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PubMed2026

Unveiling the BMI Risk Threshold for Osteoarthritis: Multi-Database Causal and Nonlinear Evidence.

OBJECTIVE: To characterize the nonlinear relationship between BMI and osteoarthritis (OA), and to identify BMI thresholds that inform precise prevention strategies. METHODS: This multi-database study integrated Global burden of disease 2021, National Health and Nutrition Examination Survey 2007-2018, and Genome-Wide Association Studies. A generalized additive model was performed to visualize the BMI-OA relationship, adjusting for multiple confounders. We applied segmented logistic regression models to identify potential threshold effects and used Mendelian randomization to estimate the causal effects of BMI on OA subtypes. RESULTS: From 1990 to 2021, the age-standardized prevalence and years lived with disability rates for OA were highest in regions with high SDI. OA prevalence rose nonlinearly with BMI, with breakpoints at 24.00 and 41.58 kg/m2. Each unit increase in BMI was associated with higher odds of OA between 24.00 and 41.58 kg/m2 (OR = 1.022, 95% CI: 1.003-1.041) and above 41.58 kg/m2 (OR = 1.055, 95% CI: 1.022-1.090). Women and individuals aged ≥ 45 years exhibited a higher susceptibility to knee osteoarthritis. BMI was causally associated with knee osteoarthritis (OR = 1.63, 95% CI 1.50-1.77) and hip osteoarthritis (OR = 1.54, 95% CI 1.40-1.70). CONCLUSIONS: These findings suggest that OA risk awareness and weight-management strategies should begin before BMI reaches the high range, particularly among individuals with BMI exceeding 24.00 kg/m2.

Humans↗

PubMed2026

Multilevel genomic, transcriptomic, and epidemiologic evidence linking diabetic retinopathy to Alzheimer disease.

BACKGROUND: Diabetic retinopathy (DR) and Alzheimer disease (AD) share metabolic and vascular dysfunctions, but the extent to which they reflect overlapping genetic susceptibility and neurovascular-metabolic regulatory pathways remains unclear. We combined multi-omics analyses with population-based data to examine the genetic convergence, cellular pathways, and longitudinal association between DR and AD. METHODS: We performed a two-sample Mendelian randomisation (MR) to estimate the association between genetically predicted DR liability and AD risk. We used Bayesian colocalisation analysis to identify shared genomic loci, and summary-data-based MR (SMR) to detect expression-mediated genes jointly associated with DR and AD. We analysed single-cell RNA sequencing data to characterise shared cellular features and related biological pathways. We also conducted an MR-based mediation analysis to explore whether lipid-related, metabolic, or inflammatory traits mediated the observed DR-AD association, and a longitudinal analysis of the UK Biobank cohort to assess the association between DR and incident AD. RESULTS: With the MR analysis, we found that genetically predicted liability to DR was associated with a modest increase in AD risk. Colocalisation analysis supported a shared genetic signal. We identified three genes with shared expression-mediated associations across DR and AD through SMR. Functional enrichment analyses revealed partially overlapping neurovascular and metabolic pathways. Using MR-based mediation analysis, we found no significant intermediary traits linking DR and AD. Findings from the UK Biobank cohort were directionally consistent with the genetic analyses. CONCLUSIONS: Genetic liability to DR is associated with an increased risk of AD and is accompanied by shared expression-mediated effects and convergent neurovascular-metabolic pathways. These findings support the possibility that DR may serve as a clinically accessible indicator of increased neurodegenerative vulnerability.

Humans↗

PubMed2026

Assessing the impact of maternal blood pressure during pregnancy on perinatal health: a wide-angled Mendelian randomization study.

