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PubMed2026

ReverseGWAS identifies combined phenotypes associated with a genotype in GWA studies.

MOTIVATION: Traditional genome-wide association studies (GWAS) aim to uncover the genetic variants associated with a single phenotype of interest (typically a disease), and to elucidate its genotypic architecture. However, many of today's GWAS simultaneously measure multiple related phenotypes, leading to the possibility of pursuing the reverse aim of elucidating the "phenotypic architecture" of a single genetic variant. In other words, we may ask what combination of measured phenotypes is associated with a given genotypic variant. ReverseGWAS is an algorithmic platform for answering such questions in the context of large-scale multi-phenotype GWAS. RESULTS: We demonstrate the effectiveness of ReverseGWAS on simulated data, showing its ability to identify logical combinations of phenotypes with a reasonable amount of noise. We then apply it to a selection of combined phenotypes from the UK Biobank, obtaining 719 candidate associations using autoimmune diseases and 205 using common ICD10 codes. We find that the majority of these associations (546/719 and 111/205, respectively) successfully replicate in an independent cohort, FinnGen. AVAILABILITY AND IMPLEMENTATION: The source code of ReverseGWAS is freely available to non-commercial users as an installable R package at https://github.com/Leonardini/rgwas.

Phenotype↗

PubMed2026

Sex-specific associations of the plasma-proteome with incident coronary artery disease.

AIMS: The etiology of coronary artery Disease (CAD) appears different for men and women, yet insights into underlying sex-specific biological mechanisms are limited. We integrated genomic and proteomic analyses to investigate sex-specific associations of the plasma-proteome with CAD. METHODS AND RESULTS: In 40,829 UK Biobank participants (free-of-CAD, baseline-365 days thereafter; 55% women; mean age 56.9 ± 8.1 years), we examined associations between 2,922 plasma proteins and incident CAD over a median follow-up of 13.7 years (IQR 13.1-14.4) using multivariable-adjusted Cox proportional hazards models. Sex-specific analyses identified 440 female exclusive and 32 male exclusive proteins associated with incident CAD (FDR-corrected p < 0.05), revealing distinct pathway enrichments, including innate immune response in women and angiogenesis in men. Causality was assessed through combined and sex-stratified two-sample Mendelian randomization (MR) using inverse-variance-weighted analyses with genome wide association summary statistics from 422,108 men (61,969 cases) and 521,695 women (27,128 cases) (UK Biobank, FinnGen freeze 9). Integration of direct sex-protein interaction analyses with sex-combined MR identified 59 proteins with evidence for sex-specific causal effects. Four proteins demonstrated concordant directionality in sex-stratified MR analyses (n = 943,803) and multivariable regression models, namely CDKN2D, MYH9, and SKAP2 (women), and CTSH (men). To assess translational relevance, prioritized targets were further evaluated in secondary major adverse cardiovascular events among carotid endarterectomy patients (MACE; Athero-Express) and acute myocardial infarction (AMI; MISSION!) using plasma proteomics and ELISA. After further top-target identification in the context of MACE and AMI, clinical drug candidates were identified through a machine learning framework, including CTSH (men), and TNFRSF4 (both sexes). CONCLUSIONS: We identified sex-specific associations of proteins and biological pathways with incident CAD. Whereas the majority of proteins had consistent associations in both men and women, our findings suggest a degree of sex-specific pathogenesis with evidence for potential causality, opening new alleys for tailored prevention strategies and clinical cardiovascular risk management.

Journal Article↗

PubMed2024

Whole -genome survival analysis of 144 286 people from the UK Biobank identifies novel loci associated with blood pressure.

This study utilized UK Biobank data from 144 286 participants and employed whole-genome sequencing (WGS) data and time-to-event data over a 12-year follow-up period to identify susceptibility in genetic variants associated with hypertension. Following genotype quality control, 6 319 822 single nucleotide polymorphisms underwent analysis, revealing 31 significant variant-level associations. Among these, 29 were novel - 15 in Fibrillin-2 ( FBN2 ) and 4 in Junctophilin-2 ( JPH2 ). Mendelian randomization utilizing two identified variants (rs17677724 and rs1014754) suggested that a genetically induced decrease in heart FBN2 expression and an increase in adrenal gland JPH2 expression were causally linked to hypertension. Phenome-wide association (PheWAS) analysis using the FinnGen dataset confirmed positive associations of rs17677724 and rs1014754 with hypertension, assessed across 2727 traits in 377 277 individuals. Lastly, rs1014754 positively associated with kallistatin, whereas rs17677724 negatively associated with renin in the Fenland study, suggesting a counterregulatory response to high blood pressure. This study, employing WGS data, identified novel genetic loci and potential therapeutic targets for hypertension.

