Hypertensive disorders of pregnancy (HDPs), which include gestational hypertension (GH) and preeclampsia (PE), are the primary causes of maternal morbidity and mortality worldwide. Recent studies have found a correlation between metabolic dysfunction-associated steatotic liver disease (MASLD) and HDPs, but the causality of this association remains to be identified. Therefore, this study aims to evaluate the causal relationship between MASLD and HDPs through Mendelian randomization (MR) analysis.

The summary statistics from genome-wide association studies were employed to conduct a two-sample MR analysis. Five complementary MR methods, including inverse variance weighting (IVW), MR-Egger, weighted median, simple mode and weighted mode were performed to assess the causality of MASLD on GH and PE. Furthermore, we conducted various sensitivity analyses to ensure the stability and reliability of the results.

Genetically predicted MASLD significantly increased the risk of GH (IVW: OR = 1.138, 95% CI: 1.062-1.220, p < 0.001), while there was little evidence of a causal relationship between MASLD and PE (IVW: OR = 0.980, 95% CI: 0.910-1.056, p = 0.594). The sensitivity analyses indicated no presence of heterogeneity and horizontal pleiotropy.

This MR study provided evidence supporting the causal effect of MASLD on GH. Our findings underscore the significance of providing more intensive prenatal care and early intervention for pregnant women with MASLD to prevent potential adverse obstetric outcomes.

Identifying risk factors for disease onset and progression has been a core focus in nephrology research. Mendelian Randomization (MR) has emerged as a powerful genetic epidemiological approach, utilizing genome-wide association studies (GWAS) to establish causal relationships between modifiable risk factors and kidney disease outcomes. MR uses genetic variants as instrumental variables to infer causal relationships between exposures and disease outcomes. This method leverages the natural randomization of genetic variants to balance confounders, akin to matched cohorts in observational research. The rapid increase in MR studies on kidney disease poses challenges for journals and peer reviewers, especially clinicians unfamiliar with the methodology. High-quality MR studies use strong, well-validated genetic instruments with clear biological relevance, thoroughly testing for pleiotropy and confounding factors using methods like MR-Egger. Sensitivity analyses, such as MR-PRESSO, should ensure findings remain consistent across various assumptions. Effect sizes with confidence intervals should be reported and discussed within established biological mechanisms. Additionally, limitations must be transparently addressed, with recommendations for replication in future studies, to strengthen findings. This article guides readers in understanding MR application in nephrology and identifying high-quality MR studies, helping peers avoid pitfalls while seizing new opportunities in advancing kidney disease research.

This study seeks to elucidate the association between depression and the risk of chronic obstructive pulmonary disease (COPD) by Mendelian randomization (MR) analysis, motivated by prior observational studies indicating a potential link between these conditions.

Data from individuals of European (EUR) and East Asian (EAS) ancestries diagnosed with major depressive disorder (MDD) were selected for analysis. The primary method utilized was inverse variance weighted (IVW) method, supplemented by a series of sensitivity analyses and false discovery rate (FDR) corrections. Subsequently, multivariable and mediation MR analyses were conducted to assess the impact of potential confounders and their mediating effects.

IVW revealed a significant causal relationship between MDD and COPD within EUR ancestry (OR 1.425, 95 % CI 1.243-1.633, P = 3.56 × 10-7, PFDR = 2.14 × 10-6). Additionally, replication datasets provided consistent evidence for these causal associations. Multivariable and mediation MR analyses identified gastroesophageal reflux disease (GORD) as a complete mediator (mediation effect: 98.97 %, P = 1.38 × 10-15), while smoking initiation (SI) (26.30 %, 5.54 × 10-9), age of smoking initiation (ASI) (18.73 %, 0.019), and cigarettes per day (CPD) (18.72 %, 0.004) were identified as partial mediators of this causal relationship. No causal association was detected in EAS ancestry, nor was reverse analysis.

This study established a causal relationship between MDD and COPD risk in EUR ancestry, identifying GORD and smoking as pivotal mediators. Future research involving larger cohorts is essential to validate the generalizability of these findings across other ancestries.

Several studies have identified biomarkers that help in the prevention, diagnosis, and treatment of psychiatric disorders. The current study aimed to explore the association between circulating branched-chain amino acids (BCAA) and the risk of five psychiatric disorders.

GWAS summary statistics were obtained from the UK Biobank and the FinnGen Biobank. The inverse variance weighted (IVW) method was used as a primary method to assess causal effects. The heterogeneity test, the horizontal pleiotropy test, and leave-one-out analysis were used to assess the robustness and reliability of the results.

Total BCAA levels were not significantly associated with the risk of anxiety disorders, alcohol dependence, depression, panic disorder, and bipolar affective disorders. Separate analyses for each BCAA showed that the levels of valine and leucine were not associated with the risk of the mentioned five psychiatric disorders, and the levels of isoleucine were not associated with the risk of depression, panic disorder, and bipolar affective disorders, but with the risk of anxiety disorders (IVW: OR = 0.814, 95 %CI = 0.716-0.925) and alcohol dependence (IVW: 0.690, 95 %CI = 0.560-0.849).

Circulating isoleucine was a protective factor for anxiety disorders and alcohol dependence, offering a new research direction and theoretical basis for preventing and managing psychiatric disorders.

Epidemiologic studies and clinical trials have reported inconsistent findings regarding omega-3 fatty acids' protective role in age-related macular degeneration (AMD). We investigated their association in a prospective cohort and examined causality using Mendelian randomization (MR) analyses.

Prospective cohort study and 2-sample MR analyses.

The cohort included 258 350 AMD-free individuals of European descent from the UK Biobank. Mendelian randomization analyses used genome-wide association study data on plasma omega-3 and docosahexaenoic acid (DHA) (UK Biobank, n = 115 006) and AMD (dry, wet, and any; FinnGen, n = 208 690-209 122).

Cox regression assessed the association between plasma omega-3 and DHA levels and AMD incidence, adjusting for systemic covariates and AMD polygenetic risk score (PRS). Interaction effects of AMD genetic risk (PRS, complement factor H and age-related maculopathy susceptibility 2 genotypes), and plasma omega-3 and DHA levels were tested. For MR analyses, we used random-effect inverse-variance weighted model as primary, with 5 sensitivity models. Causality was considered significant if P < 0.05 in the primary model and at least 2 sensitivity models.

Risk of AMD.

Over 12.9 years, 5068 people (1.9%) demonstrated AMD. Higher plasma levels (in millimoles per liter) of omega-3 (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.72-0.95; P = 0.006) and DHA (HR, 0.65; 95% CI, 0.44-0.96; P = 0.029) were associated with lower risk of receiving an AMD diagnosis. Mendelian randomization showed genetic predisposition to higher plasma omega-3 levels reduced the risk of dry AMD (odds ratio [OR], 0.83; 95% CI, 0.73-0.96; P = 0.010), wet AMD (OR, 0.76; 95% CI, 0.65-0.88; P < 0.001), and any AMD (OR, 0.82; 95% CI, 0.74-0.92; P < 0.001). Similar results were found for plasma DHA levels (wet AMD:OR, 0.79; 95% CI, 0.65-0.96; P = 0.017; any AMD: OR, 0.84; 95% CI, 0.72-0.98; P = 0.030). No significant interaction was found between omega-3 and DHA levels and AMD genetic risk (all P > 0.05).

Both the prospective and MR analyses suggest omega-3 and DHA may protect against AMD, supporting the need for further clinical trials to test their effectiveness in AMD prevention and treatment.