BACKGROUND: Observational studies link high blood pressure in pregnancy to numerous adverse pregnancy and perinatal outcomes; however, findings may be affected by residual confounding or reverse causation. This study aimed to assess the causal effect of blood pressure during pregnancy on a range of pregnancy and perinatal outcomes. METHODS: We performed two-sample Mendelian randomization (MR) to assess the effect of systolic and diastolic blood pressure (SBP/DBP) during pregnancy on 16 primary and eight secondary adverse pregnancy and perinatal outcomes. We obtained genetic association data from large-scale meta-analyses of genome-wide association studies involving predominantly European ancestry individuals for SBP/DBP (N = 1,028,980), and pregnancy and perinatal outcomes (N = 74,368-714,899). We used inverse-variance weighted (IVW) MR for main analyses and MR-Egger, weighted median, weighted mode, multivariable MR, and IVW adjusted for fetal genetic effects for sensitivity analyses. RESULTS: A 10 mmHg higher genetically predicted maternal SBP increased the odds of gestational diabetes, induction of labour, low birth weight (LBW), small-for-gestational age (SGA), preterm birth (PTB), and neonatal intensive care unit (NICU) admission (OR ranging from 1.11 [95% CI 1.02 to 1.20] for NICU admission to 1.33 [1.26 to 1.41] for LBW); while decreasing the odds of high birth weight (HBW), large-for-gestational age (LGA), and post-term birth [OR ranging from 0.76 (0.69 to 0.83) for HBW to 0.94 (0.90 to 0.99) for post-term birth]. We did not find evidence that genetically predicted higher maternal SBP was related to miscarriage or stillbirth. The results for maternal DBP were similar to the results for SBP. Overall, the main results were consistent across sensitivity analyses accounting for pleiotropic instruments and fetal genetic effects. CONCLUSIONS: Higher maternal blood pressure reduces gestation duration and fetal growth and increases the risks of induction of labour, gestational diabetes, and neonatal intensive care unit admission. This and other emerging evidence highlight the value of interventions aimed at controlling blood pressure in the population to reduce the burden of adverse pregnancy outcomes.

Humans↗

PubMed2026

Drug targets for lipid modification and risk of type 2 diabetes: a cis-Mendelian randomization study.

BACKGROUND AND AIMS: Reducing plasma levels of low-density lipoprotein cholesterol (LDL-C) is the cornerstone in the prevention of coronary artery disease (CAD) but may also increase risk of type 2 diabetes (T2D). A comprehensive examination of the genetic evidence of T2D related side-effects of all current lipid-modifying drugs, including those in development, has not yet been performed. METHODS: This cis-Mendelian randomization study used individual level data from the UK Biobank, Lifelines, and publicly available genome-wide association data. We identified loci that are either targeted directly with drugs, or alternatively, targeting their gene products (mRNA and/or protein). Included are, in alphabetical order, the loci ACLY, ANGPTL3, ANGPTL4, APOB, APOC3, CETP, HMGCR, LDLR, LIPG, LPA, MTTP, NPC1L1, and PCSK9. We used cis-genetic instruments weighted for LDL-C, HDL-C, triglycerides, and apolipoproteins as downstream proxies for the drug targets. Main outcomes were prevalent and incident T2D, with CAD as a contrast outcome. RESULTS: Lipid modification through HMGCR is predicted to reduce CAD risk and increase T2D risk. Modification through targeting APOC3, LDLR, LPA, MTTP, NPC1L1, and PCSK9 is predicted to reduce CAD risk without a change in T2D risk. Modification through ANGPTL4 and CETP is predicted to reduce risk of both CAD and T2D. For ACLY, ANGPTL3, APOB, and LIPG, we found evidence for neither CAD nor T2D. CONCLUSIONS: This study provides genetic evidence for variation in diabetes-related side-effects of different lipid-modifying drugs, with potential relevance for future clinical trials and individual treatment decisions.

Humans↗

PubMed2026

Cerebral Cortical Structural Variation and General Cognitive Ability: Evidence From Mendelian Randomization.

Understanding the cortical architecture underlying individual differences in general cognitive ability (GCA) remains a central question in cognitive neuroscience. Prior work has established associations between global brain size and GCA, yet the regional effects and directionality of these relationships remain debated. Using a genetically informed cortical parcellation in 11,289 UK Biobank participants, we examined associations between cortical surface area (SA), cortical thickness (CT), and GCA measured via verbal-numerical reasoning. Total SA showed a robust positive association with GCA. At the regional level, dorsolateral prefrontal and superior temporal SA exhibited the strongest positive associations, which persisted after adjustment for global SA. In contrast, CT showed comparatively modest associations. Using Mendelian randomization (MR) with genome-wide significant genetic instruments, we observed evidence consistent with a bidirectional relationship between total SA and GCA. At the regional level, dorsolateral prefrontal and temporal SA demonstrated evidence of MR-inferred directional effects on GCA, while GCA showed evidence of MR-inferred directional effects on total SA and perisylvian thickness. These findings support a polyregional SA architecture underlying GCA, with prominent contributions from prefrontal and temporal association cortices. Our results refine global brain-GCA models and highlight the value of genetically informed parcellation for identifying regional cortical contributions.

