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PubMed2026

Hidradenitis Suppurativa and Smoking, Obesity, Psoriasis, Inflammatory Bowel Disease, and Systemic Sclerosis: Results From A 2-Sample Mendelian Randomization Study.

IMPORTANCE: Smoking and obesity are associated with risk of hidradenitis suppurativa, and both are considered important environmental risk factors. However, a causal relationship remains unproven. OBJECTIVE: To primarily investigate the relationship between body mass index (BMI, calculated as weight in kilograms divided by height in meters squared) and smoking and HS, and secondarily to investigate potential relationships between 3 inflammatory diseases (psoriasis, inflammatory bowel disease [IBD], and systemic sclerosis [SSc]) and HS. DESIGN, SETTING, AND PARTICIPANTS: A mendelian randomization (MR) study conducted in 2024 on 5 exposure phenotypes (BMI, smoking, psoriasis, IBD, and SSc) on the outcome of phenotype HS was conducted. The MR analyses used large genetic White European cohorts from genome-wide association studies (GWAS) of each of the 6 phenotypes. Initial analyses were conducted May, 2024, and were updated in May, 2025. EXPOSURE: The 5 exposure phenotypes using predetermined genome-wide significant single-nucleotide variants as proxies for each particular exposure. RESULTS: The GWAS on HS included 4814 case patients and more than 1.2 million controls from Denmark, Iceland, Finland, the UK, and the US. The BMI GWAS involved 700 000 individuals from the UK Biobank and GIANT consortium. Smoking data were obtained from 1.23 million participants in an international consortium. The psoriasis GWAS analyzed 39 498 case patients and 286 769 controls from White European populations and a DNA genetic testing company. The IBD GWAS meta-analysis included 38 155 case patients and 48 485 controls from the International Inflammatory Bowel Disease (IBD) Genetics Consortium. The SSc GWAS included 9095 case patients and 17 584 controls from White European populations. Genetic correlations (rg) were found between HS and all exposure phenotypes except SSc (BMI: rg = 0.36, P < .001; smoking: rg = 0.33, P < .001; IBD: rg = 0.25, P < .001; psoriasis: rg = 0.34, P < .001; SSc: rg = 0.33, P = .22). MR analyses supported an effect of BMI on HS (β = 0.87; odds ratio [OR] per BMI unit, 1.20; 95% CI, 1.17-1.23; P < .001) without signs of pleiotropy (slope: β = 0.91, P < .001, P for intercept = .76). Smoking showed a significant causal estimate (β = 0.59, P < .001), but results became inconclusive in subsequent sensitivity analyses. Among IBD, psoriasis, and SSc, results supported a causal effect of IBD on HS (β = 0.18, OR = 1.20; 95% CI, 1.15-1.24; P < .001), without signs of pleiotropy. CONCLUSIONS AND RELEVANCE: These findings indicate causal effects of IBD and increased BMI on the risk of HS. This information may help physicians inform patients about disease risk contributed by modifiable lifestyle behaviors, which can be beneficial for planning lifestyle interventions.

Humans↗

PubMed2025

New evidence for the protective effect of gut microbiota regulation of ferroptosis-related proteins against osteoporosis.