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Endocrine diseases are suspected contributors to lymphoid malignancies, but their precise association is unclear. This study aimed to investigate the causal relationship between various endocrine diseases-specifically type 2 diabetes, obesity, diabetic hypoglycemia, hyperlipidemia, and hyperthyroidism-and lymphoid malignancies, including lymphocytic leukemia and non-Hodgkin's lymphoma with subtypes like diffuse large B-cell lymphoma and follicular lymphoma. Utilizing data from genome-wide association studies, a two-sample Mendelian randomization analysis was performed. The primary approach involved the inverse-variance weighted method, supplemented by other robust techniques such as the weighted median and MR-Egger regression to ensure reliability. The analysis indicated a significant causal connection between genetically predicted diabetic hypoglycemia and lymphocytic leukemia (Odds ratio = 1.0004, 95% Confidence interval = 1-1.0007, P = 0.03). Conversely, no associations were found for the other endocrine diseases with lymphoid malignancies (P > 0.05 for all). The findings suggest that while diabetic hypoglycemia may influence lymphocytic leukemia risk, further research is necessary to clarify the roles of other endocrine diseases in lymphoid malignancies, including cross-population validations and biological investigations.

It is an indisputable fact that patients with urolithiasis are prone to osteoporosis (OP), but the specific mechanism of their association is unclear. Previous studies have focused on the mediation of environmental factors such as diet; however, the potential of urolithiasis itself to induce OP remains uncertain.

In this study, we used data from the Japan BioBank (6638 urolithiasis and 7788 OP cases) to investigate the direct causal relationship and mechanism between urolithiasis and OP, applying Mendelian randomization, genetic correlation analysis, colocalization, and pathway analysis. We selected 10 genetic variants as instrumental variables for urolithiasis.

The results showed a positive association between genetically predicted urolithiasis and OP, with significant direct effects persisting after adjusting for OP-associated factors in 4 models. Reverse analysis revealed no significant causal effect of genetically predicted OP on urolithiasis. While genetic correlation analysis and colocalization did not find conclusive evidence, mediation analysis identified estimated glomerular rate as a significant contributor. Co-risk factor analysis unveiled cardiovascular elements as common risks for both conditions. Bioanalysis implicates that cytokine, metabolic, and calcium signaling pathways may bridge urolithiasis and OP, with BCAS3, DGKH, TBX2, and TBX2-AS1 identified as potential causal genes.

In conclusion, the study establishes a direct causal link between urolithiasis and OP, independent of environmental factors. Regardless of lifestyle, urolithiasis patients should remain vigilant about the risk of OP and consider regular OP screening. The biological mechanism of urolithiasis combined with OP and related drugs still needs to be further explored.

A potential association of endogenous circadian rhythm disruption with risk of cancer development has been suggested, however, epidemiological evidence for the association of sleep traits with colorectal cancer (CRC) is limited and often contradictory. Here we investigated whether genetically predicted chronotype, insomnia and sleep duration are associated with CRC risk in males, females and overall and according to CRC anatomical subsites using Mendelian randomization (MR). The two-sample inverse variance weighted (IVW) method was applied using summary-level data in up to 58,221 CRC cases and 67,694 controls and genome-wide association data of genetic variants for self-reported sleep traits. Secondary analyses using alternative instruments and sensitivity analyses assessing potential violations of MR assumptions were conducted. Genetically predicted morning preference was associated with 13% lower risk of CRC in men (ORIVW = 0.87, 95% CI = 0.78, 0.97, P = 0.01), but not in women or in both sexes combined. Τhis association remained consistent in some, but not all, sensitivity analyses and was very similar for colon and rectal cancer. There was no evidence of an association for any other sleep trait. Overall, this study provides little to no evidence of an association between genetically predicted sleep traits and CRC risk.

Mitochondrial dysfunction has been hypothesized to play a role in the etiology of congenital birth defects. However, evidence from observational studies is susceptible to bias and confounding. Mendelian randomization uses genetic variants as instrumental variables to investigate causal relationships. This study aimed to investigate the causal effect of mitochondrial proteins on risk of common congenital defects including orofacial clefts, congenital heart defects, external ear malformations, urinary system malformations, nervous system malformations, and limb malformations.

Summary statistics data on congenital birth defects were obtained from the FinnGen consortium. This included 1,994 cases of congenital heart malformations, 258 cases of nervous system malformations, 185 cases of ear malformations, 813 cases of urinary system malformations, 92 cases of limb malformations, and 181 cases of cleft lip and cleft palate, alongside 216,798 to 218,611 controls, depending on the defect type. Data on genetic variants associated with 66 mitochondrial proteins were extracted from the Human Plasma Proteome Atlas (n = 3,301 healthy individuals). The inverse-variance weighted method was applied as the primary analysis, with sensitivity analyses using MR-Egger regression, weighted median estimation, and MR-PRESSO to assess pleiotropy and outliers.

Among the 66 mitochondrial protein traits examined, several displayed significant associations with congenital birth defects. Negative associations were found between pyruvate dehydrogenase kinase isozyme 1 and ATP synthase subunit beta mitochondrial levels and congenital heart malformation risk. GrpE protein homolog 1 mitochondrial was negatively associated with cleft lip/palate risk. 39S ribosomal protein L14 and GrpE protein homolog 1 mitochondrial showed positive and negative links with urinary malformations, respectively. Positive associations were noted between cytochrome c oxidase subunit 4 isoform 2, protein SCO1 homolog, and tRNA pseudouridine synthase A mitochondrial and nervous system malformations, while peptide chain release factor 1-like mitochondrial was negatively related. Cytochrome c oxidase subunit 7 A1 mitochondrial associated positively with ear malformations. Positive relationships were identified between cytochrome c oxidase subunit 7 A1, ADP-ribose pyrophosphatase, coiled-coil-helix-coiled-coil-helix domain-containing protein 10, NFU1 iron-sulfur cluster scaffold homolog mitochondrial, and limb malformation risk. Meanwhile, NADH dehydrogenase [ubiquinone] iron-sulfur protein 4 mitochondrial displayed a negative association.

This Mendelian randomization study provides evidence that mitochondrial protein levels may be causally implicated in congenital heart, urinary, nervous system, ear, and limb malformations. The findings highlight potential etiological roles for mitochondrial dysfunction in the pathogenesis of structural birth defects. Further large-scale and functional investigations are warranted to corroborate these genetic inference results and elucidate underlying mechanisms that may inform translational applications.

Subjective well-being (SWB) is important for understanding human behaviour and health. Although the connection between SWB and psychiatric disorders has been studied, common genetic mechanisms remain unclear. This study aimed to explore the genetic relationship between SWB and psychiatric disorders. Bivariate causal mixture modelling (MiXeR), polygenic risk score (PRS) and Mendelian randomization (MR) analyses showed substantial polygenic overlap and associations between SWB and the psychiatric disorders. Subsequent replication studies in East Asian populations confirmed the polygenic overlap between schizophrenia and SWB. The conditional and conjunctional false discovery rate analyses identified additional or shared genetic loci associated with SWB or psychiatric disorders. Functional annotation revealed enrichment of specific brain tissues and genes associated with SWB. The identified genetic loci showed cross-ancestry transferability between the European and Korean populations. Our findings provide valuable insights into the common genetic mechanisms underlying SWB and psychiatric disorders.