Humans↗

PubMed2026

Genetic and epigenetic underpinnings of biological aging: a multi-omics study integrating Mendelian randomization, spatial transcriptomics, and drug target discovery.

Inflammaging represents a hallmark of biological aging, yet the causal inflammatory mediators driving multi-dimensional epigenetic aging and their effector genes remain poorly characterized at the genetic level. We developed a four-tier analytical framework integrating causal screening, multi-omics effector gene mapping, spatial transcriptomics, and drug target evaluation. Two-sample Mendelian randomization (MR) of 91 circulating inflammatory proteins against six aging phenotypes identified IL-12B, IFNG, and IL-2 as the most robust pro-aging mediators with consistent effects across independent outcomes. Using multi-omics summary-based MR (SMR) as the core analytical engine, we integrated four-layer whole-blood molecular QTL resources eQTL (eQTLGen, n = 31,684), sQTL (GTEx, n = 755), pQTL (INTERVAL + SCALLOP, n = 34,232), and mQTL (McRae et al., n = 1,980) - with GWAS summary statistics for four epigenetic age acceleration measures. At a stringent threshold (P_SMR < 1×10⁻¹²), seven high-confidence effector genes were identified: NHLRC1, TPMT, SELP, and RIPPLY3 for IEAA; ZNF373A and PLDN for HannumAA; and EDARADD for PhenoAA. The chromosome 6p21 NHLRC1-TPMT locus, overwhelmingly driven by methylation QTL signals (-log₁₀P = 26.06), emerged as the dominant genetic node of epigenetic aging. Spatial projection via gsMap onto a mouse E16.5 embryo atlas (121,767 cells) revealed preferential enrichment in smooth muscle and lung, with EDARADD showing marked specificity in mucosal epithelium. Cross-database drug target mining classified TPMT and SELP as repurposable known targets and NHLRC1 as a high-priority novel druggable candidate. This study provides multi-omics convergent causal evidence for inflammation-driven epigenetic aging and delivers genetically anchored targets for precision anti-aging intervention.

Aging↗

PubMed2025

Shared Genetic Architecture Between Atopic Dermatitis and Autoimmune Diseases.

Atopic dermatitis (AD) and autoimmune diseases exhibit epidemiological comorbidity, yet the shared genetic architecture remains incompletely understood. We investigated the genetic overlap between AD and three autoimmune disorders including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and vitiligo, leveraging genome-wide association data. Despite modest evidence for global genetic correlations, we found 113 independent pleiotropic loci shared among AD and autoimmune diseases, with 11 displaying a concordant effect across all 3 pairwise comparisons. Gene-set and tissue enrichment analyses evidenced the inflammatory background of pleiotropic associations. Multi-trait colocalization analysis prioritized 22 loci, linking the tissue-specific expression of DOK2, GPR132, RERE, RERE-AS1, SUOX, TNFRSF11A, and TRAF1 pleiotropic genes with AD risk. Mendelian randomization revealed no causal effect of genetic liability to AD on autoimmune diseases. Nevertheless, genetic liability to IBD increased AD risk, while vitiligo exhibited a protective effect post outlier correction. Our findings provide mechanistic insights into the multimorbidity of atopic dermatitis (AD) and autoimmune diseases, offering additional evidence for the pleiotropic genetic architecture of AD that contributes to systemic immune dysregulation across multiple organ systems.

Humans↗

PubMed2026

Immune Cell-Stratified Regulatory Contexts Associated With BMI-Related Multi-System Disease Risk: A Cell-Stratified Mendelian Randomization Study Using Single-Cell eQTL Data.

