk of MI, heart failure, and ischemic stroke (specifically large artery atherosclerotic and cardioembolic stroke). Conclusions: M-CSF is a strong causal driver of cardiovascular disease morbidity whose concentration is causally influenced by body mass index. Our analysis suggests a role for macrophage activity in mediating the relationship between body mass index and cardiovascular disease outcomes.

Causal links of human serum metabolites on the risk of prostate cancer: insights from genome-wide Mendelian randomization, single-cell RNA sequencing, and metabolic pathway analysis

BackgroundRecently, serum metabolites have shown potential in predicting survival outcomes and may be related to the pathogenesis of prostate cancer. Nevertheless, the precise impact concerning the genetic effect of metabolites on prostate cancer risk remains obscure. In this context, we conducted a Mendelian randomization (MR) study aiming to explore the causality between genetically determined metabolites and the risk of prostate cancer.MethodsWe conducted a two-sample MR analysis aiming to identify the underlying metabolites associated with prostate cancer. Exposure information was obtained from the largest metabolome-based genome-wide association (GWAS) data containing 7,824 Europeans. Genome-wide association analysis was utilized to detect instrumental variables (IVs) for metabolites. We applied the inverse-variance weighted (IVW) approach as the primary method, and to augment the reliability and robustness of our findings, additional analysis methods encompassing weighted median, MR-Egger, and leave-one-out analysis were utilized. MR-Egger intercept test was implemented to explore the pleiotropy. Cochran’s Q test was utilized to quantify the degree of heterogeneity. Additionally, we performed metabolic pathway analysis and single-cell RNA sequencing analysis.ResultsWe found that three serum metabolites were causally associated with prostate cancer after utilizing rigorous screening standards. Utilizing single nucleotide polymorphisms as IVs, a 1-SD increase in fructose was associated with 77% higher risk of prostate cancer (OR:1.77, 95%CI: 1.05-2.97, PIVW=0.031), a 1-SD increase in N1-methyl-3-pyridone-4-carboxamide was associated with 29% higher risk of prostate cancer (OR:1.29, 95%CI: 1.05-1.58, PIVW=0.017), and a 1-SD increase in 12-hydroxyeicosatetraenoate (12-HETE) was associated with 18% higher risk of prostate cancer (OR:1.18, 95%CI: 1.07-1.31, PIVW=0.0008). Metabolites that were causally linked to the risk of prostate cancer were mainly enriched in the valine, leucine and isoleucine biosynthesis pathway (P=0.026) and the nicotinate and nicotinamide metabolism pathway (P=0.048).ConclusionsOur MR analysis provided suggestive evidence supporting the causal relationships between three identified serum metabolites and prostate cancer, necessitating further investigation to elucidate the underlying mechanisms through which these blood metabolites and metabolic pathways may impact the initiation and progression of prostate cancer.

Causal impact of gut microbiota on five liver diseases: insights from mendelian randomization and single-cell RNA sequencing

BackgroundLiver disease is among the top ten causes of death globally. With studies suggesting a link between gut microbiota (GM) and liver disease.MethodWe selected summary statistics data from the largest available whole-genome association study (n = 13,266) of GM by the MiBioGen consortium as the exposure, and obtained liver disease-related data from IEU Open GWAS and The NHGRI-EBI GWAS Catalog. A two-sample Mendelian Randomization (MR) analysis employing various methods, to establish the causal relationship between GM and five liver diseases. Meanwhile, single-cell RNA sequencing data were used to examine Prevotella-related genes expression under healthy and disease liver.ResultsThe IVW analysis indicate a causal relationship between GM and liver diseases, with Prevotella exhibiting a protective effect in all five liver diseases: Alcoholic liver disease (OR:0.81,95% confidence interval:0.66-1.00,PIVW = 0.0494); Cirrhosis (OR: 0.85,95% confidence interval: 0.73-0.99,PIVW = 0.0397); Hepatic failure, not elsewhere classified (OR:0.60,95% confidence interval:0.37-0.95,PIVW = 0.0305); Benign neoplasm:Liver (OR:0.39,95% confidence interval:0.2-0.75,PIVW = 0.0046); Malignant neoplasm of liver, primary (OR:0.41, 95% confidence interval:0.18-0.93,PIVW = 0.0334). The single-cell results suggest differential expression of Prevotella-related genes between liver disease patients and healthy individuals.ConclusionOur MR results show a causal relationship between the GM and liver disease. Prevotella displays a notable protective effect. This finding may enhance the precision of GM-based therapies and offer new insights for clinical research.