Humans↗

PubMed2025

Causal relationships between modifiable risk factors and heart failure: A comprehensive Mendelian randomization study.

Heart failure threatens human health across the globe. Comprehensively identifying its risk factors has public health importance. This work utilized the Mendelian randomization (MR) method to evaluate the effects of over 200 modifiable factors on heart failure. The data from genome-wide association studies (GWAS) was used, with the sample size ranging from 711 to 1232,091. Two distinct GWAS datasets for heart failure were employed for results validation. The inverse variance weighted (IVW) method was used and other supplementary models were employed for comparison. Sensitivity analysis was conducted to verify the results. After integrating the MR estimates derived from heart failure GWAS datasets from integrative epidemiology unit (IEU) and Finngen, we found that body measurement indices like body mass index, whole body fat mass, trunk fat mass, basal metabolic rate, body fat percentage, waist circumference, and waist-hip ratio, were associated with a higher risk of heart failure. Similarly, smoking behavior, sedentary behavior, overall health rating, and type 2 diabetes were determined to increase the risk of heart failure. In contrast, college or university degree showed a protective effect on heart failure. Among these significant findings, body mass index, whole body fat mass, trunk fat mass, basal metabolic rate, body fat percentage, overall health rating, smoking initiation, waist circumference, lifetime smoking index, college or university degree, sedentary behavior, waist-hip ratio, and type 2 diabetes were replicated validated. This MR work figured out that obesity, socioeconomic factors, lifestyle factors, and metabolic features showed broad relations with heart failure. The findings would provide evidence for future policy development for the management of heart failure.

Humans↗

PubMed2025

Causal relationship between albumin, total protein, and colorectal cancer risk: A 2-sample Mendelian randomization study.

Albumin (ALB) and total protein (TP) are vital constituents of the blood, and their levels and roles in the risk of colorectal cancer (CRC) are of significance. Previous observational studies have reported correlations among ALB, TP, and CRC. However, the existence of a causal relationship between ALB and CRC in European populations has not been adequately investigated and the causal link between TP and CRC remains unexplored. To address these gaps, we applied Mendelian randomization (MR) to investigate the potential causal relationship between ALB, TP, and CRC. Two-sample MR analysis was used to investigate whether there was a causal relationship between ALB, TP, and CRC. Our exposure data were extracted from genome-wide association study (GWAS) databases sourced from the UK Biobank, containing 315,268 and 314,921 Europeans participants for ALB and TP analyses, respectively. Single nucleotide polymorphisms that were significantly associated with ALB and TP were assessed using GWAS datasets. Our data were derived from the FinnGen Consortium CRC GWAS, which contained 6509 CRC cases and 28,7137 controls. Causal inference between ALB, TP, and CRC was performed using 3 MR methods: inverse variance weighting (IVW), MR-Egger, and weighted median. The IVW analysis showed no significant causal association between ALB and CRC (OR = 1.04, 95% CI = 0.89-1.21, P = .65). In contrast, the IVW analysis for TP and CRC showed a significant causal association (OR = 0.78, 95% CI = 0.66-0.92, P = .003), suggesting a reduced risk of CRC. Through a 2-sample MR study investigating the causal relationship between ALB, TP, and CRC in a European population, our findings revealed a significant causal relationship between TP and a reduced risk of CRC.

Humans↗

PubMed2026

Plasmacytoid dendritic cell-mediated L-glutamate catabolism links gut microbiota to male infertility.