AIMS: Body mass index (BMI) is associated with multisystem disease risk, but the immune cell-specific regulatory contexts underlying BMI-related genetic associations with disease outcomes remain unclear. METHODS: We applied a cell-stratified Mendelian randomization framework integrating European-ancestry BMI GWAS data, GWAS datasets for 33 disease outcomes across five disease systems, single-cell cis-eQTL data from 28 peripheral blood immune cell types, and dynamic CD4+ T cell eQTL data. SuSiE-based colocalization was used to identify BMI-associated loci sharing causal variants with immune-cell gene expression. These variants were used as cell-stratified instruments for Mendelian randomization. RESULTS: Across 28 immune cell types, 1326 colocalized variants regulating 1426 genes were identified. In primary MR analyses, genetically predicted BMI showed Bonferroni-significant associations with 26 disease outcomes. Cell-stratified analyses identified 87 Bonferroni-significant associations across 17 disease outcomes. Cardiovascular diseases showed the broadest cell-stratified associations, followed by respiratory and metabolic diseases. CD4+ T cell regulatory contexts contributed one of the largest shares of prioritized associations, and BMI-related effects varied across CD4+ T cell activation states. Cross-disease prioritization highlighted recurrent immune feature genes, including TRAF3 and FGFR1. CONCLUSION: These findings prioritize CD4+ T cell regulatory contexts as potential immunogenetic links between BMI and multi-system disease risk, while requiring further validation in diverse populations and mechanistic models.

Humans↗

PubMed2026

Comparing genome-wide significant and chemosensory variants as instruments for dietary patterns in Mendelian randomization.

BACKGROUND: Diet is a modifiable risk factor for cardiometabolic disease, yet establishing causality remains challenging. Mendelian randomization (MR) leverages genetic variants as instrumental variables (IVs) to enable causal inference. METHOD: Using two-sample MR, we assessed the causal effects of four principal component-derived dietary patterns (DPs)-Unhealthy, Healthy, Meat-based, Pescatarian-on cardiometabolic outcomes including body mass index, coronary artery disease, blood lipids, blood pressures, type 2 diabetes, fasting glucose and insulin, and glycated haemoglobin. Two sets of IVs were employed: conventional genome-wide significant variants associated with each DP, filtered for pleiotropy and directionality; and biologically informed variants in chemosensory receptor genes, given the role of taste and smell perception in food choice. RESULTS: Using conventional IVs, the Pescatarian DP was associated with reduced fasting insulin (βIVW = -0.10 pmol/L per SD increase in the Pescatarian DP score, 95% confidence interval -0.15, -0.04; P = 1.19 × 10-3), surviving multiple sensitivity analyses. Associations between the Unhealthy DP and elevated blood pressure and glycated haemoglobin should be interpreted cautiously; one of the two filtered IVs was strongly associated with caffeine intake, limiting the attribution of these findings to the DP itself. Chemosensory Receptor IVs yielded null findings, reflecting insufficient power. CONCLUSION: Evidence for causal effects of DPs on cardiometabolic traits was limited, with the strongest support for a protective effect of the Pescatarian DP on fasting insulin. Chemosensory IVs demonstrated limited utility for DPs, likely reflecting the heterogeneous and complex sensory profiles of overall diets. Future efforts should consider guideline-based dietary indices to facilitate interpretability and translation.

Humans↗

PubMed2026

Adolescent depression as a systemic multimorbidity catalyst: integrated genetic and metabolic pathway analysis.

BACKGROUND: Although adolescent depression has been linked to individual chronic conditions, its broader role in shaping multimorbidity risk remains understudied. METHODS: A total of 87,562 UK Biobank participants were included, of whom 18,851 had documented adolescent depression. Cox proportional hazards models were applied to evaluate associations between adolescent depression and 24 chronic diseases, followed by stratified analyses by sex and age. Two-sample Mendelian randomization (MR) was then conducted to infer causality for diseases showing significant associations. Genomic colocalization analyses were performed using relevant GWAS data to identify shared causal variants. Mediation analyses were performed to detect possible mediating factors, including the frailty index, KDM biological age acceleration, allostatic load and 30 circulating biomarkers. RESULTS: Adolescent depression was associated with elevated risk for 12 chronic diseases, with strongest associations for hypothyroidism (HR = 1.29 [1.18-1.42]), diabetes (HR = 1.25 [1.13-1.38]) and chronic obstructive pulmonary disease (COPD) (HR = 1.74 [1.50-2.01]). Risks were notably higher among females and younger adults. MR confirmed likely causal relationships for hypothyroidism (OR = 1.45 [1.03-2.05]), diabetes (OR = 1.01 [1.01-1.02]) and COPD (OR = 1.04 [1.02-1.06]). Genomic colocalization revealed a shared genetic signal at the CDSN/PSORS1C1 locus between adolescent depression and hypothyroidism. Mediation analyses revealed disease-specific pathways: creatinine for hypothyroidism, testosterone for diabetes, KDM biological ageing for COPD and frailty index across all three conditions. CONCLUSIONS: Adolescent depression confers systemic vulnerability through genetic and metabolic mechanisms, with amplified risks in females and individuals aged ≤55 years. These findings support early, integrated interventions to mitigate long-term multimorbidity.