Although treatment options for B-cell malignancies have expanded, many patients continue to face limited response rates, highlighting an urgent need for new therapeutic targets. To prioritize candidate drug targets for B-cell malignancies, we employed Mendelian Randomization to estimate potentially causal relationships between 445 immune cell traits and six B-cell cancers: follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Hodgkin lymphoma (HL), marginal zone lymphoma (MZL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM), totaling 22,922 cases and 394,204 controls. 163 traits showed a suggestive association with at least one B-cell malignancy (P < 0.05), with 34 traits being significant after correction for multiple testing (P < 2 × 10-4). By integrating findings with observational data and clinical trial evidence to support drug target candidacy, 24 cell surface markers were identified as druggable targets. In addition to established therapeutic targets such as CD3, CD20 and CD38, our analysis highlights BAFF-R and CD39 in HL, CD25 in MM, CD27 in CLL, CD80/86 in DLBCL, and CCR2 in FL and MZL as promising candidates for therapeutic inhibition. Our findings provide further support for the potential of human genetics to guide the identification of drug targets and address a productivity-limiting step.

Immune cells and metabolites significantly impact organism health and disease processes. The interaction between non-small cell lung cancer (NSCLC) and metabolites and immune cells remains underexplored.

To investigate the causal relationships between immune cells, metabolites, and NSCLC, we used Mendelian randomization (MR). The research design comprehensively embraced the direct correlation and the role that metabolites play as an intermediate in the interaction between NSCLC and immune cells.

MR analysis allowed us to finally identify one immune cell, there was a substantial causal connection between CD64 on CD14⁻CD16⁻ and NSCLC. Furthermore, we discovered four metabolites that showed strong causal links to NSCLC: 1-(1-enyl-stearoyl)-2-arachidonoyl-GPE (p-18:0/20:4) levels, phenyllactate (PLA) levels in elite athletes, the caffeine to paraxanthine ratio and 1-palmitoyl-2-arachidonoyl-GPC (16:0/20:4n6) levels. Finally, through a two-step MR mediation analysis, we found that CD64 on CD14⁻CD16⁻ mediated the occurrence of NSCLC via 1-palmitoleoyl-2-linolenoyl-GPC (16:1/18:3) levels and the caffeine to paraxanthine ratio, with mediation proportions of - 11.89% and 21.69%, respectively.

Our findings show the complicated link between immune cells, metabolites, and NSCLC. The discovered connections and mediating effects provide important insights.

Sweeteners have been widely added to food and beverages due to their low-calorie and sweetening properties. However, the role of sweeteners in cancer risk has been a subject of extensive debate over the past few decades.

We aimed to elucidate the causation between the commonly used natural sweetener erythritol and the risk of lung cancer (LC) using Mendelian randomization (MR).

Data on erythritol and its metabolites were obtained from publicly available genome-wide association studies data. Summary data on LC and its subtypes were obtained from a large-scale genetic study conducted by the Transdisciplinary Research of Cancer in Lung of the International Lung Cancer Consortium and the Lung Cancer Cohort Consortium. We conducted independent two-sample MR analyses to assess the causation between erythritol and LC and its subtypes.

The inverse variance weighted method of MR analysis showed no evidence supporting causation between erythritol and LC or its histological subtypes. Sensitivity analysis further supported the results.

Our study findings do not support genetic association between erythritol and LC or its subtypes.

Observational studies have found that cigarette smoking increased the prevalence and incidence of sarcopenia, whereas alcohol consumption appeared to decrease the risk. These findings, however, may be susceptible to either confounding bias or reverse causation. We conducted a Mendelian randomisation (MR) study to appraise the causal relation of cigarette smoking and alcohol consumption to the risk of sarcopenia.

Genetic instruments associated with cigarette smoking (cigarettes per day) and alcohol consumption (drinks per week) were retrieved from the publicly available genome-wide association data. Individual-level, electronic medical record-linked data on sarcopenia, grip strength and appendicular lean mass were obtained from the UK Biobank. We performed two-sample univariable and multivariable MR analyses to examine the relation of genetically determined cigarette smoking and alcohol consumption to the risk of sarcopenia and its indices.

One SD increase of genetically determined cigarette smoking was associated with an increased risk of sarcopenia (OR=2.51, 95% CI: 1.26 to 5.01, p=0.001), decreased grip strength (β=-0.63 kg, 95% CI: -1.13 to -0.13, p=0.01) and less appendicular lean mass (β=-0.22 kg, 95% CI: -0.44 to -0.01, p=0.04). Although one SD increase of genetically determined alcohol consumption was associated with decreased grip strength (β=-1.15 kg, 95% CI: -2.09 to -0.10, p=0.02), no statistically significant causal association was observed between genetically determined alcohol consumption and either sarcopenia (OR=0.96, 95% CI: 0.35 to 2.62, p=0.94) or appendicular lean mass (β=-0.23 kg, 95% CI: -0.91 to 0.45, p=0.51).

Our findings showed that genetically determined cigarette smoking, but not alcohol consumption, was causally associated with the risk of sarcopenia.

Previous observational studies have suggested a potential link between Type 1 Diabetes (T1D) and site-specific cancer risk. However, the nature of this association remains uncertain due to confounding factors, reverse causation, and biases inherent in observational research. To address this gap, we conducted a two-sample Mendelian randomization (MR) study to assess the causal relationship between T1D and 22 site-specific cancers. Using summary statistics from large-scale genome-wide association studies of European ancestry, comprising data on T1D (N = 520,580) and the 22 site-specific cancers, we selected single nucleotide polymorphisms strongly associated with T1D as instruments for our analysis. Causal relationships were primarily evaluated through inverse-variance weighting-based analyses, supplemented by three additional methods: MR-Egger, weighted median, and mode-based estimate. Sensitivity analyses were performed, excluding genetic variants with potential pleiotropic effects. The finding demonstrated a causal association between T1D and increased risks of lung cancer (OR = 1.018, 95% CI 1.004-1.033, p = 0.011), colorectal cancer (OR = 1.022, 95% CI 1.003-1.041, p = 0.019), and prostate cancer (OR = 1.018, 95% CI 1.005-1.030, p = 0.006). Conversely, T1D was associated with decreased risks of breast cancer (OR = 0.989, 95% CI 0.981-0.998, p = 0.016), lymphoma (OR = 0.999, 95% CI 0.974-0.999, p = 0.003), malignant melanoma (OR = 0.999, 95% CI 0.989-0.999, p = 0.001), and non-melanoma skin cancer (OR = 0.999, 95% CI 0.899-0.999, p = 0.003). Our MR study provides an evidence of causal association between T1D and altered risks of various site-specific cancers. Further research is recommended to validate this finding in diverse populations to enhance the generalizability of findings across different ethnic groups.

Preclinical studies have suggested that Annexin A1 and Annexin A2 act as anti-inflammatory agents, slowing the progression of atherosclerosis and further potentially reducing the risk of ischemic stroke. Since the causality of Annexins and ischemic stroke remains uncertain, this study aimed to investigate the causal effects of both using a two-sample Mendelian randomization (MR) method.

The genetic instruments associated with Annexin A1 and Annexin A2 originated from a European-descent genome-wide association study (GWAS) of 50,000 participants from the INTERVAL study. Summary statistics for ischemic stroke and ischemic stroke subtypes were derived from the MEGASTROKE consortium's GWAS dataset, involving 40,585 cases and 406,111 controls of European ancestry. The inverse-variance weighted method was utilized in the main analysis, followed by a series of sensitivity analyses for robustness validation.

In the primary analysis, genetically predicted high Annexin A1 levels were associated with decreased risks of ischemic stroke (OR = 0.96; 95 % CI = 0.93-0.99; p = 0.023) and large artery stroke (OR = 0.88; 95 % CI = 0.81-0.96; p = 0.004). Similarly, genetically predicted high Annexin A2 levels also had significant associations with decreased risks of ischemic stroke (OR = 0.97; 95 % CI = 0.95-1.00; p = 0.019) and large artery stroke (OR = 0.90; 95 % CI = 0.85-0.96; p = 0.001).