Emerging evidence suggests that gut microbiota composition influences male reproductive health; however, the immunometabolic mechanisms underlying this association remain insufficiently characterized. We investigated whether specific immune cell-mediated metabolic pathways, particularly plasmacytoid dendritic cell (pDC)-driven L-glutamate catabolism via the hydroxyglutarate pathway, contribute to the causal link between gut microbiota and male infertility. We conducted a 2-sample, 2-step Mendelian randomization (MR) analysis using inverse-variance weighting as the primary estimator and Bayesian weighted MR for robustness. Exposure data comprised 412 gut microbial taxa/metabolic pathways and 731 immune cell phenotypes from large European-ancestry genome-wide association studies. Male infertility genome-wide association studies data (1429 cases; 128,710 controls) were obtained from FinnGen R10. Only exposure-mediator-outcome pairs meeting stringent pleiotropy, heterogeneity, and reverse-causality criteria were retained for mediation analysis. Nine microbial taxa/metabolic pathways and 18 immune traits exhibited putative causal associations with male infertility. The L-glutamate degradation V pathway via hydroxyglutarate was linked to reduced infertility risk (inverse-variance weighting odds ratio [OR] = 0.68; 95% confidence interval, 0.52-0.89; P = .005). Two-step MR suggested that forward scatter area on pDCs may mediate this association, although the mediation effect was imprecise (effect = 0.0277; 95% confidence interval, -0.0348 to 0.0903). This study provides suggestive genetic evidence that pDC-mediated glutamate catabolism may connect gut microbial metabolic activity to male infertility. These findings highlight immunometabolic pathways as testable targets for mechanistic validation and microbiota-directed interventions.

Male↗

PubMed2026

Association between 1400 blood metabolites and the risk of ankylosing spondylitis: A 2-stage, 2-sample Mendelian randomization study.

Human blood metabolites have been closely linked to ankylosing spondylitis (AS) in observational studies, yet direct causal evidence remains limited. This study aims to use Mendelian randomization (MR) to pinpoint causal metabolites associated with AS and to predict potential side effects of metabolite interventions. Genetic instruments for exposure were sourced from a genome-wide association study of 1400 blood metabolites, while genome-wide association study data for AS outcomes were derived from the FinnGen cohort. The primary MR analysis was conducted using the inverse variance weighted method. Supplemental analyses were conducted using weighted median, MR-Egger, simple mode, and weighted mode methods, while sensitivity analyses were performed to evaluate heterogeneity and pleiotropy. A replication analysis using an additional the UK Biobank cohort was also performed to determine metabolites associated with AS. The Steiger test and linkage disequilibrium score regression were used to further strengthen causal inference. Lastly, a phenome-wide Mendelian randomization analysis was performed to investigate the potential on-target side effects of metabolite interventions. After comprehensive analyses, 3 metabolites (the 2'-deoxyuridine levels, the hate to mannose ratio, and the Uridine to 2'-deoxyuridine ratio) were identified as being genetically associated with AS. The phenome-wide Mendelian randomization analysis revealed that the hate to mannose ratio might have deleterious effects on 4 other diseases, while no significant associations were found for the 2'-deoxyuridine levels or the uridine to 2'-deoxyuridine ratio with other diseases. This systematic MR analysis unveiled the potential role of the 2'-deoxyuridine levels, hate to mannose ratio and uridine to 2'-deoxyuridine ratio as the causal mediator in the development of AS. Considering the advantages and disadvantages, 2'-deoxyuridine appears as the most promising prospective therapeutic target for the prevention of AS.

Humans↗

PubMed2026

Ferroptosis as a mediator of gut microbiota-driven inflammatory bowel disease: Evidence from genetic analyses.

Gut microbiota dysbiosis is increasingly recognized as a contributor to inflammatory bowel disease (IBD), yet causal relationships and underlying mechanisms remain unclear. Ferroptosis, an iron-dependent form of regulated cell death, plays a key role in epithelial barrier damage and inflammation. This study aimed to determine whether specific gut microbial taxa are causally associated with IBD and whether ferroptosis-related genes mediate this association using Mendelian randomization (MR). Two-sample MR and mediation MR analyses were performed using genome-wide association study summary data from the FinnGen consortium (IBD), the genome-wide association study catalog (473 gut microbial taxa), and the deCODE database (ferroptosis-related genes). Instrumental variables were selected with thresholds of P < 1 × 10-6 for microbes and P < 5 × 10-8 for traits, and linkage disequilibrium clumping (r2 < 0.001) was applied. Twenty-three microbial taxa showed significant causal associations with IBD (e.g., Chromatiales, OR = 0.51; Acetobacterales, OR = 2.61). Several ferroptosis-related genes were linked to IBD risk (e.g., GPX4, STAT3, IDO1). Mediation MR revealed that genes such as MUC1, IDO1, and ADAM23 partially mediated microbial effects on IBD, with mediation proportions up to 7.6%. This study provides novel genetic evidence supporting a gut microbiota-ferroptosis-IBD axis. Ferroptosis-related pathways may partially mediate microbial effects on IBD pathogenesis and represent promising targets for future therapeutic interventions.