Humans↗

PubMed2026

Multiple metabolic factors and kidney dysfunction: Causal evidence and translational insights from a mendelian randomization study.

Chronic kidney disease is a major global public health burden. This study investigated the causal effects of systolic blood pressure (SBP), apolipoprotein B (ApoB), and serum urate on renal function and albuminuria, and explored potential mechanistic implications. Two-sample Mendelian randomization (MR) analyses were conducted using large-scale genome-wide association study summary statistics from European populations. Univariable MR estimated total causal effects on estimated glomerular filtration rate (eGFR) and albuminuria. Multivariable MR assessed independent effects of correlated exposures, and 2-step MR evaluated albuminuria as a mediator. Cis-MR analyses were performed to explore target-proximal genetic evidence for lipid-related drug targets. Genetically predicted SBP was causally associated with reduced eGFR, while ApoB was inversely associated with albuminuria risk. serum urate showed no significant causal effects. Multivariable and mediation analyses supported distinct roles of SBP and ApoB, with albuminuria partially mediating the SBP-eGFR association. Cis-MR analyses indicated heterogeneous renal effects of lipid-lowering targets. These findings provide genetic evidence linking SBP to renal dysfunction, suggest that albuminuria may partially mediate the association between SBP and renal function, and highlight the complex renal relevance of lipid-related pathways.

Mendelian Randomization Analysis↗

PubMed2025

A Multi-omics Exploration Revealing SLIT2 as a Prime Therapeutic Target for Peripheral Facial Paralysis: Integrating Single-Cell Transcriptomics and Plasma Proteome Data.

Peripheral facial paralysis (PFP) is a common neurological disorder characterized by facial-nerve dysfunction. Identifying therapeutic targets and understanding the molecular and cellular mechanisms underlying PFP are crucial for developing effective treatment strategies. This study combined Mendelian randomization (MR) analysis and single-cell RNA sequencing (scRNA-seq) to explore potential therapeutic candidates and their roles in PFP pathophysiology. The MR analysis included 1925 publicly available plasma protein cis-heritability instruments. Instrumental variables were selected for MR analysis to identify plasma proteins associated with PFP, followed by colocalization analysis to evaluate shared genetic variants between the identified proteins and PFP. After the initial identification of plasma proteins associated with Bell's palsy using MR analysis, a rat model of facial-nerve injury was established to further dissect underlying mechanisms at cellular and molecular levels. Using scRNA-seq technology, we delved deeply into cellular Heterogeneity and dynamic changes in gene expression in the facial-nerve nucleus tissues under both injured and control conditions, thereby achieving a systematic study ranging from macroscopic genetic associations to microscopic cellular functions. Finally, expression patterns were preliminarily validated by performing in vitro immunofluorescence analysis on the facial-nerve nucleus samples of SD rats. The MR analysis results identified 30 plasma proteins significantly associated with PFP, with nine target genes showing differential expression in the scRNA-seq data. Colocalization analysis demonstrated that slit guidance Ligand 2 (SLIT2), semaphorin 4D (SEMA4D), EGF containing fibulin extracellular matrix protein 1 (EFEMP1), and sprouty related EVH1 domain containing 2 (SPRED2) shared causal variants with PFP. SLIT2 was highly expressed in the microglia and inhibitory neurons in the experimental group, whereas SEMA4D showed elevated expression across multiple glial cell types in the same group. In contrast, EFEMP1 and SPRED2 showed distinct expression patterns in fibroblasts and oligodendrocytes. The role of SLIT2 has been previously well-documented in many central nervous system diseases. However, for the first time, this study detected SLIT2 alteration after facial-nerve injury. Altered intercellular signaling, particularly enhanced SLIT2-ROBO signaling between neurons and glial cells, was observed in the PFP group. Pseudotime analysis revealed dynamic SLIT2 expression during microglia and inhibitory neuron differentiation, mirroring changes in ROBO1 expression. Immunofluorescence analysis of rat facial-nerve nucleus samples verified that SLIT2 protein levels were significantly increased in the facial-nerve nuclei of injured samples. In conclusion, despite the fact that this study is primarily founded on animal models and despite notable differences existing between animals and humans in terms of the facial motor nucleus, this study successfully identified SLIT2 as potential therapeutic targets for PFP. The SLIT2-ROBO axis stands out as a particularly promising candidate. SLIT2 may play a role in modulating neuroimmune interactions and promoting nerve repair. These findings provide a foundation for future clinical studies and targeted interventions to enhance recovery from PFP. Future research should focus on human sample validation to enhance clinical translation.