In this two-sample MR study, we found that Annexins had causal protective effects against ischemic stroke, especially large artery stroke. Further basic mechanistic studies should be conducted to investigate the biological roles of these genes.

Despite the widespread clinical use of allopurinol for managing hepatocellular carcinoma (HCC) and gout, its potential hepatotoxicity and its effect on the risk of HCC remain unclear. This study aimed to comprehensively assess the potential correlations between allopurinol exposure and HCC risk.

We utilized genome-wide association study data from the IEU OpenGWAS project as instrumental variables (IVs) for Mendelian randomization (MR) analysis to investigate the causal relationship between allopurinol and HCC. Subsequently, we investigated the potential mediating factors (gout, liver fat, and percentage of liver fat, etc.) between allopurinol use and HCC. Furthermore, we analyzed assessed survival outcomes using the Kaplan-Meier method to compare patient subgroups by differential Xanthine dehydrogenase (XDH) expression.

MR analysis established a causal link between allopurinol use and increased HCC risk (OR: 1.013, 95% CI 1.004-1.023, p = 0.006). Causal relationships were also observed between gout (OR: 1.011, p = 0.008) and HCC. Mediation analysis indicated that gout mediated 61.6% of the effect of allopurinol on HCC. Survival analysis showed that higher expression of XDH was associated with improved survival of HCC patients (HR = 0.62, 95% CI 0.441-0.884, p = 0.008), indicating a 38% decrease in mortality risk compared to the lower expression group.

This study demonstrated a causal relationship between allopurinol use and an increased risk of HCC based on genetic evidence. Allopurinol should be used with caution in patients with or at risk for HCC.

Abnormal α-Klotho (KL) levels play an essential role in the pathogenesis of aging-related lung diseases. However, the correlation between circulating KL levels and aging-related lung diseases has not been determined. This study aimed to determine whether circulating KL levels causally affect aging-related lung diseases using Mendelian randomization (MR).

Five KL-associated Single-nucleotide polymorphisms (SNPs) were analyzed using two-sample MR to assess their effects on three aging-related lung diseases: idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and lung cancer.

Based on a main casual effects model with MR analyses by the inverse variance weighted (IVW) method including multiplicative random-effects model (IVW-mre) and fixed-effects inverse variance-weighted model (IVW-fe), genetically predicted circulating KL levels were negatively related with risk of IPF (Odds ratio (ORIVW-mre), 0.999, 95 % CI, 0.999-1.000, PIVW-mre = 0.008; OR IVW-fe, 0.999, 95 % CI, 0.999-1.000, PIVW-fe = 0.042). Inversely, the circulating levels of KL displayed no clear association with COPD and lung cancer. No pleiotropy was detected.

Genetically predicted circulating KL was causally associated with a lower risk of IPF, suggesting a protective effect in preventing IPF risk. Therefore, KL may be a promising target for the prevention and therapeutic intervention in patients with IPF.

Objective: The aim of this study was to explore the causal relationships between chronic pains (back pain, facial pain, general pain, headaches, knee pain, hip pain, neck/shoulder pain, stomach/abdominal pain) and analgesics (codeine, diclofenac, ibuprofen, morphine, paracetamol, tramadol) with telomere length using Mendelian randomization methods. Methods: In the study, various statistical methods including inverse variance weighted (IVW), Mendelian Randomization-Egger, weighted median, simple mode, and weighted mode were used to investigate the relationships between chronic pains, analgesics, and telomere length. Heterogeneity and pleiotropy tests were conducted to ensure the accuracy of the results. Results: The results of the IVW analysis revealed positive causal relationships between hip pain (odds ratio (OR): 1.145; 95% confidence interval (CI): 1.021-1.285; p = .020), and stomach/abdominal pain (OR: 1.100; 95% CI: 1.008-1.200; p = 0.033) with telomere length. Use of tramadol (OR: 0.074; 95% CI: 0.009-0.605; p = 0.015) had a negative causal relationships with telomere length. Conclusion: This study found positive associations between hip pain and stomach/abdominal pain with telomere length, and a negative association between tramadol and telomere length. However, no significant causal relationships were found with other types of chronic pains and analgesics. This could help develop healthier chronic pain treatments, avoiding the abuse of analgesics.

An increasing number of Mendelian randomization (MR) studies have evaluated the causal link between smoking and venous thromboembolism (VTE). However, previous studies often rely on single genetic variants related to smoking quantity and exhibit various other shortcomings, making them prone to pleiotropy and potentially leading to imprecise causal estimates. Thus, the deeper causal mechanisms remain largely unexplored. This MR study reassessed the causal relationship between smoking and VTE, including its subtypes-deep vein thrombosis (DVT) and pulmonary embolism (PE). Data on VTE were sourced from the FinnGen consortium with nonoverlapping sample sizes. The smoking phenotypes analyzed included smoking initiation, lifetime smoking, the number of cigarettes smoked per day by both current and former smokers (CigDay), and total pack-years of smoking in adulthood. The primary analytical method was inverse-variance-weighted (IVW), supplemented by multiple verification methods to ensure robust results. Statistical rigor was ensured through LDtrait pruning and Steiger filtering for reverse causation, with comprehensive sensitivity analyses including RadialMR confirming the findings' robustness. After Bonferroni correction, this study demonstrates significant causal evidence linking lifetime smoking with the incidence of VTE (odds ratio [OR]IVW = 1.50, 95% confidence interval [CI] 1.21-1.85, p = 1.75 × 10-4) and PE (ORIVW = 1.69, 95% CI 1.25-2.28, p = 6.55 × 10-4), and suggestive evidence with DVT, consistent in direction with previous studies but showing considerable differences in effect sizes and significance. Additionally, CigDay (past and current) increases the risks of VTE and DVT, while no causal link was found between smoking initiation and VTE or its subtypes (p < 0.05), both directly contradicting previous conclusions. Furthermore, our study is the first to suggest a causal link between pack-years and an increased risk of VTE. This MR study employed rigorous statistical pruning of its instrumental variables, using the most comprehensive smoking phenotype to date. It successfully mitigated biases such as winner's curse, yielding causal effect results distinct from previous studies.

Patients with type 1 diabetes mellitus have been at heightened risk for developing atrial fibrillation. We aimed to investigate whether this association is causal using Mendelian randomization.

Using publicly available genome-wide association studies data, we selected single nucleotide polymorphisms significantly associated with type 1 diabetes mellitus as instrumental variables. We employed inverse variance-weighted, weighted median, MR-Egger regression, simple mode, and weighted mode methods within a two-sample Mendelian randomization framework to assess the causal relationship between type 1 diabetes mellitus and atrial fibrillation. We evaluated the pleiotropy and heterogeneity levels of the included genetic instruments using MR-PRESSO, MR-Egger intercept test, Cochran's Q test, funnel plots, and leave-one-out plots.

Causal impact of type 1 diabetes mellitus on atrial fibrillation: Inverse variance weighted (odds ratio [OR] = 0.996, 95 % confidence interval [CI]: 0.985-1.007, P = 0.498). MR-Egger (OR = 1.000, 95 % CI: 0.985-1.016, P = 0.963). Weighted median (OR = 0.985, 95 % CI: 0.973-0.998, P = 0.022). Simple mode (OR = 1.007, 95 % CI: 0.974-1.040, P = 0.698). Weighted mode (OR = 0.995, 95 % CI: 0.984-1.005, P = 0.298). MR-Egger intercept test (P = 0.437). There was no evidence of pleiotropy among the genetic instrumental variables included in the analysis.