Ferroptosis↗

PubMed2026

Genetically predicted childhood traits and parental health and risk of pediatric psychiatric disorders: A 2-sample Mendelian randomization study.

The etiology of pediatric psychiatric disorders is complex, involving intergenerational influences and a child's own developmental health. We aimed to investigate the potential effects of genetically predicted childhood traits (childhood obesity, absence epilepsy, intelligence) and parental health traits (longevity, Alzheimer disease, severe depression) on the risk of several childhood and adolescent psychiatric disorders. We employed a 2-sample Mendelian randomization (MR) design using summary statistics from large-scale genome-wide association studies. Data for parental health exposures were primarily from the UK Biobank. Data for childhood trait exposures were from various consortia. Data for outcomes - conduct disorder, mixed conduct and emotional disorders, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and broader behavioral/emotional and social disorders - were sourced from FinnGen and the Psychiatric Genomics Consortium, among others. We used the inverse-variance weighted method for the primary analysis, with MR-Egger, weighted median, and weighted mode as additional analyses. To test the robustness of the results, we conducted sensitivity analyses using MR-Egger regression, Cochran Q test for heterogeneity, the MR-pleiotropy residual sum and outlier test, and a leave-one-out analysis. Genetic liability for childhood obesity was associated with an increased risk of ASD (odds ratio = 1.06, P = .016) and ADHD (odds ratio = 1.09, P = .026), even though these associations did not withstand multiple testing correction. No other robust, statistically significant causal associations were identified. Sensitivity analyses showed limited evidence of bias from horizontal pleiotropy for the main findings. Our findings provide MR evidence supporting potential links from genetic liability for childhood obesity to increased risks of ASD and ADHD. These results highlight the importance of considering a child's early-life health trajectory in the etiology of pediatric psychiatric disorders.

Humans↗

PubMed2026

Genetically predicted lower FLT3L levels increase the risk of hypertrophic cardiomyopathy partly mediated by phosphate: Evidence from a 2-step Mendelian randomization analysis.

We performed a 2-step Mendelian randomization (MR) study to investigate the associations of Fms-related tyrosine kinase 3 ligand (FLT3L) and phosphate levels with the risk of hypertrophic cardiomyopathy (HCM). Genetic instruments for 75 circulating inflammatory factors were obtained from the NHGRI-EBI GWAS Catalog, while summary statistics for circulating phosphate and HCM were derived from the UK Biobank and FinnGen, respectively. Univariable MR analysis using the inverse-variance weighted method indicated that genetically predicted higher phosphate levels were associated with an increased risk of HCM (OR = 1.36, P = 4.82 × 10-2). Among the inflammatory markers, FLT3L emerged as a significant candidate and showed inverse associations with phosphate levels (β = -0.05, P = 1.70 × 10-9) and HCM (OR = 0.79, P = 4.10 × 10-2). Bidirectional MR analyses did not support a causal effect of phosphate on FLT3L. Mediation analysis suggested that phosphate levels accounted for an estimated 12.05% of the total effect of FLT3L on HCM. Genetic liability to lower FLT3L levels is associated with a higher risk of HCM, and this relationship may be partially mediated through circulating phosphate levels.

Humans↗

PubMed2026

Genetically proxied circulating PD-1/PD-L1 levels and broadly defined myocarditis: A bidirectional Mendelian randomization study with exploratory lipidomic analyses.