Osteoporosis (OP), characterized by bone degradation and increased fracture susceptibility, constitutes a significant global health burden. Recent findings implicate gut microbiota and ferroptosis in the regulation of bone metabolism; however, causal evidence for the gut microbiota's influence on OP specifically via ferroptosis regulation remains to be established. This study employed two-sample Mendelian randomization (MR) using genome-wide association study (GWAS) summary statistics to investigate these causal relationships and delineate mediating pathways.We assessed causal links between gut microbiota, ferroptosis-related proteins, and OP risk. Associations for gut microbiota abundance and ferroptosis-related proteins were derived from GWAS data and Icelandic blood-derived protein quantitative trait loci, respectively. Outcome data for OP were obtained from the FinnGen Release R12. The primary analysis utilized the inverse variance weighted (IVW) method, supplemented by sensitivity analyses to evaluate heterogeneity and horizontal pleiotropy.  MR analysis identified 33 gut microbial taxa causally associated with OP risk: 13 protective and 20 detrimental. Similarly, 34 ferroptosis-related proteins were categorized as protective (18) or detrimental (16) for OP. Mediation analysis revealed that the protective effect of Terrisporobacter othiniensis on OP is partially mediated by the ferroptosis regulator MDM4 (indirect effect β = -0.020, 95% CI: -0.068 to 0.029), accounting for 6.8% of the total effect. Sensitivity analyses showed no significant evidence of heterogeneity or horizontal pleiotropy. This study provides the first genetically validated evidence supporting a causal relationship between specific gut microbiota, ferroptosis-associated proteins, and OP susceptibility. Specifically, Terrisporobacter othiniensis demonstrates a novel protective mechanism, modulating OP risk partly through the ferroptosis regulator MDM4. These findings broaden understanding of the "gut-bone axis" and highlight the gut microbiota-ferroptosis pathway, particularly the MDM4/p53 axis, as a promising target for novel OP prevention and therapeutic strategies.

Ferroptosis↗

PubMed2026

Limited evidence for causal effects of circulating inflammatory cytokines on the risk of selected hematologic malignancies: a two-sample Mendelian randomization study.

BACKGROUND: Hematologic malignancies have been linked to inflammatory cytokine levels; however, whether a causal relationship exists between inflammatory cytokines and hematologic malignancies remains uncertain. This study aimed to explore the causal association between inflammatory cytokines and hematologic malignancies using Mendelian randomization (MR) analysis. METHODS: Summary statistics from genome-wide association studies of 41 inflammatory cytokines, C-reactive protein, and selected hematologic malignancies were obtained from the UK Biobank, YFS, FINRISK, and FinnGen consortia. The inverse-variance weighted (IVW) method with false discovery rate (FDR) adjustment was used as the primary MR method. The weighted median, MR-Egger regression, MR-Robust Adjusted Profile Score, and MR pleiotropy residual sum, and outlier methods were used as supplied analyses. MR-Egger intercept estimates and Cochran's Q test were used to assess pleiotropy and heterogeneity. Leave-one-out analysis and the MR Steiger test were used to assess sensitivity and the direction of causality. RESULTS: Although the primary IVW analysis indicated that some inflammatory cytokines were associated with risk of selected hematologic malignancies, no significant causal relationship between cytokines and selected hematologic malignancies was detected after FDR correction. CONCLUSION: Genetically predicted cytokine levels did not have a significant effect on the risk of the selected hematologic malignancies. Further research is warranted to confirm the potential association between cytokine levels and the risk of selected hematologic malignancies.

C-reactive protein↗

PubMed2025

Mendelian randomization and FinnGen analysis of the causal relationship between 473 gut microbiota species and chronic sinusitis.

OBJECTIVE: To investigate the causal associations between Gut Microbiota (GM) and Chronic Sinusitis (CRS) using Mendelian Randomization (MR). METHODS: Genome-Wide Association Study (GWAS) summary statistics for 473 GM taxa were obtained from MiBioGen consortium. CRS data (22,099 cases vs. 371,520 controls) were sourced from the FinnGen R12 cohort. Causal effects were estimated via Inverse Variance-Weighted (IVW), MR-Egger, weighted median, and Bayesian-weighted MR methods. Sensitivity analyses (heterogeneity and horizontal pleiotropy tests) were performed to validate robustness. RESULTS: IVW analysis identified 20 GM taxa significantly associated with CRS risk (p < 0.05). Of these, 7 taxa (e.g., Francisellales, Roseibacillus, Merdibacter massiliensis) exhibited risk-increasing effects, while 13 taxa (e.g., Firmicutes I, Succinivibrionaceae) showed protective effects. Sensitivity analyses confirmed the absence of significant heterogeneity (Cochran's Q p > 0.05) or pleiotropy (MR-Egger intercept p > 0.05). Bayesian-weighted MR validated 18 causal relationships (posterior probability > 95%), except for RUG420 sp900317985 and UBA7703 (non-significant). CONCLUSIONS: This MR study provides genetic evidence supporting causal roles of specific GM taxa in CRS pathogenesis. These findings highlight the gut-sinus axis as a potential therapeutic target and underscore the utility of large-scale biobanks (e.g., FinnGen) in advancing precision medicine. LEVEL OF EVIDENCE: Level 5. Mendelian Randomized (MR) studies are second only to randomized controlled trials in terms of the level of evidence.