A causal association between obesity and constipation: a two-sample bidirectional Mendelian randomization study and meta-analysis

ObjectiveObservational studies suggest a potential link between obesity and constipation, but existing results are conflicting. Therefore, we conducted a Mendelian randomization (MR) study and meta-analysis to assess the causal relationship between obesity and the risk of constipation.MethodsIn this study, independent genetic variants closely related to constipation were acquired from a genome-wide association study (GWAS) to analyze the relationship between genetically predisposed obesity and the risk of constipation. Waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), and body mass index (BMI) were collected from the GWAS. Then, the causal relationship between constipation and obesity was explored using a two-sample MR study in both directions. The robustness of the results was evaluated using sensitivity analysis. Furthermore, a systemic review and meta-analysis were performed to calculate relative risks (RRs) with corresponding 95% confidence intervals (95% CIs). Subgroup analyses stratified by age and obesity degree were completed. To evaluate whether the current studies were affected by unmeasured confounders, E-values of each study were determined.ResultsIn MR analysis, the incidence of constipation increased with the increase in BMI [inverse variance-weighted (IVW) odds ratio (OR) = 1.138 (1.029, 1.260), p = 0.012]. In addition, constipation was impacted by WC [IVW OR = 1.220 (1.061, 1.402), p = 0.005]. However, there was no evidence that WHR [IVW OR = 1.833 (0.826, 4.065), p = 0.136] or HC [IVW OR = 0.949, (0.836, 1.077), p = 0.415] has a causal effect on constipation. In reverse MR analysis, there was no evidence supporting the causality between constipation and obesity [BMI IVW OR = 1.010 (0.998, 1.022), p = 0.089; WHR IVW OR = 1.000 (0.946, 1.057), p = 0.994; WC IVW OR = 1.008 (0.995, 1.022), p = 0.217; HC IVW OR = 0.996 (0.982, 1.011), p = 0.626]. In the meta-analysis, 14 eligible articles were included, involving 43,488 subjects. According to the results of the meta-analysis, the risk of obesity and overweight significantly increased the risk of constipation [RR = 1.145 (0.952, 1.376)]. This was consistent with the MR analysis results. Moreover, overweight and obesity were significantly related to a higher constipation risk among children [overweight RR = 1.112 (0.943, 1.312); obesity RR = 1.407 (1.282, 1.544)]. Additionally, overweight in adults could decrease the risk of constipation [RR = 0.940 (0.827, 1.068)]. Nevertheless, no significant association was observed between obesity in adults and the risk of constipation [RR = 1.000 (0.768, 1.303)]. Sensitivity analysis revealed the robustness of our findings.ConclusionIn this combined MR study and meta-analysis, obesity is associated with an increased risk of constipation. The MR analysis demonstrates the causal relationship between genetically predisposed obesity and the risk of constipation. More research is required to investigate the potential correlation between obesity and the risk of constipation and associated mechanisms.

A Comprehensive Mendelian Randomization Study Investigating Multiple Exposures and Outcomes: Focusing on Nontoxic Goitre and Type 2 Diabetes Mellitus.