Myocarditis is an inflammatory myocardial disease with potentially severe outcomes. Programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) regulate immune tolerance, but the association between lifelong genetically proxied circulating PD-1/PD-L1 levels and broadly defined myocarditis remains uncertain. We investigated these associations and explored related plasma lipid species. We conducted bidirectional 2-sample Mendelian randomization using proteomic genome-wide association data from the UK Biobank Pharma Proteomics Project and INTERVAL. FinnGen Release 10 was the primary broadly defined myocarditis outcome, and an independent myocarditis genome-wide association study (GCST90018882) provided outcome-level validation. Complementary estimators, heterogeneity and pleiotropy diagnostics, influence analyses, MR-RAPS, and supportive meta-analyses were performed. Associations with 179 plasma lipid species were examined in exploratory analyses. Higher genetically proxied circulating PD-L1 was inversely associated with broadly defined myocarditis in UKB-PPP (odds ratio [OR] 0.834, 95% confidence interval [CI] 0.698-0.995; P = .0441), and the independent INTERVAL analysis yielded a concordant inverse estimate (OR 0.619, 95% CI: 0.434-0.883; P = .0083); no clear association was observed for PD-1. The MR-RAPS estimate retained the inverse direction; estimates against the independent broadly defined myocarditis dataset were also inverse, and supportive meta-analyses across protein and outcome sources yielded inverse pooled estimates. Reverse MR did not support effects of broadly defined myocarditis liability on circulating PD-1 or PD-L1. Exploratory lipid analyses identified nominal associations requiring confirmation. Higher genetically proxied circulating PD-L1 may be associated with a lower risk of broadly defined myocarditis, supporting further investigation of PD-L1-related immune regulation. These findings do not directly estimate the effects of pharmacologic PD-1/PD-L1 blockade. The lipid findings are hypothesis-generating.

Myocarditis↗

PubMed2026

Investigating the causal effects of physical activity and sedentary behavior on hernia risk: A two-sample Mendelian randomization approach.

The global prevalence of hernia is increasing, particularly due to the aging population. Although physical activity and sedentary behavior are known to influence various health outcomes, their specific roles in hernia development remain inadequately investigated. This study aimed to systematically assess the causal relationships between physical activity, sedentary behavior, and the risk of hernia development using Mendelian randomization (MR) analysis. We used genome-wide association study data from the UK Biobank and FinnGen Biobank to explore the causal effects of sedentary behavior on hernia risk via 5 distinct MR approaches. To ensure the reliability of our risk models, we performed sensitivity analyses, including Cochran's Q test, MR-Egger intercept analysis, leave-one-out analysis, and funnel plots. Furthermore, we employed multivariable MR analysis to determine the independent causal effects of both physical activity and sedentary behavior. Our findings indicate that moderate-to-vigorous physical activity (MVPA) was significantly associated with an increased risk of inguinal hernia, with an odds ratio of 1.844 (95% confidence interval, 1.181-2.879; P = .007). Associations between sedentary behavior and diaphragmatic or umbilical hernia were inconsistent across methods and were sensitive to pleiotropy; thus, no robust causal relationship was established. Multivariable MR analysis further confirmed the independent and significant causal relationship between MVPA and inguinal hernia, with an odds ratio of 1.901 (95% confidence interval, 1.098-3.291; P = .022). Our study highlights a significant association between MVPA and an increased risk of inguinal hernia, suggesting that physical activity should be carefully considered in preventive strategies for hernias. However, the relationship between sedentary behavior and hernia development warrants further investigation.

Mendelian Randomization Analysis↗

PubMed2026

Association of gestational diabetes with other lactation-related disorders: A 2-sample Mendelian randomization analysis of causal effects.

Gestational diabetes mellitus (GDM) is associated with adverse metabolic outcomes and may also be related to postpartum breast and lactation disorders. Observational studies are susceptible to confounding and reverse causation. We used a 2-sample Mendelian randomization design to examine the association between genetic liability to GDM and other disorders of the breast and lactation associated with childbirth. Genetic liability to GDM was associated with higher odds of a composite phenotype of breast and lactation disorders associated with childbirth. Replication using independent samples and more specific clinical outcomes is required. Summary statistics for GDM and the FinnGen outcome "other disorders of breast and lactation associated with childbirth" were obtained from the Integrative Epidemiology Unit open genome-wide association study resource. single nucleotide polymorphisms associated with GDM (P < 5 × 10-6) were clumped (R2 < 0.001) within 10,000 kb. The inverse-variance weighted method was the primary analysis; Mendelian randomization-Egger, weighted median, simple mode, and weighted mode analyses were complementary methods. Heterogeneity, directional horizontal pleiotropy, leave-one-out, and Steiger directionality analyses were performed. Nineteen single nucleotide polymorphisms were retained; F statistics ranged from 21.08 to 288.04. Genetic liability to GDM was associated with higher odds of the outcome in the inverse-variance weighted analysis (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.08-2.09; P = .0165). The weighted median (OR, 1.76; 95% CI, 1.09-2.84; P = .0216) and weighted mode estimates (OR, 1.98; 95% CI, 1.21-3.26; P = .0148) were directionally consistent. There was no statistical evidence of heterogeneity or directional horizontal pleiotropy. The Steiger test supported the direction from GDM to the outcome (P = 1.30 × 10-11).