Animals↗

PubMed2026

Hypothesis-free evaluation of circulating metabolome provides cell-specific insights regarding the role of energy substrate availability in amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with limited therapeutic options. The circulating metabolome comprises small molecules present in plasma/serum which are the intermediates and end-products of cellular metabolism, and is linked to ALS pathogenesis. METHODS: We conducted hypothesis-free two-sample Mendelian randomisation (MR) analysis of the concentration of 575 plasma/serum metabolites, to determine which are causally linked to risk of ALS. Significant metabolites were validated in an independent GWAS of plasma/serum metabolite concentrations and evaluated for sex-specific effects. Correlations between directly measured patient biofluid metabolite concentrations and ALS risk/severity were examined in 94 ALS patients and 40 controls. We experimentally assessed metabolic function in a murine neurons and human astrocytes carrying an ALS-associated G4C2-repeat expansion within C9orf72. RESULTS: MR causally associated five metabolites with ALS risk after multiple-testing correction. Higher serum concentration of glycoprotein acetyls (P = 9.7e - 9, β = 0.21) and the peptide DSGEGDFXAEGGGVR (P = 8.0e - 6, β = 0.22) was associated with increased ALS risk, whereas higher plasma concentration of phenylalanylserine, isobutyrylcarnitine, and acetylcarnitine was protective (P < 5e - 5, β = - 0.29 to - 0.72). DSGEGDFXAEGGGVR has been linked to glucose metabolism but we have used genetic fine-mapping to link DSGEGDFXAEGGGVR, neuronal glucose uptake through GLUT3, and ALS risk. Direct measurement of metabolite concentrations in patient biofluids revealed elevated acetylcarnitine levels in patients with ALS, which were associated with delayed symptom onset (Cox regression, P = 0.02, HR = 0.4). Similarly, lactate is elevated in ALS patient CSF (ANOVA, P = 1.3e - 3) and in patients with longer survival time (Cox regression, P = 0.03, HR = 0.3). Plasma fructose is elevated in ALS patients with shorter survival time (Cox regression, P = 0.02, HR = 1.1). In vitro, neurons and astrocytes carrying an ALS-associated G4C2-repeat expansion within C9orf72 demonstrated reduced metabolic flexibility. CONCLUSIONS: We provide evidence that impaired energy substrate availability contributes to ALS risk and severity. CNS cell types differ in their use of energy substrates and therefore we postulate the relative importance of different cell types for different stages of disease. Our findings support further investigation of metabolic interventions to treat or prevent ALS.

Amyotrophic Lateral Sclerosis↗

PubMed2026

Causal determinants of gout in 614,000 adults: A two-sample Mendelian randomization study of dietary, lifestyle, and metabolic traits.