Humans↗

PubMed2026

Causal Relationships Between Oral Microbiota and Inflammatory Skin Diseases.

INTRODUCTION AND AIMS: The oral microbiome has been increasingly linked to systemic inflammation and immune dysregulation, but whether specific oral bacteria causally contribute to inflammatory skin diseases remains unclear due to confounding and reverse causation. This study aimed to assess the causal effects of 43 oral microbiota taxa on the risk of five inflammatory skin diseases using a Mendelian randomization (MR) approach. METHODS: We performed a two-sample MR analysis using genetic instruments for oral microbiota derived from publicly available genome-wide association studies and outcome data from the FinnGen consortium. Causal effects of oral taxa on systemic lupus erythematosus, vitiligo, pemphigus, localized scleroderma, and dermatitis herpetiformis were estimated. The inverse-variance weighted method served as the primary analysis, complemented by sensitivity analyses to evaluate horizontal pleiotropy, heterogeneity, and reverse causality. RESULTS: MR analyses identified several putative causal associations between oral microbiota and inflammatory skin diseases. Genus Granulicatella and an unknown Streptococcus species (ASV0009) showed causal effects on systemic lupus erythematosus. Family Lachnospiraceae_[XIV] and an unknown Rothia species (ASV0016) were associated with vitiligo. Five oral microbiota taxa demonstrated causal associations with pemphigus. Actinomyces species micronuciformis was linked to localized scleroderma. Order Fusobacteriales and an unknown Neisseria species (ASV0004) were associated with dermatitis herpetiformis. No significant heterogeneity or horizontal pleiotropy was detected in sensitivity analyses. CONCLUSION: This MR study provides genetic evidence supporting a causal role of specific oral bacteria in the development of several inflammatory skin diseases, highlighting the oral microbiome as a potential contributor to cutaneous autoimmunity and inflammation. CLINICAL RELEVANCE: Our findings highlight the putative role of the oral microbiome as a plausible candidate for mechanistic and clinical investigations into the prevention or adjunctive management of selected inflammatory skin diseases. However, oral hygiene improvement, targeted antimicrobials, and other microbiota-directed interventions were not directly tested in this MR study and remain hypothetical strategies requiring validation in experimental and clinical studies.

Humans↗

PubMed2026

Mapping the immune-genetic architecture of Epstein-Barr virus-related phenotypes and multiple sclerosis through a single-cell genetic framework for target prioritization and pharmacologic hypothesis generation.

BACKGROUND: Multiple sclerosis (MS) is a severe neuroinflammatory disease causing substantial long-term disability. Strong epidemiologic evidence links Epstein-Barr virus (EBV) exposure with MS risk, but genetic evidence for immune target prioritization in EBV-related phenotypes remains limited. METHODS: We integrated single-cell cis-eQTL data from 14 immune cell types with GWASs of an EBV-related clinical phenotype and MS using a single-cell Mendelian randomization framework with colocalization analyses. Candidate eGenes were evaluated in independent cohorts. For multi-SNP instruments, we performed heterogeneity, pleiotropy, MR-Egger, weighted median, mode-based, and MR-PRESSO sensitivity analyses. We also conducted phenome-wide association analyses and queried DrugBank to annotate candidate compounds targeting prioritized genes. RESULTS: We prioritized 43 immune-cell-specific candidate eGenes with convergent genetic support, including 6 for the EBV-related phenotype and 37 for MS. SERPINB1 in NK cells was associated with increased risk of the EBV-related phenotype, whereas HLA-G was associated with decreased risk. For MS, APOM and MSH5 showed protective associations, while AHI1 showed cell-type-dependent, bidirectional associations across immune lineages. Colocalization and independent cohort evaluation supported these findings. Among FDR-significant multi-SNP associations, MR-Egger intercept tests did not indicate directional pleiotropy, although a small subset showed heterogeneity or MR-PRESSO signals. Phenome-wide analyses identified no significant adverse phenotypic associations among evaluable genes at the prespecified threshold. DrugBank annotation nominated sodium nitroprusside, fasudil, artenimol, and choline as hypothesis-generating compounds for experimental follow-up. CONCLUSIONS: This study provides a single-cell genetic framework for prioritizing immune-cell-specific candidate targets for EBV-related phenotypes and MS, and nominates genetically supported targets and pharmacologic hypotheses for experimental investigation.