In Mendelian randomization analysis, we did not find evidence of a causal relationship between genetically determined type 1 diabetes mellitus in European ancestry populations and atrial fibrillation.

Clarifying the uncertain causal relationship between periodontitis and infective endocarditis using Mendelian randomization analysis, given their historically perceived association and clinical significance.

Genetic variation data for acute periodontitis, chronic periodontitis, aggressive periodontitis, and infective endocarditis were obtained from published GWAS in individuals of European ancestry. Instrumental variables significantly associated with periodontitis were selected and univariable Mendelian randomization was conducted to infer the causal association between periodontitis and infective endocarditis. Multivariable Mendelian randomization was also performed to adjust for potential confounders including smoking, drinking, diabetes, and education.

Our analysis found no evidence of a causal association between periodontitis and infective endocarditis, with odds ratios (ORs) of 0.992 (95% CI: 0.879-1.120), 0.947 (95% CI: 0.738-1.214), and 1.056 (95% CI: 0.916-1.217) for acute periodontitis, chronic periodontitis, aggressive periodontitis, respectively. The robustness of our findings was confirmed by heterogeneity tests, pleiotropy tests, leave-one-out analyses, and MR-PRESSO. In the multivariable MR analysis, adjusting for smoking, drinking, diabetes, and education, the overall patterns between genetic liability to periodontitis and infective endocarditis remained consistent (all P > .05).

Our findings indicate that there is no genetic causal association between periodontitis and infective endocarditis.

Neuroticism has been associated with asthma, but the nature of this relationship remains unclear due to limited understanding of the impact of psychological factors on asthma risk. While Neuroticism is known to affect various health outcomes, its specific role in respiratory conditions like asthma is not fully understood.

We conducted Mendelian randomization (MR) analyses using genome-wide association studies (GWAS) to explore the causal link between 12 Neuroticism traits and asthma. Various MR approaches, including MR-PRESSO, were employed, with validation through independent GWAS and the FinnGen dataset.

MR-PRESSO revealed a significant causal relationship between mood swings and asthma (OR: 1.927, 95% CI: 1.641-2.263), surpassing the Bonferroni-corrected threshold (p < 4.167 × 10-³). Mood swings emerged as the only significant trait associated with asthma, with reverse MR analyses showing no causal links for other traits. Secondary analyses supported these findings. Multivariate analysis showed mood swings increased asthma risk, independent of smoking, BMI, and air pollution. Mediation analysis indicated that BMI partially mediates the mood swing-asthma relationship, accounting for 9.87% of the effect (95% CI: 4.54%-15.2%, p = 2.850 × 10-4).

Mood swings elevate asthma risk, with BMI partially mediating this effect, highlighting a potentially significant pathway through which psychological traits influence asthma.

The results of earlier observational research on the relationships between the usage of non-steroidal anti-inflammatory medicines (NSAIDs) and the risk of benign prostatic hyperplasia (BPH) have been inconsistent.

To assess these associations, we performed both univariable and multivariable Mendelian randomization (MR) studies. Instrumental variables (IVs) associated with exposures at the significance level (p < 5 × 10-6) were selected from a comprehensive meta-analysis conducted by the United Kingdom Biobank (UKB). Summary data for BPH were obtained from the FinnGen consortium, which comprised 30,066 cases and 119,297 controls. Sensitivity analyses were performed to evaluate heterogeneity and pleiotropy.

We found evidence by univariable MR (UVMR) that genetically predicted NSAIDs use increased the risk of BPH (odds ratio [OR] per unit increase in log odds NSAIDs use: 1.164, 95% confidence interval [CI]: 1.041-1.302, p = 0.008). After controlling for inflammation in multivariable MR (MVMR), the link persisted (OR: 1.165, 95% CI: 1.049-1.293, p = 0.004). There were no indications of potential heterogeneity and pleiotropy in UVMR and MVMR analyses.

The results of the MR estimates suggest that genetically predicted NSAIDs use may elevate the risk of BPH. This outcome prompts the imperative for deeper exploration into potential underlying mechanisms.

Observational studies have demonstrated an association between vitiligo and psoriasis. However, to date, the causal nature of this association remains uncertain. The objective of this study was to investigate the potential bidirectional causal relationship between vitiligo and psoriasis by employing a bidirectional two-sample Mendelian randomization (MR) approach. We utilized summary statistics obtained from the genome-wide association study (GWAS) conducted in European ancestry for vitiligo (N = 44,266) and psoriasis (N = 373,338). We first performed univariate MR analysis to detect potential bidirectional causality between vitiligo and psoriasis. Then, for directions in which univariate MR confirmed a causal relationship, we further conducted multivariate MR analysis to investigate independent causal effects on the outcome considering exposure to confounders. The bidirectional two-sample MR analysis showed genetic liability to vitiligo was significantly associated with an increased risk of psoriasis (OR = 1.094, 95% CI: 1.052, 1.138), but there was no significant association between genetic liability to psoriasis and risk of vitiligo (OR = 1.176, 95% CI: 0.915, 1.511). For the vitiligo to psoriasis direction, multivariate MR adjusting for smoking, drinking, body mass index, and rheumatoid arthritis showed the presumed causality was despite attenuated (OR = 1.060, 95% CI:1.035, 1.085), and remained statistically significant. Our study suggests that vitiligo is a causal risk factor for psoriasis, but the reverse may not be true. It is emphasized by the evidence from this study that enhanced early screening for psoriasis among patients with vitiligo may help to reduce the incidence of psoriasis.

Preexisting epidemiological studies suggest that early pubertal development in males is associated with externalizing (e.g. conduct problems, risky behavior, and aggression) and internalizing (e.g. depression and anxiety) traits and disorders. However, due to problems inherent to observational studies, especially of residual confounding, it remains unclear whether these associations are causal. Mendelian randomization (MR) studies take advantage of the random allocation of genes at conception and can establish causal relationships.

In this study, N = 76 independent genetic variants for male puberty timing (MPT) were derived from a large genome-wide association study (GWAS) on 205,354 participants and used as an instrumental variable in MR studies on 17 externalizing and internalizing traits and psychopathologies utilizing outcome GWAS with 16,400-1,045,957 participants.

In these MR studies, earlier MPT was significantly associated with higher scores for the overarching phenotype of 'Externalizing Traits' (b = -0.03, 95% CI [-0.06, -0.01]). However, this effect was likely driven by an earlier age at first sexual contact (b = -0.17, 95% CI [-0.21, -0.13]), without evidence for an effect on further externalizing phenotypes. Regarding internalizing phenotypes, earlier MPT was associated with higher levels of the 'Depressed Affect' subdomain of neuroticism (b = -0.04, 95% CI [-0.07, -0.01]). Late MPT was related to higher scores of internalizing traits in early life (b = 0.04, 95% CI [0.01, 0.08]).

This comprehensive MR study supports a causal effect of MPT on specific traits and behaviors. However, no evidence for an effect of MPT on long-term clinical outcomes (depression, anxiety disorders, alcohol dependency, cannabis abuse) was found.

Venous thromboembolism (VTE) is a significant global health burden, and metabolic alterations play a key role in its pathogenesis. However, previous studies have been constrained by several limitations, hindering clarification of the causal role of metabolites.

To comprehensively evaluate the causal roles of metabolites in the pathogenesis of VTE and determine whether metabolites mediate the relationships between modifiable risk factors and VTE.