Previous research suggests a correlation between nontoxic goitre and type 2 diabetes mellitus (T2DM). However, the causality was vulnerable to confounding variables. Therefore, there is an urgent need for a more rigorous research approach to examine the causal connection between nontoxic goitre and T2DM. Multiple exposures and outcomes two-sample Mendelian randomization (MR) study was carried out in two stages: nontoxic goitre traits (including nontoxic diffuse goitre, NDG; nontoxic multinodular goitre, NMG; and other/unspecified nontoxic goitre, OUNG) were investigated as exposure while T2DM was investigated as an outcome in the first step, whereas the second step was reversed. The GWAS summary data for nontoxic goitre traits and T2DM were collected from the Finngen database. The summary data for fasting glucose, fasting insulin, and HbA1c were obtained from the open GWAS database established by the MRC Integrated Epidemiology Unit (IEU). The inverse-variance weighted (IVW) approach was used to obtain MR estimates, and various sensitivity analysis was also performed. NDG had a potential protective causal relationship with T2DM (OR = 0.978; 95% CI: 0.957-0.998; p = 0.034) and fasting glucose (OR = 0.995; 95% CI: 0.990-0.999; p = 0.011), while NMG had a potential protective causal relationship with T2DM (OR = 0.941; 95% CI: 0.902-0.982; p = 0.008) and HbA1c (OR = 0.992; 95% CI: 0.986-0.998; p = 0.015). OUNG was found to decrease the odds of T2DM by 4.4% (OR = 0.966; 95% CI: 0.938-0.995, p = 0.023). T2DM had a potential causal relationship with NDG (OR = 1.239; 95% CI: 1.020-1.504; p = 0.031), and a potential protective effect against NMG (OR = 0.669; 95% CI: 0.566-0.792; p < 0.001) and OUNG (OR = 0.694; 95% CI: 0.545-0.883; p = 0.004). There was no evidence of a positive association between glycemic traits and nontoxic goitre traits (p > 0.05). Our findings indicate a potential causal relationship between nontoxic goitre traits and T2DM. Specifically, our study addresses that NMG and T2DM may have a significant causal effect on each other in both directions.

Shared genetic architecture of psychiatric disorders and hemorrhoidal disease: a large-scale genome-wide cross-trait analysis

BackgroundThe genetic association between psychiatric disorders and hemorrhoidal disease (HEM) is still not well known. The work aims to investigate their comorbidity at a genetic level.MethodsUtilizing recent large-scale genome-wide association studies (GWAS), we investigated the genetic overlap at the single nucleotide polymorphism (SNP), gene, and molecular level between depression and HEM, bipolar disorder (BD) and HEM, neuroticism and HEM, as well as schizophrenia (SCZ) and HEM. The cross-trait genes were validated through the utilization of transcriptome and proteome methodologies. The causal link was assessed using bidirectional two-sample Mendelian randomization analysis (MR) analysis. MRlap corrects for the potential bias in estimation caused by sample overlap.ResultsWe discovered significant positive genetic associations between these four types of psychiatric disorders and HEM. Cross-phenotypic association analyses identified shared SNPs along with 17 specific loci between psychiatric disorders and HEM. MAGMA identified a total of 2304 pleiotropic genes, several of which showed significant expression in the results of transcriptome and proteome analyses. We observed that these genes are mostly associated with the regulation of transcription factors and particular DNA binding activities. Lastly, MR analysis provided evidence supporting a correlation between these conditions.ConclusionThis study revealed a genetic correlation between four psychiatric disorders and HEM, identified pleiotropic loci, found multiple candidate genes, and confirmed causal relationships. This has enhanced our comprehension of the common genetic mechanisms of psychiatric disorders and HEM.

Causal association of plasma n-3 PUFA with peptic ulcer disease: a two-sample Mendelian randomisation study.

Dietary n-3 PUFA may have potential benefits in preventing peptic ulcer disease (PUD). However, data from observational epidemiological studies are limited. Thus, we conducted a Mendelian randomisation analysis to reveal the causal impact of n-3 PUFA on PUD. Genetic variants strongly associated with plasma levels of total or individual n-3 PUFA including plant-derived α-linolenic acid and marine-derived EPA, DPA and DHA were enrolled as instrumental variables. Effect size estimates of the n-3 PUFA-associated genetic variants with PUD were evaluated using data from the UK biobank. Per one sd increase in the level of total n-3 PUFA in plasma was significantly associated with a lower risk of PUD (OR = 0·91; 95 % CI 0·85, 0·99; P = 0·020). The OR were 0·81 (95 % CI 0·67, 0·97) for EPA, 0·72 (95 % CI 0·58, 0·91) for DPA and 0·87 (95 % CI 0·80, 0·94) for DHA. Genetically predicted α-linolenic acid levels in plasma had no significant association with the risk of PUD (OR = 5·41; 95 % CI 0·70, 41·7). Genetically predicted plasma levels of n-3 PUFA were inversely associated with the risk of PUD, especially marine-based n-3 PUFA. Such findings may have offered an effective and feasible strategy for the primary prevention of PUD.