Humans↗

PubMed2026

Causal associations between hormone replacement therapy and brain structure: Evidence from large-scale Mendelian randomization and double machine learning.

BACKGROUND: Hormone replacement therapy (HRT) is widely prescribed for the management of hormone deficiency, particularly during menopause, yet its causal effects on human brain structure remain incompletely understood. Observational studies have reported heterogeneous associations, underscoring the need for robust causal inference. METHODS: We applied an integrated causal framework combining two-sample Mendelian Randomization (MR) and Double Machine Learning (DML) to evaluate the effects of four HRT-related exposures-age at initiation, age at cessation, ever-use of HRT, and a composite medication-based phenotype-on 1366 brain imaging-derived phenotypes from the UK Biobank. Genetic instruments were derived from large-scale GWAS summary statistics, and causal estimates were validated using non-parametric DML models with cross-fitting and performance evaluation. RESULTS: Genetic instruments for age at HRT initiation, age at cessation, and ever-use of HRT were strong (median F-statistics 16.29-36.66). MR analyses identified a causal association between later initiation of HRT and lower orientation dispersion in the right inferior cerebellar peduncle (ubm-a-542; primary finding, no pleiotropy detected). An additional association with the left tapetum FA (ubm-a-243) was identified but exhibited significant directional horizontal pleiotropy (MR-Egger intercept P = 0.001) and is excluded from primary conclusions (Supplementary Note S2). Later cessation of HRT was associated with increased cortical thickness in the left middle occipital gyrus, reduced surface area in the left frontopolar cortex, and increased orientation dispersion in the splenium of the corpus callosum. Ever-use of HRT was causally linked to larger volumes of the right inferior frontal gyrus and right nucleus accumbens. These associations were corroborated by independent DML validation, which provided causally debiased estimates robust to high-dimensional confounding. Results for ukb-b-8080 (median F = 1.45) are provided in Supplementary Note S1 only; weak-instrument bias precludes causal inference. CONCLUSIONS: This study provides genetic-instrument-based and machine-learning-validated evidence for causal associations between HRT exposure-particularly its timing and lifetime use-and specific features of human brain structure, including white-matter microarchitecture, cortical thickness, and regional brain volume. These findings are FDR-controlled within exposures and independently replicated by DML, but require replication in external neuroimaging GWAS cohorts to establish definitive causal conclusions. They highlight the neurobiological relevance of sex steroid exposure and inform future research on brain aging and personalized hormone-based interventions.

Humans↗

PubMed2026

Genetic trade-offs in fertility and longevity explain the maintenance of disease-associated alleles in humans.

Genetic variants that increase the risk for complex diseases persist in human populations, despite adverse effects on health and longevity. Life-history theory predicts that such alleles can be maintained by trade-offs arising from pleiotropy, yet direct genomic evidence has been limited. We asked whether disease-associated variants persist because they enhance reproduction, despite costs to health and lifespan. By analysing genome-wide data across 62 diseases, longevity and fertility, we show that disease-risk alleles are, on average, associated with reduced longevity and increased fertility. Moreover, the subset of alleles that increase both fertility and disease risk appear to have been favoured by natural selection over the past 50,000 years. Using Mendelian randomization, we detect a causal effect of genetic liability to disease on longevity, but no robust evidence for a causal effect on fertility; importantly, these estimates remain stable after adjusting for socioeconomic factors. At the individual level, we compared offspring numbers between affected and unaffected individuals with high polygenic disease risk. For most diseases, affected individuals had more children than unaffected ones. But for early-onset diseases, the pattern reverses, indicating reproductive costs of early morbidity. Together, these results support antagonistic pleiotropy and help explain the persistence of disease-risk alleles in human populations.