Genetic associations involving 690 plasmas and 211 urinary metabolites were analyzed as exposures, while the outcomes for VTE were derived from a large-scale meta-analysis of genome-wide association studies. Metabolome-wide Mendelian randomization and colocalization analyses were performed to assess the causal role of metabolites in VTE. Metabolic pathway analysis was performed using MetOrigin, and druggability assessments were conducted to prioritize potential therapeutic targets. Additionally, a 2-step Mendelian randomization framework was employed to elucidate the mediating effects of metabolites on the relationships between modifiable risk factors and VTE.

After Bonferroni correction, 51 plasma metabolites and 18 urinary metabolites were significantly associated with VTE risk. Colocalization evidence supported causal relationships for 37 metabolites with VTE. Eleven metabolic pathways were identified for VTE-related metabolites, and 6 metabolites were prioritized as potential therapeutic targets. Twenty-four modifiable risk factors were associated with 28 VTE-related metabolites, 7 of which were linked to VTE risk. Mediation analyses further revealed significant mediating effect of 8 metabolites on how 6 modifiable factors influenced VTE.

This study identifies potential metabolite biomarkers associated with VTE risk and uncovered the metabolic mediators between modifiable risk factors and VTE, offering new insights for future prevention and treatment strategies.

Epidemiological studies have observed an association between atrial fibrillation (AF) and breast cancer (BC). However, the underlying mechanisms linking these two conditions remain unclear. This study aims to systematically explore the genetic association between AF and BC.

We utilized the largest available genome-wide association study (GWAS) datasets for European individuals, including summary data for AF (N = 1,030,836) and BC (N = 247,173). Multiple approaches were employed to systematically investigate the genetic relationship between AF and BC from the perspectives of pleiotropy and causality.

Global genetic analysis using LDSC and HDL revealed a genetic correlation between AF and BC (rg = 0.0435, P = 0.039). Mixer predicted genetic overlap between non-MHC regions of the two conditions (n = 125, rg = 0.05). Local genetic analyses using LAVA and GWAS-PW identified 22 regions with potential genetic sharing. Cross-trait meta-analysis by CPASSOC identified one novel pleiotropic SNP and 14 pleiotropic SNPs, which were subsequently annotated. Eight of these SNPs passed Bayesian colocalization tests, including one novel pleiotropic SNP. Further fine-mapping analysis identified a set of causal SNPs for each significant SNP. TWAS analyses using JTI and FOCUS models jointly identified 10 pleiotropic genes. Phenome-wide association study (PheWAS) of novel pleiotropic SNPs identified two eQTLs (PELO, ITGA1). Gene-based PheWAS results showed strong associations with BMI, height, and educational attainment. PCGA methods combining GTEx V8 tissue data and single-cell RNA data identified 16 co-enriched tissue types (including cardiovascular, reproductive, and digestive systems) and 5 cell types (including macrophages and smooth muscle cells). Finally, univariable and multivariable bidirectional Mendelian randomization analyses excluded a causal relationship between AF and BC.

This study systematically investigated the shared genetic overlap between AF and BC. Several pleiotropic SNPs and genes were identified, and co-enriched tissue and cell types were revealed. The findings highlight common mechanisms from a genetic perspective rather than a causal relationship. This study provides new insights into the AF-BC association and suggests potential experimental targets and directions for future research. Additionally, the results underscore the importance of monitoring the potential risk of one disease in patients diagnosed with the other.

As the population ages rapidly, cognitive impairment, especially in conditions like Alzheimer's disease (AD) and mild cognitive impairment (MCI), has become a crucial public health issue. Nutritional interventions have garnered attention as a promising non-pharmacological strategy for maintaining cognitive function and decelerating its decline.

This study aimed to evaluate the effectiveness of various nutritional interventions in preventing cognitive impairment and elucidate intricate biological pathways linking nutritional interventions to cognitive function through a comprehensive approach involving systematic review, network meta-analysis (NMA), and Mendelian randomization (MR) analysis.

We utilized pair-wise comparisons and NMA to evaluate the efficacy of different nutritional interventions on cognitive function in patients with decreased cognitive abilities. A systematic search in three biomedical databases was performed for double-blinded, randomized controlled trials (RCTs) or head-to-head comparisons up to December 31, 2024. The NMA has been registered at the International Prospective Register of Systematic Reviews (PROSPERO; CRD42022331173). Moreover, to clarify the biological mechanisms linking nutritional interventions to cognitive impairment, we conducted two-sample MR analyses to assess the potential causal relationships between 9 genetically predicted nutrient levels derived from extensive genome-wide association studies (GWASs) and 12 biomarkers linked to brain aging.

This study encompassed 52 trials with 8452 participants, 9 GWASs examining genetically predicted nutrient levels with a total of 603,996 participants, and 12 GWASs investigating brain aging biomarkers with a total of 2,405,530 participants. The NMA demonstrated that the multi-ingredient intervention outperformed other interventions significantly (standardized mean difference [SMD] = 2.03; 95 % credible interval [95 % CrI] = 0.97-3.09, P = 0.0002). In the MR analysis, the findings indicated that the multi-ingredient intervention was linked to reduced C-reactive protein (CRP) levels (odds ratios [OR] = 0.96, 95 % confidence interval [95 % CI] = 0.93-0.99, P = 0.014), suggesting that the multi-ingredient intervention may mitigate cognitive impairment by reducing inflammation.

Our NMA amalgamated evidence underscoring multi-ingredient interventions as the most efficacious strategy for attenuating cognitive decline in individuals with MCI and AD. Furthermore, the MR analysis unveiled the mechanisms underpinning the protective effects of multi-ingredient interventions, potentially offering benefits even in the early stages of neurodegeneration by mitigating oxidative stress and inflammation.

Previous observational studies have not clearly examined the impact of gastroesophageal reflux disease (GERD) on the risk of oral cavity and pharyngeal cancer (OCPC). To provide more evidence to elucidate this issue, we used Mendelian randomization (MR) to analyze the causal effect of GERD on OCPC and its subtypes.

We obtained the summary data of genome-wide association studies (GWAS) of European ancestry to perform MR analysis. GERD was considered the exposure, and OCPC (subtypes include oral cavity cancer (OCC) and oropharynx cancer (OPC)) was defined as the outcome. We aimed to investigate whether GERD has a causal effect on OCPC. We then attempted to obtain more accurate causal estimates by correcting for potential confounders such as smoking behavior, drinking behavior, body mass index (BMI), and type 2 diabetes (T2D). We also performed extensive sensitivity analyses to assess the robustness of the primary analysis results.

Univariate MR analysis showed that GERD had a positive causal effect on OCPC (IVW: discovery, OR = 2.09 (95% CI 1.30-3.37), P = 0.0023; validation, OR = 1.90 (95% CI 1.26-2.87), P = 0.0020) and OCC (IVW: discovery, OR = 2.01 (95% CI: 1.21-3.33), P = 0.0066; validation, OR = 2.60 (95% CI 1.47-4.59), P = 0.0010). Although GERD increased the risk of OPC, this effect was statistically significant only in the discovery analysis (IVW: discovery, OR = 2.30 (95% CI 1.08-4.89), P = 0.0307; validation, OR = 1.15 (95% CI 0.67-1.97), P = 0.6199), the causal direction remained consistent. After adjusting for smoking, alcohol consumption, BMI, and T2D in multivariate analysis, the results remained largely consistent.

Our study showed that GERD significantly increased the overall risk of OCPC, and similar results were found for its subtype OCC. This causal effect appears to be independent of cigarette use, drinking habits, BMI, and T2D. However, evidence for a causal effect of GERD on OPC is limited, and further research is expected to extend this finding. Future studies should explore the specific biological mechanisms through which GERD increases OCPC risk.