Diabetes, Gestational↗

PubMed2025

THE CAUSAL ASSOCIATION OF CARDIOMETABOLIC DISEASES AND SEPSIS-RELATED OUTCOMES: A MENDELIAN RANDOMIZATION AND POPULATION STUDY.

Objective: The causality between cardiometabolic disease (CMD) and sepsis has remained largely unknown. To elucidate this, we conducted a Mendelian randomization (MR) and population study. Methods: First, we used univariable and multivariable MR analyses to investigate causal associations between CMD and sepsis-related outcomes. We obtained genome-wide association study summary from both the MRC Integrative Epidemiology Unit and the FinnGen consortium. Subsequently, a two-step mediation MR analysis was performed to explore mediators. Afterward, we conducted an observational study using the Medical Information Mart for Intensive Care IV database, in which multivariable logistic regression models were utilized to examine the relationship between CMD and sepsis-related outcomes. Results: In the MR study, type 2 diabetes mellitus (OR = 1.058, 95% CI = 1.017-1.100, P = 0.005), obesity (OR = 1.113, 95% CI = 1.057-1.172, P < 0.001), and heart failure (HF) (OR = 1.178, 95% CI = 1.063-1.305, P = 0.002) were independently causally related to sepsis. Obesity (OR = 1.215, 95% CI = 1.027-1.437, P = 0.023) and HF (OR = 1.494, 95% CI = 1.080-2.065, P = 0.015) also showed independent causal associations with sepsis critical care admission. Mediation MR analysis identified 23 blood metabolites potentially causally linked to sepsis ( P < 0.05), yet none mediated the relationship between CMD and sepsis. In the observational study, we found associations between sepsis and several conditions including type 2 diabetes mellitus, obesity, hypertension, stroke, HF, and hyperlipidemia after adjusting for confounding factors. Moreover, hypertension, stroke, HF, coronary artery disease, and hyperlipidemia were linked to sepsis critical care admission. Conclusion: This study has, for the first time, revealed indicative evidence of a causal relationship between CMD and sepsis through observational and genetic evidence. Taken together, clinical attention to sepsis may be warranted among patients with CMD.

Humans↗

PubMed2025

Genetic liability to meniscus degeneration and its comorbidity patterns: a phenome-wide association study in the UK Biobank.

Meniscus degeneration is a common knee pathology causing pain, disability, and osteoarthritis. While mechanical factors are established, the contribution of inherited genetic liability to its systemic disease patterns remains unclear. We applied a polygenic risk score (PRS) for meniscus degeneration, derived from FinnGen genome-wide association study (GWAS) results to 323,999 UK Biobank participants and conducted a phenome-wide association study (PRS-PheWAS) across 962 clinical phenotypes. The PRS-PheWAS revealed significant associations beyond musculoskeletal traits, extending to metabolic, cardiovascular, psychiatric, and gastrointestinal domains, indicating broad shared genetic architecture. To support these findings, linkage disequilibrium score regression confirmed strong genetic correlations with osteoarthritis and related arthropathies, and genotype-tissue expression (GTEx) analysis highlighted tissue-specific expression of lead genes (e.g., GDF5, SOX5, BMP6) in connective and metabolic tissues. The results demonstrate that genetic liability to meniscus degeneration extends beyond the knee, sharing pathways with systemic conditions. This systemic genetic architecture underscores the need for integrative management approaches that combine orthopedic care with metabolic and lifestyle interventions.