Humans↗

PubMed2025

EP300-mediated lactylation leads to ulcerative colitis via CD86-positive plasmacytoid dendritic cells: A Mendelian randomization and mediation analysis.

This study explores the potential mechanism between lactylation and ulcerative colitis (UC) using two-sample Mendelian randomization and multi-omics analysis. This study employed expression quantitative trait loci and protein quantitative trait loci as exposures, with UC from the Finnish database as the outcome, to conduct Mendelian randomization analysis on lactylation-related target genes, aiming to investigate the causal relationships between these exposures and the outcome. Sensitivity and pleiotropy tests, combined with colocalization analysis, are performed to identify the best target genes and ensure the robustness of the results. Finally, immune cells are included for mediation analysis between lactylation and UC to explore potential mechanisms of action. Through Mendelian randomization analysis combined with sensitivity and pleiotropy tests, 2 lactylation target genes were found to have a significant causal relationship with UC. Subsequent colocalization analysis confirmed EP300 as a potential gene target. After including immune cells in the mediation analysis, it was discovered that there is a potential mechanism involving EP300, CD86+ plasmacytoid dendritic cells (pDCs), and UC. There is a significant causal relationship between lactylation and UC. Furthermore, the lactylation-modified gene EP300 may lead to UC occurrence by regulating CD86+ pDCs.

Humans↗

PubMed2025

Genetic predisposition to systemic inflammatory proteins is causally associated with inflammatory bowel disease: Insights from multi-omics association study and single-cell RNA-sequencing analysis.

Systemic inflammatory proteins have been reported to be related to inflammatory bowel disease (IBD) in previous observational research. However, their causal links remain obscure. Herein, we performed a Mendelian randomization (MR) analysis to analyze the causality between systemic inflammatory proteins and IBD. Genetic variants related to systemic inflammatory proteins were extracted from a meta-analysis of genome-wide association study (GWAS) data of 8293 European participants. Summary statistics of IBD diverse subtypes were obtained from the international IBD genetic consortium (IIBDGC). We conducted multi-omics method and MR study to detect the causal links through integrating GWAS and protein quantity trait loci (pQTL) data. Inverse variance weighted (IVW) approach was utilized as the dominated analysis method. Moreover, complementary approaches such as MR-Egger intercept test, Cochran Q test and leave-one-out analysis were utilized to validate pleiotropy and heterogeneity. Finally, single-cell RNA-sequencing analysis was performed to detect the expression of significant genes. For IBD, IVW estimates suggested that genetically predicted IL-10 and IL-13 were suggestively associated with an elevated risk of IBD (IL-10: OR: 1.12, 95% CI: 1.00-1.24, P = .04; IL-13: OR: 1.09, 95% CI: 1.01-1.18, P = .023), while CXCL10 was suggestively linked to a lower risk of IBD (CXCL10: OR: 0.90, 95% CI: 0.82-0.99, P = .037). For Crohn disease (CD), the IVW approach provided evidence to sustain that genetically determined IL-13 and CCL3 had a suggestive association with a higher risk of CD (IL-13: OR: 1.13, 95% CI: 1.02-1.26, P = .023; CCL3: OR: 1.22, 95% CI: 1.03-1.45, P = .018). Sensitivity analysis did not explore any heterogeneity and pleiotropy. Our findings supported the causal relationships between 4 specific inflammatory proteins (IL-10, IL-13, CXCL10, and CCL3) and the risk of IBD and CD, thereby providing promising biomarkers of various subtypes stratification and new insights for the prevention and therapeutic target of IBD.

Humans↗

PubMed2026

Causality between noise pollution and Alzheimer disease: A Mendelian randomization analysis.