Asthma is a prevalent chronic respiratory condition with multifactorial pathogenesis. Emerging evidence suggests that gut microbiota and their metabolites influence asthma risk. This study explores the mediation effects of plasma metabolites between gut microbiota and asthma using Mendelian randomization (MR) analysis.

Publicly available genome-wide association study (GWAS) data were analyzed, comprising 5,959 individuals for gut microbiota, 8,299 for plasma metabolites, and 543,586 (86,923 cases and 456,663 controls) for asthma outcomes. MR analyses were conducted to evaluate causal relationships between gut microbiota, plasma metabolites, and asthma. Mediation effects were assessed using the product of coefficients approach, and statistical significance was determined with Bonferroni correction.

The MR analysis identified 24 gut microbiomes and 88 plasma metabolites with suggestive associations with asthma. Notably, mediation analysis revealed that the phylum Cyanobacteria reduced asthma risk via the alpha-tocopherol to glycerol ratio (mediated proportion: 37.48%), while the species UBA2922 sp900313925 and the order Parachlamydiales increased risk through arachidonate to linoleate (14.62%) and hypotaurine to taurine (29.36%) ratios, respectively.

This study underscores the significant role of the gut microbiota-lung axis in asthma pathogenesis. By identifying specific gut microbiota and metabolite pathways, the findings pave the way for innovative biomarkers and therapeutic strategies targeting gut microbiota and its metabolites to manage and prevent asthma.

Epidemiological studies proposed a bidirectional link between psoriasis (Ps) and diabetes mellitus (DM); their causal relationship remains inadequately explored. We obtained summary statistics of genome-wide association analyses for Type 1 diabetes mellitus (T1DM), Type 2 diabetes mellitus (T2DM), and Ps from individuals of European ancestry by accessing the UK Biobank and FinnGen datasets. Inverse-variance weighted (IVW) method was utilized as the primary method. Additional analyses included debiased IVW (dIVW), constrained maximum likelihood with model averaging, robust adjusted profile score, Mendelian randomization (MR)-Egger, weighted median, and weighted mode. Moreover, sensitivity tests were conducted, including Cochran's Q, MR pleiotropy residual sum, and outlier analyses. Eventually, bidirectional MR was conducted to examine the possibility of a causal link between Ps and DM. No significant causal associations were indicated between DM and Ps. Moreover, there was no causal link between Ps and T1DM. Although certain positive correlations were identified between Ps and T2DM, aggregate evidence remains insufficient to establish a causal relationship. The results demonstrated no evidence of horizontal pleiotropy between genetic variants. Furthermore, a leave-one-out test validated the stability and robustness of this correlation. Our study identifies no genetic causal effect of Ps on DM and of DM on Ps in European ancestry. Additional research is warranted to verify the presence of an association between Ps and DM in diverse populations.

Viral infections have been a severe challenge for global public health, and viral pneumonia is becoming increasingly critical in the post-pandemic era. Observational and basic studies have demonstrated a strong link between host nutrient status and anti-viral immune responses, and nutritional supplements were shown to improve the prognosis of viral infectious diseases. However, there is limited research on the relationship between essential micronutrients and the susceptibility to viral pneumonia. In addition, current studies are often confounded by biases and reverse causality, undermining their reliability. In this study, to fill the gap, we employed Mendelian randomization to investigate the causal relationship between supplementation of vitamins and minerals and the susceptibility to viral pneumonia. Our analysis found that vitamin B6 is a protective factor against viral pneumonia, while selenium supplementation is a risk factor. These findings provide insights for the use of dietary supplements and the prevention and control of viral pneumonia, especially when micronutrient supplementation is used as an adjunctive therapy for viral infections.

This study aims to elucidate the potential impact of basal metabolic rate on ischemic stroke at the genetic prediction level through a two-sample Mendelian randomization analysis.

Using summary data from genome-wide association studies, we obtained information on basal metabolic rate and ischemic stroke from a large-scale genome-wide association study. MR analysis used inverse variance weighting, weighted median, MR-Egger, simple mode, and weighted estimation. Sensitivity analyses, including the MR-Egger method, MR-PRESSO, Cochran's Q-test, and leave-one-out assessment, were performed to assess the reliability of the results.

Genetic susceptibility to basal metabolic rate was significantly associated with ischemic stroke in multiple models, including the inverse variance weighting model (OR, 1.108 [95% CI: 1.005-1.221]; p = 0.0392), the weighted median method (OR, 1.179 [95% CI: 1.020-1.363]; p = 0.0263), and MR-Egger (OR, 1.291 [95% CI: 1.002-1.663]; p = 0.0491). These results indicate a positive causal relationship between basal metabolic rate and ischemic stroke. The MR-Egger intercept and Cochran's Q-test indicated the absence of heterogeneity and horizontal pleiotropy in the analyses of basal metabolic rate and ischemic stroke.

The MR analysis suggests a positive correlation between basal metabolic rate and ischemic stroke.

Proteins are involved in multiple biological functions. High-throughput technologies have allowed the measurement of thousands of proteins in population biobanks. In this study, we aimed to identify proteins related to Alzheimer's disease, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis by leveraging large-scale genetic and proteomic data. We performed a two-sample cis Mendelian randomization study by selecting instrumental variables for the abundance of >2700 proteins measured by either Olink or SomaScan platforms in plasma from the UK Biobank and the deCODE Health Study. We also used the latest publicly available genome-wide association studies for the neurodegenerative diseases of interest. The potentially causal effect of proteins on neurodegenerative diseases was estimated based on the Wald ratio. We tested 13 377 protein-disease associations, identifying 169 associations that were statistically significant (5% false discovery rate). Evidence of co-localization between plasma protein abundance and disease risk (posterior probability > 0.80) was identified for 61 protein-disease pairs, leading to 50 unique protein-disease associations. Notably, 23 of 50 protein-disease associations corresponded to genetic loci not previously reported by genome-wide association studies. The two-sample Mendelian randomization and co-localization analysis also showed that APOE abundance in plasma was associated with three subcortical volumes (hippocampus, amygdala and nucleus accumbens) and white matter hyper-intensities, whereas PILRA and PILRB abundance in plasma was associated with caudate nucleus volume. Our study provided a comprehensive assessment of the effect of the human proteome that is currently measurable through two different platforms on neurodegenerative diseases. The newly associated proteins indicated the involvement of complement (C1S and C1R), microglia (SIRPA, SIGLEC9 and PRSS8) and lysosomes (CLN5) in Alzheimer's disease; the interleukin-6 pathway (CTF1) in Parkinson's disease; lysosomes (TPP1), blood-brain barrier integrity (MFAP2) and astrocytes (TNFSF13) in amyotrophic lateral sclerosis; and blood-brain barrier integrity (VEGFB), oligodendrocytes (PARP1), node of Ranvier and dorsal root ganglion (NCS1, FLRT3 and CDH15) and the innate immune system (CR1, AHSG and WARS) in multiple sclerosis. Our study demonstrates how harnessing large-scale genomic and proteomic data can yield new insights into the role of the plasma proteome in the pathogenesis of neurodegenerative diseases.

Previous studies have suggested that hypoxia-inducible factor 1-α (HIF-1α) exerted multiple effects on different central nervous system disorders. However, it is still uncertain whether plasma HIF-1α can be a causal indicator for the relevant diseases. This study aimed to test the causality relationship between plasma HIF-1α and neurological diseases, including cerebrovascular diseases, migraines, and neurodegenerative diseases with a Mendelian randomization (MR) method.