Journal Article↗

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↗

PubMed2026

Hyperthyroidism Is Genetically Associated With Reduced Risk of Parkinson's Disease: A Mendelian Randomization Analysis.

Parkinson's disease (PD) is a progressive neurodegenerative disorder whose aetiology involves an intricate interplay of genetic, immune, metabolic and environmental factors. Endocrine dysfunction-particularly disturbances of thyroid hormone signalling-has been proposed as a contributor to neurodegeneration, but conventional observational studies have produced inconsistent results, and prior Mendelian randomization (MR) work has largely focused on continuous thyroid biomarkers rather than clinically defined hyperthyroid disease states. To clarify this relationship, we performed a two-sample bidirectional and multivariable MR (MVMR) analysis using large-scale genome-wide association study (GWAS) summary statistics from the FinnGen and IEU Open GWAS databases (European ancestry). Single-nucleotide polymorphisms (SNPs) reaching genome-wide significance (p < 5 × 10-8) for Graves' disease and thyrotoxicosis with diffuse goitre served as instrumental variables. The inverse-variance weighted (IVW) method was the primary analysis, complemented by MR-Egger, weighted median, weighted mode and simple mode estimators, and MVMR adjusted for smoking, alcohol consumption, and body mass index (BMI). In forward analyses, genetically proxied Graves' disease (OR = 0.942, 95% CI 0.901-0.985, p = 0.008) and thyrotoxicosis with diffuse goitre (OR = 0.929, 95% CI 0.879-0.982, p = 0.009) were associated with a lower risk of PD, whereas reverse analyses showed no significant effect of genetic liability to PD on either thyroid trait. The inverse associations remained stable across MVMR models, and sensitivity analyses (Cochran's Q, MR-Egger intercept, MR-PRESSO, leave-one-out) showed no evidence of heterogeneity or horizontal pleiotropy. Collectively, these findings provide genetic evidence consistent with a protective relationship between hyperthyroid disease states and PD, independent of major lifestyle confounders. By focusing on clinically defined hyperthyroid entities rather than continuous thyroid indices, our study complements prior MR work and highlights the thyroid-brain axis-encompassing thyroid hormone signalling and autoimmune-mediated immune modulation-as a biologically plausible and potentially modifiable contributor to PD risk that warrants further mechanistic and translational investigation.

Humans↗

PubMed2025

New insights into genetic comorbidity mechanisms: type 2 diabetes and primary open-angle glaucoma.

AIMS: To investigate the shared genetic mechanisms between type 2 diabetes (T2D) and primary open-angle glaucoma (POAG). Using large-scale genome-wide association study (GWAS) data, we performed single nucleotide polymorphism (SNP) level analysis to detect pleiotropic variants and loci, paired eQTL mapping analysis and gene-level analysis to identify candidate pleiotropic genes. In addition, Mendelian randomisation (MR) analysis was performed to assess causal associations. MATERIALS AND METHODS: We used POAG GWAS data from Finngen (9565 cases and 430 250 controls) and T2D GWAS data from 55 555 European ancestry samples. We used Linkage Disequilibrium SCore (LDSC) regression to assess the genetic association between T2D and POAG and further used PLeiotropic Analysis under the COmposite null hypothesis (PLACO) to identify shared genetic variants between paired traits. Finally, we further used MR analysis to explore the causal association between T2D and POAG at the genetic level. RESULTS: The LDSC results and MR analysis revealed that the T2D effect was significantly higher than that of the POAG (OR=1.09, 95% CI 1.03 to 1.14, p=1.50×10-3). The PLACO property analysis determined that the T2D sum POAG shared 178 individual SNPs, separate localisation of 79 individual causes. The five most popular choices are based on the effectiveness of CCND2, SVEP1, ST6GAL1, TCF7L2 and HMGA2. expression quantitative trait loci mapping further revealed 36 genes with regulatory roles in optic nerve-related brain tissues. Functional enrichment analyses indicated that these pleiotropic genes are involved in neurodevelopmental, neuroprotective and metabolic pathways, with tissue-specific enrichment observed in neural, pancreatic, adipose and retinal tissues. It is possible to present the main comorbid mechanisms of T2D and POAG. CONCLUSIONS: Our study provides new insights into the aetiology and pathogenesis of T2D and POAG at the genetic level.

Humans↗