The role of noise pollution as a risk factor for Alzheimer disease (AD) is unclear, with observational studies yielding conflicting results susceptible to confounding and reverse causality. To clarify this relationship, we performed a 2-sample Mendelian randomization (MR) study using summary statistics from large-scale genome-wide association studies of European populations. Genetically predicted daytime and evening noise exposure was used as an instrumental variable to assess a causal effect on AD risk. The primary analysis was conducted using the inverse-variance weighted method, with weighted median and MR-Egger methods as key sensitivity analyses. We assessed instrument validity and pleiotropy using the Cochran Q test, the MR-Egger intercept, and leave-one-out analysis. Our MR analysis found no evidence of a causal association between genetically predicted daytime noise (odds ratio [95% confidence interval] = 0.999 [0.993-1.006], P = .819) or evening noise (odds ratio [95% confidence interval] = 0.999 [0.993-1.005], P = .643) and the risk of AD. Sensitivity analyses were consistent, with no evidence of heterogeneity or directional pleiotropy. In conclusion, this study does not support a direct causal link between noise and AD. While our findings mitigate common observational biases, they do not preclude indirect mechanisms whereby noise may influence AD pathogenesis via established risk pathways, such as chronic sleep disruption and cardiovascular stress. Studies are needed to focus on disentangling these potential indirect effects.

Alzheimer Disease↗

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

Human skin microbiota and postpartum depression: A bidirectional Mendelian randomization study.

Postpartum depression (PPD) is a common mental health disorder after childbirth. Although microbiome research in PPD has mainly focused on the gut, the role of skin microbiota remains unclear. We used Mendelian randomization (MR) to assess potential causal associations between skin microbiota and PPD. A bidirectional 2-sample MR analysis used genome-wide association study (GWAS) summary statistics. Genetic instruments for skin microbial features were obtained from a published skin microbiota GWAS, and PPD data were derived from 67,205 mothers (7604 cases, 59,601 controls). Instruments were selected at P <1 × 10-5, linkage disequilibrium-clumped, harmonized, and filtered for weak instruments (F statistic <10). Because this microbiome threshold is exploratory, Benjamini-Hochberg false discovery rate correction was applied within taxonomic levels. The inverse-variance weighted method was primary, complemented by weighted median and mode-based methods. Heterogeneity, pleiotropy, and outliers were assessed using Cochran Q, MR-Egger intercept, and MR-PRESSO. Three skin microbial taxa showed nominal associations with PPD. Higher genetically predicted Acinetobacter on the dorsal forearm (dry skin; 9 single nucleotide polymorphisms [SNPs]; mean F = 22.12) and Proteobacteria in the antecubital fossa (moist skin; 6 SNPs; mean F = 23.44) were associated with increased PPD risk, whereas Betaproteobacteria in the antecubital fossa (11 SNPs; mean F = 21.54) was associated with decreased risk. Associations were directionally consistent, with no substantial heterogeneity or horizontal pleiotropy. After multiple-testing assessment, the findings were exploratory rather than definitive. Reverse MR did not support an effect of PPD on the identified skin microbiota. This MR study provides exploratory genetic evidence linking specific skin microbial features to PPD risk. The findings extend microbiota-related hypotheses beyond the gut microbiome but require validation in larger microbiome GWAS datasets, longitudinal cohorts, and mechanistic studies before clinical or causal conclusions are drawn.

Humans↗

PubMed2026

Causal relationships between oral-gut microbiome and bone neoplasm-related phenotypes: Insights from bidirectional Mendelian randomization.