Serum vitamin C levels and risk of osteoporosis: results from a cross-sectional study and Mendelian randomization analysis

BackgroundThe role of vitamin C as an antioxidant in guarding against osteoporosis in adults is still debated. This research employs both a cross-sectional study and a two-sample bidirectional Mendelian randomization (MR) analysis to explore how serum vitamin C levels correlate with the incidence of osteoporosis among adults.MethodsIn this study, we utilized data from the National Health and Nutrition Examination Survey (NHANES) database for the years 2003–2006, and 2017–2018 to conduct both a cross-sectional analysis and MR to investigate the relationship between serum vitamin C levels and the risk of osteoporosis in adults. We adjusted our analyses for essential demographic and lifestyle variables, and applied logistic regression techniques. Genetic determinants of vitamin C levels were analyzed through MR, using methods like inverse-variance weighted (IVW) and MR-Egger to assess causality. Statistical computations were carried out in R, incorporating visual tools such as restricted cubic spline curves (RCS) and forest plots to clarify the dose–response dynamics and variations across different subgroups. This study was approved by the NCHS Ethics Review Board, and informed consent was obtained from all participants.ResultsIn our investigation, we analyzed data from 3,940 participants, among whom 291 were diagnosed with osteoporosis. The logistic regression analysis of serum vitamin C quartiles did not indicate a significant trend. The most adjusted model showed a slight, albeit inconsistent, protective effect in the highest quartile (OR = 0.68, 95% CI: 0.47–0.99, P = 0.22). Mendelian randomization, employing methods such as IVW, reinforced the absence of a significant causal relationship between serum vitamin C levels and osteoporosis risk (IVW OR = 1.000, 95% CI: 0.999–1.001, P = 0.601).Subgroup analyses, visualized through forest plots and restricted cubic spline (RCS) curves, supported the primary findings, showing no significant effects or interactions between vitamin C levels and osteoporosis risk across different demographic and lifestyle subgroups. The RCS analysis particularly highlighted a lack of significant non-linear relationships between serum vitamin C concentration and the odds of osteoporosis (P for nonlinear = 0.840).ConclusionsThe cross-sectional study revealed that higher serum vitamin C levels do not consistently correlate with a reduced risk of osteoporosis. Meanwhile, the Mendelian randomization analysis confirmed that there is no genetic evidence to suggest a causal relationship between vitamin C levels and osteoporosis risk. Recent research highlights the polygenic nature of osteoporosis, with genetic predispositions playing a significant role in disease risk. The relationship between serum vitamin C and osteoporosis requires further research. This suggests the need for further investigation into the connection between vitamin C and bone health.

Recurrent aphthous stomatitis and neoplasms of the mouth and pharynx: a two-sample Mendelian randomization study

BackgroundThe association between recurrent aphthous stomatitis (RAS) and neoplasms of the mouth and pharynx (NOMAP) has been reported in some previous observational studies. However, causality is still confused. Our research aims to explore the relationship between RAS and NOMAP through a Mendelian randomization (MR) analysis and to explore whether RAS can serve as a risk factor for NOMAP to provide a reference for the clinical strategy.MethodsAn exposure dataset for RAS were collected from a published study based on the UK Biobank (UKB). Outcome datasets included Genome-wide association studies (GWAS) summary statistics of NOMAP from the FinnGen datasets. The core method was inverse variance weighting (IVW). The Bonferroni correction, MR-Egger, weighted median, weighted mode, Cochcan’s Q test, MR-PRESSO, and leave-one-out methods served as complementary methods.ResultsWe found no significant evidence of causal relationships between RAS and NOMAP. After applying the Bonferroni correction, the corrected P was equal to 0.00625 (0.05/1/8). The IVW method provided the sole evidence for RAS on Benign neoplasm of floor of mouth (BNFM) (OR = 2.509, 95% CI: 1.296–4.857, P = 0.006), but the subsequent MR-Egger regression method showed that this result may be due to horizontal pleiotropy (P = 0.035). The Cochran Q-test, MR-Egger regression, and MR-PRESSO did not reveal any heterogeneity or directional pleiotropy for the other outcomes.ConclusionsIn conclusion, this is the first MR analysis to investigate the relationship between RAS and NOMAP. Our research confirmed at the genetic level that no causal association has been identified between RAS and NOMAP, therefore facilitating a logical therapeutic perspective and the development of clinical therapies for them.