Single-nucleotide polymorphisms (SNPs) genetically representing plasma HIF-1α were screened as instrumental variables (IVs). Summary-level data for neurological disorder from genome-wide association studies (GWAS) were identified as outcomes. The causal effects between the IVs and outcomes were determined via the major analysis of inverse-variance-weighted (IVW) method. The reverse causal direction was also performed to investigate the possibility of reverse causation.

The findings revealed that plasma HIF-1α was identified to be genetically associated with cardioembolic stroke (CES) (OR = 0.885; 95% confidence interval [CI] = 0.796-0.985, p = 0.026), migraine (OR = 0.941, 95% CI = 0.888-0.998, p = 0.041), and drug-induced migraine without aura (MOA) (OR = 0.586, 95% CI = 0.375-0.916, p = 0.019). There was no association identified in plasma HIF-1α with subarachnoid hemorrhage (SAH), other stroke and migraine subtype, and neurodegenerative disorders. The reverse-MR analysis revealed that the above-stated neurological diseases did not have a causal effect on plasma HIF-1α levels. Sensitivity and validation analyses support that the above results are stable.

Our research indicated that plasma HIF-1α may have a causal effect on the risk of CES, migraine and drug-induced MOA, providing new insights for those disease prevention and therapeutic approaches.

Primary glomerular diseases (PGDs), including nephrotic syndrome (NS), membranous nephropathy (MN), and IgA nephropathy (IgAN), are complex renal conditions influenced by immune system dysregulation. Although associations between immune cell phenotypes and PGDs have been observed, the precise causal relationships have not been fully elucidated.

Utilizing genetic association data from genome-wide association studies (GWASs), we investigated 731 immunophenotypes in relation to PGDs. A bidirectional two-sample Mendelian randomization (MR) approach, primarily employing inverse variance weighting (IVW), was conducted to establish causality. MR-Egger, weighted median, simple mode, and weighted mode were used as complementary methods to reinforce the robustness and validity of the results. Sensitivity analyses further validated the sensitivity and stability of our results.

We identified 38 immunophenotypes suggestively related to IgAN, with 20 as risk factors and 18 as protective effects. Six immunophenotypes remained significant after Bonferroni correction: The percentage of CD25hi among T cells; the percentage of CD25hi CD45RA- CD4 not T regulatory (Treg) among T cells; the percentage of CD25hi CD45RA- CD4 not Treg within the CD4+ T cell population; CX3CR1 expression on monocytes; CD40 expression on monocytes; and CD64 expression on CD14+ CD16- monocytes. In the validation analysis of IgAN, CD3 expression on effector memory CD4+ T cells further confirmed the predisposing risk role of effector memory T cells in the development of IgAN. Additionally, the MR analysis demonstrated suggestive associations between 25 immunophenotypes and MN (8 risk factors and 17 protective factors), as well as between 22 immunophenotypes and NS (10 risk factors and 12 protective factors). Last, by intersecting the immunophenotypes showing suggestive associations with PGDs, we identified two common immunophenotypes shared by IgAN and MN, three by IgAN and NS, and one by MN and NS.

This genetic-level investigation uncovers causal associations between immunophenotypes and PGDs, providing valuable insights into the immunological underpinnings of PGDs. Our findings suggest potential targets for treatment strategies, thereby facilitating more personalized and effective therapeutic approaches in PGDs management.

A relationship between frailty index (FI) and metabolic diseases (MDs) has been reported in previous observational studies. However, the causality between them remains unclear. This study aimed to examine the causal effect of FI on MDs.

We performed a bidirectional two-sample Mendelian randomization (MR) study. A recent large-scale genome-wide association study (GWAS) provided available data associated with FI, and summary statistics on eight MDs were collected from the IEU OpenGWAS database. Inverse variance weighted (IVW) was used as the main analysis to estimate causal effects, together with MR pleiotropy residual sum and outlier (MR-PRESSO), MR-Egger, Cochran's Q test, pleiotropy test, leave-one-out method, and MR Steiger analysis were used in the sensitivity analyses.

Our MR study demonstrated for the first time that elevated FI was causally associated with an increased risk of MDs including obesity (odds ratio [OR] = 1.78; 95% confidence interval [CI]: 1.17-2.70; p = 0.0075), T2DM (OR = 1.67; 95% CI: 1.24-2.24; p = 6.95 × 10-4), gout (OR = 2.45; 95% CI: 1.29-4.64; p = 0.006), hypothyroidism (OR = 1.96; 95% CI: 1.47-2.60; p = 3.47 × 10-6), and HTN (OR = 2.17; 95% CI: 1.72-2.74; p = 5.25 × 10-11). However, no causal association was found between FI and osteoporosis, vitamin D deficiency, and hyperthyroidism.

Our findings support a causal relationship between FI and multiple MDs. This is crucial for the prevention of associated MDs in patients with frailty.

The regulation of the immune system is crucial in the pathogenesis of various diseases. The direct involvement of immune cells in the development of rheumatoid arthritis (RA) and the potential mediation by metabolites remains to be elucidated. This study utilized a two-step, two-sample Mendelian randomization (MR) approach employing the inverse variance weighted (IVW) method to investigate the causal role of immune cells in RA and to assess the mediation effect of metabolites on the association between immune cells and RA. MR analyses identified 44 immune cell traits that were suggestively associated with RA. Additionally, five metabolites demonstrated protective effects against RA. Notably, mediation MR indicated that the causal role of CD14+ CD16- monocyte activation complex (AC) on RA (total effect IVW: OR = 0.978, 95% CI [0.959, 0.998], P = 0.028) was significantly mediated by X-26109 levels, accounting for 7.32% of the total effect. This study provides evidence of a causal relationship between immune cells and RA, with metabolites potentially mediating this relationship. Key Points • Mendelian randomization (MR) analysis was used to investigate the causal impact of immune cells on RA progression and the potential mediating role of metabolites, identifying 44 immune cell traits and several metabolites associated with RA risk • The study found that CD14 + CD16 - monocyte activation complex (AC) is associated with a reduced RA risk, with this effect largely mediated by metabolite X-26109 levels, suggesting a potential therapeutic target for RA prevention and treatment.

Previous research has demonstrated that even minor changes in thyroid function are associated with an increased risk of osteoporosis (OP). However, the causal relationship between thyroid disorders and the development of OP remains unclear. To address this, we aim to investigate the connection between genetic predispositions to various thyroid disorders and OP using a two-sample Mendelian randomization (MR) approach.

Instrumental variables (IVs) for multiple thyroid disorders were sourced from a large genome-wide association study (GWAS) meta-analysis dataset. Summary-level data for OP were obtained from the FinnGen consortium. Inverse variance weighting (IVW) methods served as the primary approach for MR analysis. Sensitivity analyses included MR-Egger regression, heterogeneity testing, multiple validity tests, and leaFve-one-out sensitivity tests.

IVW analysis revealed a direct causal effect of hypothyroidism (OR = 1.105, 95% CI 1.023-1.194, P 0.011) and Hashimoto's thyroiditis (OR = 1.142, 95% CI 1.026-1.271, P 0.015) on OP. However, no direct causal association was found between hyperthyroidism (OR = 1.030, 95% CI 0.944-1.123, P 0.508) or thyroid cancer (OR = 0.971, 95% CI 0.898-1.051, P 0.469) and OP.

Our MR analysis revealed a causal association between hypothyroidism, Hashimoto's thyroiditis, and OP. This highlights the significant impact of thyroid function on bone health. However, further longitudinal studies are needed to confirm these findings conclusively.