The human oral and gut microbiota are the 4 largest microbial communities in the body and play crucial roles in maintaining homeostasis and influencing disease. Observational studies have suggested links between these microbiota and bone neoplasm-related phenotypes, but establishing causality has been challenging due to confounding factors and reverse causality. We conducted a bidirectional, 2-sample Mendelian randomization (MR) study to investigate evidence consistent with a potential causal association between the saliva and gut microbiota and various bone neoplasm-related phenotypes. Genetic instruments for saliva and gut microbiota were sourced from large genome-wide association studies. Inverse variance weighted was the primary MR method, supplemented by 4 other MR techniques. Sensitivity analyses, including MR-Egger regression, were performed to assess pleiotropy and heterogeneity. In the forward MR analysis, Veillonella parvula from the saliva microbiota was associated with a decreased risk of bone and connective tissue neoplasms (β: -0.236, 95% CI: [-0.275, -0.197], P = 8.20E-33). MR analyses identified genetically predicted associations between several microbial taxa and bone neoplasm-related phenotypes. Reverse MR analyses showed that genetic liability to bone neoplasm-related phenotypes was associated with variation in the composition of the oral (e.g., Order Bacteroidales, Rothia mucilaginosa) and gut microbiota (e.g., Class Methanobacteria, Genus Eubacterium oxidoreducens group). Sensitivity analyses confirmed the robustness of these findings, as no statistical evidence of substantial heterogeneity or directional horizontal pleiotropy was detected. This study provides genetic evidence supporting a bidirectional causal relationship between specific saliva and gut microbiota and bone neoplasm-related phenotypes. Our findings identify several microbial taxa as potential candidates for future biomarker development and therapeutic investigation in bone neoplasm-related phenotypes. However, these genetically informed associations require further mechanistic, experimental, and prospective clinical validation before clinical application.

Humans↗

PubMed2026

Causal relationship between asthma and hernia risk: A Mendelian randomization study.

Epidemiological associations between asthma and various hernia subtypes have been reported, but the causality and direction remain unclear. This study employs a two‑sample Mendelian randomization (MR) approach to systematically assess the causal associations between asthma and 6 hernia subtypes. Using publicly available summary data of genome-wide association studies, asthma was selected as the exposure, and diaphragmatic hernia, umbilical hernia, femoral hernia, hiatus hernia, inguinal hernia, and ventral hernia were selected as outcomes. Instrumental variables were strictly screened (F-statistic > 10). The inverse‑variance weighted method was used as the primary analytical approach, supplemented with MR Egger and weighted median methods. Sensitivity analyses included heterogeneity tests, horizontal pleiotropy tests, Steiger directionality tests, leave‑one‑out analyses, and Radial MR. Reverse MR was performed for validation. Forward MR analyses revealed a significant positive causal effect of asthma on diaphragmatic hernia (odds ratio [OR] = 1.19, 95% confidence interval [CI]: 1.08-1.31, P < .001) and a suggestive association with umbilical hernia (OR = 1.19, 95% CI: 1.05-1.34, P = .007). The umbilical hernia association was significant only by the inverse‑variance weighted method; weighted median (P = .102) and MR-Egger (P = .210) estimates were not statistically significant, and the estimate attenuated after outlier removal (confirmatory OR = 1.13, 95% CI: 1.01-1.26, P = .028). Sensitivity analyses showed no significant heterogeneity or pleiotropy. Reverse MR did not identify significant causal effects of hernias on asthma, although power limitations for certain hernia subtypes should be considered. No significant associations were observed between asthma and the other hernia subtypes, although the null findings for femoral and ventral hernias should be interpreted with caution due to limited statistical power. This study provides genetic evidence supporting asthma as a causal risk factor for diaphragmatic hernia, with a suggestive association for umbilical hernia. The diaphragmatic hernia finding was robust across multiple sensitivity analyses, whereas the umbilical hernia association was less consistent and requires further confirmation. These findings contribute to a deeper understanding of the mechanistic links between asthma and specific hernia subtypes.

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

CAUSAL ASSOCIATION BETWEEN SEPSIS AND FIBROBLAST GROWTH FACTORS AS WELL AS THEIR RECEPTORS LEVELS: A TWO-SAMPLE MENDELIAN RANDOMIZATION STUDY.