Causal effects of Parkinson's disease on the risk of osteoporosis: A two-sample Mendelian randomization study.

Employing a two-sample Mendelian randomization (MR) analysis, we aimed to investigate the potential causal effect of Parkinson disease (PD) on osteoporosis. We conducted an in-depth MR analysis by leveraging extensive genome-wide association study datasets from the International Parkinson Disease Genomics Consortium and the Genetic Factors for Osteoporosis Consortium. We meticulously selected instrumental variables based on strict criteria, including significance thresholds, linkage disequilibrium, and the exclusion of confounding single-nucleotide polymorphisms. Our investigation utilized diverse MR methods, including inverse variance weighted, MR Egger regression, weighted median, and MR-PRESSO, to robustly evaluate the causal relationship. Our comprehensive analysis revealed noteworthy associations between PD and distinct measures of bone mineral density (BMD) (forearm BMD, femoral neck BMD, lumbar spine BMD). Specifically, the inverse variance weighted method underscored potential significant relationships between PD and forearm BMD (P = .037; odds ratio [OR], 1.04; 95% confidence interval [CI], 1.00-1.09), femoral neck BMD (P = .034; OR, 1.02; 95% CI, 1.00-1.05), and lumbar spine BMD (P = .043; OR, 1.03; 95% CI, 1.00-1.06). The consistency of results across various methods and sensitivity analyses indicated both robustness and minimal pleiotropy concerns. Through a two-sample MR approach, this study establishes a plausible causal relationship between PD and decreased BMD. The outcomes underscore the urgency of targeted interventions to mitigate bone loss and manage osteoporosis in individuals with PD.

Investigation of the Association Between Hyperlipidemia and Ossification of The Posterior Longitudinal Ligament Through Two-Sample Mendelian Randomization Analysis.

A Two-Sample Mendelian Randomization Analysis. This study aimed to investigate the association between genetically predicted hyperlipidemia and ossification of the posterior longitudinal ligament (OPLL) using two-sample Mendelian randomization (MR) analysis. Several observational studies suggested associations between hyperlipidemia and OPLL. Genome-wide association study (GWAS) summary statistics for hyperlipidemia and OPLL were retrieved from the public database. The MR analysis employed the Inverse Variance Weighted (IVW) method, which was supplemented by MR-Egger, weighted median, and weighted mode analyses. Sensitivity analyses, incorporating Cochran's Q test, MR-Egger regression and the MR pleiotropy residual sum and outlier test, additionally assessed the robustness of the findings. The IVW analysis revealed a significant association between total cholesterol levels and OPLL (OR: 1.44,95% CI:1.06-1.96, P=0.02). Similarly, a significant association was observed between LDL cholesterol and OPLL (OR: 1.31,95%CI:1.05-1.63, P=0.02). Supplementary analyses further supported the significant association of total cholesterol levels and LDL cholesterol on OPLL (P <0.05). In sensitivity analyses, LDL cholesterol exposure showed robust results, with no outliers detected by loo or mrpresso, despite MR-Egger hints at pleiotropy. For total cholesterol exposure, MR-Egger suggested no pleiotropy, though heterogeneity and outliers were present. Outlier removal confirmed the initial positive association, underlining study stability. However, no significant associations were found of hyperlipidemia, triglycerides, HDL cholesterol on OPLL. This study suggests a association of total cholesterol levels and LDL cholesterol levels on OPLL. Further research is warranted to validate these findings and explore potential therapeutic implications.

Effect of L-Carnitine Level on the Risk of Neuromyelitis Optica Spectrum Disorders: A Two-Sample Mendelian Randomization Study.