Gout affects over 55 million people worldwide, with prevalence projected to rise by 70% by 2050. Although observational studies have implicated several dietary, lifestyle, and metabolic risk factors, causal relationships remain uncertain because of confounding and reverse causation. Univariable and multivariable two-sample Mendelian randomization (MR) analyses were performed using genome-wide association data from 2 European cohorts: UK Biobank (6543 self-reported gout cases and 456,390 controls) and FinnGen (3576 cases and 147,221 controls). Genetic instruments for 12 exposures, including dried fruit, salad, and cheese intake; smoking initiation; physical activity; body mass index (BMI); and lipid traits, were derived from established genome-wide association study datasets. Inverse-variance weighted regression with multiplicative random effects was the primary analysis, complemented by weighted median, weighted mode, MR-Egger, MR-Pleiotropy RESidual Sum and Outlier, and 3 predefined multivariable models. Benjamini-Hochberg correction was applied across all 24 tests. BMI showed the strongest and most consistent causal effect on gout (FinnGen: odds ratio [OR] = 1.97, 95% confidence interval [CI] = 1.51-2.57; UK Biobank: OR = 1.006, 95% CI = 1.003-1.009; both P < .001) and remained significant in 5 of 6 multivariable models. Triglycerides increased risk in both cohorts (FinnGen: OR = 1.34, 95% CI = 1.08-1.66; UK Biobank: OR = 1.008, 95% CI = 1.004-1.012). These associations survived Benjamini-Hochberg correction, as did high-density lipoprotein cholesterol in UK Biobank (OR = 0.997, 95% CI = 0.994-0.999). Dried fruit intake was inversely associated with gout in FinnGen (OR = 0.34, 95% CI = 0.13-0.92, P = .034) but not in UK Biobank, and did not survive correction for multiple testing. No other exposure reached significance in either cohort. This study provides genetic evidence that BMI is the dominant modifiable causal determinant of gout, with triglycerides contributing independently. Dietary associations were weaker and did not withstand correction for multiple testing, and should be regarded as hypothesis-generating. These findings support prioritizing weight management and metabolic health in gout prevention.

Gout↗

PubMed2025

Plasma metabolites mediate the causal relationship between gut microbiota and erectile dysfunction: insights from Mendelian randomization study.

BACKGROUND: While the relationship between gut microbiota and erectile dysfunction (ED) has been reported, the specific pathways involved remain unclear. AIM: This study aims to investigate the causal relationship between gut microbiota and ED, and to identify the potential role of plasma metabolites as mediators. METHODS: Utilizing aggregated genome-wide association study (GWAS) data, a comprehensive two-sample Mendelian randomization (MR) analysis was performed involving 196 gut microbiota taxa, 1400 plasma metabolites and ED. Causal relationships between gut microbiota, plasma metabolites and ED were explored. In addition, mediation analysis was applied to identify the pathway from gut microbiota to ED mediated by plasma metabolites. OUTCOMES: This study reveals that plasma metabolites act as mediators regulating the influence of gut microbiota on ED. RESULTS: MR analysis identified causal relationships between six gut microbial taxa and ED, with Butyrivibrio increasing the risk of ED, while Alistipes, Prevotella 9, Dialister, Marvinbryantia, and LachnospiraceaeUCG010 exhibited protective effects. Additionally, 45 plasma metabolites demonstrated causal associations with ED. Finally, mediation analysis revealed four mediation relationships. Sensitivity analysis indicated no heterogeneity or pleiotropy in this study. CLINICAL IMPLICATIONS: Modulating gut microbiota or targeting specific metabolites may offer new therapeutic approaches for ED, highlighting the potential for microbiome-based interventions. STRENGTHS AND LIMITATIONS: The MR approach and large-scale GWAS data provide robust causal evidence, but the findings are limited by their focus on European populations and lack of experimental validation. Further studies are needed to confirm these mechanisms in diverse cohorts and functional models. CONCLUSION: This study establishes a causal link between gut microbiota, plasma metabolites, and ED, identifying specific microbial taxa and metabolites as key contributors to ED risk. The mediating role of plasma metabolites highlights potential therapeutic strategies, such as probiotics or dietary interventions targeting harmful metabolites.

Mendelian randomization↗

PubMed2025

Genetic evidence for repurposing GLP-1 receptor agonists in chronic kidney disease and IgA nephropathy: Metabolic and anti-inflammatory pathways beyond glycaemic control.