Objective: The potential association between sepsis risk and circulating levels of fibroblast growth factors (FGFs) and their receptors (FGFRs) has been a focus of research; however, the causal relationship between them remains to be elucidated. We hypothesize a causal association between genetically predicted FGFs, FGFRs, and sepsis risk, and we conduct a Mendelian randomization (MR) study to validate this hypothesis. Methods: We utilized a two-sample MR design to assess the effect of genetic variants associated with various FGFs (FGF1, FGF2, FGF7, FGF16, FGF19, FGF21, FGF23, FGF5) and FGFRs (FGFR1, FGFR2, FGFR3, α-Klotho) on sepsis risk, using genome-wide association study summary statistics. Our MR analyses employed the inverse-variance weighted (IVW) method, along with weighted median, weighted mode, and MR-Egger regression, supplemented by sensitivity analyses to ensure robustness. Results: The MR analysis identified an unequal number of instrumental variables ranging from 2 to 17 for FGFs and FGFRs when sepsis was the outcome. No significant correlation was found between genetically determined FGF levels and sepsis risk by IVW analysis (all P > 0.05). Correspondingly, similar nonsignificant associations were observed for FGFRs (all P > 0.05). Other MR methods corroborated the IVW findings. Sensitivity analyses, including Cochran's Q test, MR-Egger, and MR pleiotropy residual sum and outlier, indicated no significant heterogeneity or pleiotropy in the relationships, with the exception of a nonsignificant correlation between FGFR1 and sepsis that persisted after the exclusion of an outlier (odds ratio, 0.84; P = 0.34). Conclusion: The analysis found no significant causal associations between FGFs, their receptors, and sepsis risk, indicating a need for further research on their complex interactions.

Humans↗

PubMed2025

Associations of Genetic Liability to Six Psychiatric Disorders With Cardiometabolic Diseases.

IMPORTANCE: Individuals with psychiatric disorders have increased risk of cardiometabolic diseases (CMDs). Evaluating how psychiatric genetic liability relates to CMD may clarify mechanisms. OBJECTIVE: Identify genetic overlap between psychiatric disorders and CMDs independent of cross-disorder pleiotropy, BMI, and smoking. DESIGN SETTING AND PARTICIPANTS: Three Northern European cohorts (the Swedish Twin Registry, the Estonian Biobank, and the Norwegian Mother, Father and Child Cohort Study [MoBa]) totaling 355,159 individuals. Associations with CMDs were estimated as adjusted odds ratios (AORs) from logistic models mutually adjusted for all psychiatric PRSs and in models additionally adjusting for body mass index (BMI) and smoking. Cohort-specific AORs were pooled by inverse-variance weighting. MAIN OUTCOMES AND MEASURES: Exposures were PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), anxiety disorder, posttraumatic stress disorder (PTSD), bipolar disorder, and schizophrenia. Outcomes were diagnoses of CMDs (hyperlipidemia, obesity, type 2 diabetes, hypertensive diseases, arteriosclerosis, ischemic heart disease, heart failure, thromboembolic disease, cerebrovascular disease, and arrhythmias), ascertained from electronic health records. RESULTS: The MDD PRS was associated with increased risk of all CMDs across analyses (AORs ranged from 1.13 [95% CI, 1.10-1.15] for heart failure to 1.02 [95% CI, 1.00-1.05] for arrhythmias). The ADHD PRS was associated with increased risk of all CMDs (AOR ranged from 1.11 [95% CI, 1.09-1.12] for obesity to 1.02 [95% CI, 1.01-1.03] for hyperlipidemia), however associations where attenuated when adjusting for BMI and smoking (lifestyle adjusted AOR for obesity: 1.03 [95% CI, 1.02-1.05]). When not mutually adjusting for all psychiatric PRSs, anxiety disorder and PTSD PRSs were associated with all CMDs; these associations diminished after adjustment. The bipolar and schizophrenia PRSs were inversely associated with most CMDs (AOR for schizophrenia PRS and obesity, 0.93 [95% CI, 0.92-0.94]). CONCLUSIONS AND RELEVANCE: Associations between psychiatric PRSs and CMDs diverged: ADHD, MDD, anxiety disorder, and PTSD PRSs were positively associated with CMDs, whereas bipolar and schizophrenia PRSs were inversely associated. Genetic liability to MDD showed robust associations with CMDs independent of cross-disorder pleiotropy, BMI, and smoking status, whereas associations between the ADHD PRS and CMDs were largely attenuated after adjustment for BMI and smoking.

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