Previous research has often focused on studying the CNS damage in neuromyelitis optica spectrum disorders (NMOSD), while the role of the peripheral blood in the development of NMOSD is also of significant importance. The relationship between metabolites in blood and cerebrospinal fluid (CSF) with neuroimmune is receiving increasing attention. L-carnitine, whose astrocytic accumulation is associated with neuroinflammation and demyelination, may participate in the pathogenesis of NMOSD. However, whether circulating L-carnitine level has a causal effect on NMOSD risk needs elucidation. With large data sets now available, we used two-sample Mendelian randomization (MR) to determine whether circulating L-carnitine level is causally associated with the risk of NMOSD. Genetic variants associated with circulating L-carnitine levels were derived from a genome-wide association study (GWAS) of 7797 individuals from TwinsUK and KORA F4 cohorts. NMOSD summary statistics, including 215 cases and 1244 controls, were obtained from a separate GWAS. Subgroup analyses included aquaporin-4 (AQP4)-IgG-seropositive NMOSD (132 cases) and AQP4-IgG-seronegative NMOSD (83 cases). We used two-sample MR to explore associations between circulating L-carnitine levels and NMOSD risk, as well as its seropositive and seronegative subtypes. 16 SNPs (single nucleotide polymorphisms) were significantly associated with circulating L-carnitine level (P < 5 × 10-8), all of which were independent and available in the NMOSD dataset, after 1 SNP removed for being palindromic with intermediate allele frequencies in harmonization. Finally, a high circulating L-carnitine level conferred a protective effect against combined NMOSD (OR = 2.216 × 10-4, 95% confidence interval [CI] = 2.335 × 10-7-2.104 × 10-1, P = 0.0161) as well as AQP4-IgG-seronegative NMOSD (OR = 7.678 × 10-7, 95% CI = 2.233 × 10-11-2.640 × 10-2, P = 0.0082). There is no causal effect on AQP4-IgG-seropositive NMOSD risk (OR = 5.471 × 10-3, CI = 1.090 × 10-6-27.465, P = 0.2798) by circulating L-carnitine. Results remained positive and robust after the horizontal pleiotropy test, heterogeneity test, and Bonferroni test. In the reverse MR analysis, there was no causal effect of NMOSD and its subtypes on circulating L-carnitine levels. Our findings suggest that higher circulating L-carnitine levels may reduce the risk of NMOSD, particularly in AQP4-IgG-seronegative patients. L-carnitine could serve as a valuable biomarker and potential therapeutic target for NMOSD, especially in cases without AQP4-IgG. The genetic evidence from this study supports further exploration of L-carnitine's role in managing NMOSD.

Exploring causal associations between dietary intake and liver diseases: A bidirectional Mendelian randomization study.

Previous evidence suggests that dietary intake can affect liver diseases; However, the causal relationship between dietary intake and liver diseases remains unclear. To investigate this, we conducted a bidirectional Mendelian randomization (MR) analysis to comprehensively assess the potential causal relationship between dietary intake and liver diseases. Two-sample bidirectional MR was performed based on genome-wide association studies summary data from the UK Biobank and FinnGen database. The primary analysis method for evaluating causal relationships was inverse-variance weighted. Supplementary analyses included MR-Egger and weighted median methods. Subsequently, sensitivity analyses were performed using Cochran Q test, MR-Egger intercept test, MR-PRESSO, RadialMR, and leave-one-out analysis to assess heterogeneity and horizontal pleiotropy. MR evidence indicated that genetically predicted poultry intake (adjusted odds ratio [OR] = 0.04, 95% confidence interval [CI] = 0.00-0.43, P = .007) and salad/raw vegetable intake (adjusted OR = 0.18, 95% CI = 0.04-0.83, P = .028) were directly associated with a reduced risk of cirrhosis. Conversely, there is no causal association between dietary intake and nonalcoholic fatty liver disease, alcoholic liver disease, or hepatocellular carcinoma. This study provides evidence supporting the impact of dietary intake on liver disease. Increased intake of poultry and salad/raw vegetables is associated with a reduced risk of cirrhosis. These findings can inform preventive and therapeutic strategies for cirrhosis.