AIMS: Despite observational links between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and kidney benefits, causal mechanisms remain unclear. This study aims to dissect genetic causality and mediation pathways underlying the effects of GLP-1RAs on chronic kidney disease (CKD) and related renal outcomes. MATERIALS AND METHODS: Using large-scale Genome - Wide Association Study (GWAS) data, we applied two-sample Mendelian randomisation (MR) to estimate the causal effects of GLP-1RAs on CKD, estimated glomerular filtration rate (eGFR) and subtypes (IgA nephropathy, membranous nephropathy, nephrotic syndrome and chronic glomerulonephritis), with sensitivity analyses. The glycaemic markers (glycated haemoglobin [HbA1c] and blood glucose), type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) served as positive controls. Mediation MR assessed body mass index (BMI), lipids, glycaemic markers and inflammatory proteins. Data were sourced from MRC Integrative Epidemiology Unit Open Genome - Wide Association Studies OpenGWAS, FinnGen, GWAS Catalogue and cohort-specific studies. RESULTS: Positive control analyses revealed that genetically predicted GLP-1R activation was associated with reduced levels of HbA1c (p = 4.93E-15) and blood glucose (p = 9.73E-5), as well as a decreased risk of T2DM (p = 2.45E-4) and DN (p = 6.35E-4), fully validating the reliability of the genetic instruments. Genetic proxies for GLP-1R activation lowered risks of CKD (odds ratio [OR] = 0.83, p = 9.22E-9), immunoglobulin A nephropathy (IgAN) (OR = 0.70, p = 2.11E-3) and kidney function preservation (β = 0.01, p = 9.11E-3), but showed null effects on other CKD subtypes. Mediation analyses indicated that fibroblast growth factor 23 (FGF23) suppression mediated 26.57% of the effect on eGFR and 13.50% of CKD protection, whereas metabolic traits (BMI: 2.08% for CKD, 5.51% for eGFR; high-density lipoprotein: 0.79% for CKD, 2.34% for eGFR; HbA1c: 8.25% for eGFR) partially explained the benefits on CKD and eGFR. Only BMI exhibited a mediation effect on IgAN. Sensitivity analyses confirmed minimal pleiotropy. CONCLUSIONS: This study provides robust genetic evidence for repurposing GLP-1RAs in CKD and IgAN through anti-inflammatory (FGF23) and metabolic pathways, extending their utility beyond glucose control. While European ancestry data limit generalisability, our framework prioritises FGF23 and metabolic modulation as key targets for clinical trials in renal protection.

Humans↗

PubMed2025

Large-scale multi-omics analyses in Hispanic/Latino populations identify genes for cardiometabolic traits.

Here, we present a multi-omics study of type 2 diabetes and quantitative blood lipid and lipoprotein traits conducted to date in Hispanic/Latino populations (nmax = 63,184). We conduct a meta-analysis of 16 type 2 diabetes and 19 lipid trait GWAS, identifying 20 genome-wide significant loci for type 2 diabetes, including one novel locus and novel signals at two known loci, based on fine-mapping. We also identify sixty-one genome-wide significant loci across the lipid/lipoprotein traits, including nine novel loci, and novel signals at 19 known loci through fine-mapping. Next, we analyze genetically regulated expression, perform Mendelian randomization, and analyze association with transcriptomic and proteomic measure using multi-omics data from a Hispanic/Latino population. Using this approach, we identify genes linked to type 2 diabetes and lipid/lipoprotein traits, including TMEM205 and NEDD9 for HDL cholesterol, TREH for triglycerides, and ANXA4 for type 2 diabetes.

Female↗

PubMed2025

Exploring the causal relationship between plasma proteins and postherpetic neuralgia: a Mendelian randomization study.

BACKGROUND: The proteome represents a valuable resource for identifying therapeutic targets and clarifying disease mechanisms in neurological disorders. This study investigated potential causal relationships between plasma proteins and postherpetic neuralgia (PHN). METHODS: We conducted a two-sample Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary statistics from the Decode Genetics dataset (4,907 plasma proteins) and the FinnGen database (490 PHN cases and 435,371 controls). Instrumental variables (IVs) were selected based on relevance, independence, and exclusivity. Causal associations were assessed using inverse-variance weighted (IVW), MR-Egger regression, simple mode, weighted mode, and weighted median methods. Sensitivity analyses, including leave-one-out tests, evaluated result robustness, while colocalization analysis examined shared causal variants between traits. RESULTS: Eight plasma proteins showed significant associations with PHN (PFDR < 0.05). Higher levels of ATRN, PIANP, and CD48 correlated with increased PHN risk, whereas elevated KIR2DL5A, GPI, SEMG2, EIF4B, and HFE2 levels were associated with reduced risk. Sensitivity analyses supported these findings and excluded genetic pleiotropy as a major confounding factor. Colocalization analysis did not detect shared causal variants (PPH4 < 0.8). CONCLUSION: These results suggest a potential causal role for eight plasma proteins in PHN pathogenesis. While these proteins may serve as biomarkers or therapeutic candidates, further validation is required. This study advances understanding of PHN pathophysiology and supports future investigations into diagnostic and therapeutic strategies.

Mendelian randomization↗