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Results for “Reverse Mendelian randomization”

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PubMed2025

Exploring the causal role of plasma metabolites in pediatric asthma: a Mendelian randomization study.

BACKGROUND: Pediatric asthma (PA) is the prevailing chronic respiratory ailment in childhood. A better understanding of plasma metabolites is the goal for elucidating the molecular pathological mechanisms of PA and investigating novel therapeutic approaches. METHODS: Data for PA from Genome-Wide Association Studies (GWAS) was derived from the IEU-OpenGWAS project, featuring a collection of 1400 plasma metabolites. The inverse-variance weighting (IVW) method assessed causal relationships between plasma metabolites and PA, with measures taken to mitigate horizontal pleiotropy and heterogeneity. To select instrumental variables, a genome-wide significance threshold (p < 5 × 10-8) was applied to ensure robust genetic instruments. A Bonferroni correction controlled for multiple testing, with statistical significance defined as p < 3.57 × 10-5) (0.05/1400). To further substantiate outcomes, a reverse Mendelian randomization analysis was conducted. RESULTS: Research found 91 plasma metabolites linked to PA, ten of which showed significant associations. Of note, 20:4n6 levels (IVW: OR (95% CI) = 1.062 (1.030 to 1.094) and G/C16 (IVW: OR (95% CI) = 0.886 (0.832 to 0.943) were identified as pivotal exposure factors for PA. CONCLUSIONS: This study highlights 10 plasma metabolites that may have significant associations with PA incidence, with 20:4n6 levels and G/C16 potentially serving as valuable biomarkers for the early detection and management of PA.

Humans↗

PubMed2026

Refining the link between REM sleep behavior disorder and neurodegeneration: Genetic correlation, Mendelian randomization, and colocalization evidence.

Observational studies have proposed a link between isolated rapid eye movement sleep behavior disorder (iRBD) and several neurodegenerative diseases. We employed genome-wide linkage disequilibrium score regression (LDSC), standard two-sample Mendelian randomization (MR), and colocalization analysis to assess the causal links between iRBD and these neurodegenerative conditions. iRBD demonstrated a positive causal association with Alzheimer disease (odds ratio [OR] = 1.02, 95% confidence interval [CI]: 1.00-1.03, P = 1.10E-02), Parkinson disease (OR = 1.10, 95% CI: 1.03-1.16, P = 2.96E-03), and multiple sclerosis (OR = 1.09, 95% CI: 1.02-1.17, P = 1.61E-02). A strong positive genetic correlation with dementia with Lewy bodies was observed (rg = 1.6313, P = .0002), along with a causal association (OR = 1.45, 95% CI: 1.03-2.06, P = 3.53E-02), further supported by colocalization analysis. No significant causal relationship was identified between iRBD and amyotrophic lateral sclerosis (all P > .05). Additionally, reverse Mendelian randomization analyses did not reveal any causal relationships between the neurodegenerative diseases studied and iRBD. Our findings provide robust genetic evidence supporting a causal relationship between iRBD and the risk of multiple neurodegenerative diseases, highlighting the potential for shared pathophysiological mechanisms.

Humans↗

PubMed2024

The causal relationship between genetically predicted blood metabolites and idiopathic pulmonary fibrosis: A bidirectional two-sample Mendelian randomization study.

BACKGROUND: Numerous metabolomic studies have confirmed the pivotal role of metabolic abnormalities in the development of idiopathic pulmonary fibrosis (IPF). Nevertheless, there is a lack of evidence on the causal relationship between circulating metabolites and the risk of IPF. METHODS: The potential causality between 486 blood metabolites and IPF was determined through a bidirectional two-sample Mendelian randomization (TSMR) analysis. A genome-wide association study (GWAS) involving 7,824 participants was performed to analyze metabolite data, and a GWAS meta-analysis involving 6,257 IPF cases and 947,616 control European subjects was conducted to analyze IPF data. The TSMR analysis was performed primarily with the inverse variance weighted model, supplemented by weighted mode, MR-Egger regression, and weighted median estimators. A battery of sensitivity analyses was performed, including horizontal pleiotropy assessment, heterogeneity test, Steiger test, and leave-one-out analysis. Furthermore, replication analysis and meta-analysis were conducted with another GWAS dataset of IPF containing 4,125 IPF cases and 20,464 control subjects. Mediation analyses were used to identify the mediating role of confounders in the effect of metabolites on IPF. RESULTS: There were four metabolites associated with the elevated risk of IPF, namely glucose (odds ratio [OR] = 2.49, 95% confidence interval [95%CI] = 1.13-5.49, P = 0.024), urea (OR = 6.24, 95% CI = 1.77-22.02, P = 0.004), guanosine (OR = 1.57, 95%CI = 1.07-2.30, P = 0.021), and ADpSGEGDFXAEGGGVR (OR = 1.70, 95%CI = 1.00-2.88, P = 0.0496). Of note, the effect of guanosine on IPF was found to be mediated by gastroesophageal reflux disease. Reverse Mendelian randomization analysis displayed that IPF might slightly elevate guanosine levels in the blood. CONCLUSION: Conclusively, hyperglycemia may confer a promoting effect on IPF, highlighting that attention should be paid to the relationship between diabetes and IPF, not solely to the diagnosis of diabetes. Additionally, urea, guanosine, and ADpSGEGDFXAEGGGVR also facilitate the development of IPF. This study may provide a reference for analyzing the potential mechanism of IPF and carry implications for the prevention and treatment of IPF.

Humans↗

PubMed2026

Genetic Evidence Links Sex Hormone-binding Globulin to Total Body Bone Mineral Density at Age 45-60 Years: A Two-sample Mendelian Randomization Study.

The menopausal transition and early postmenopause represent important periods for women's skeletal health, but the genetic relevance of metabolic, behavioral, and hormone-related factors to bone mineral density during midlife remains incompletely understood. This study used publicly available genome-wide association study summary statistics to examine associations between body mass index, 25-hydroxyvitamin D, sex hormone-binding globulin, high-density lipoprotein cholesterol, smoking initiation, and alcohol intake frequency and total body bone mineral density at ages 45-60 years. Exposure genome-wide association study summary statistics were derived from large European-ancestry populations and were not restricted to midlife women, whereas the outcome genome-wide association study captured an age-stratified total body bone mineral density phenotype at age 45-60 years. This age range overlaps with the menopausal transition and early postmenopause in women. Univariable, reverse, and multivariable Mendelian randomization analyses were performed, with inverse-variance weighting as the primary method and complementary sensitivity analyses used to assess heterogeneity, pleiotropy, and result stability. Genetically predicted higher sex hormone-binding globulin was associated with lower total body bone mineral density (β = -0.111, 95% CI: -0.170 to -0.051; P = 0.0003). Reverse Mendelian randomization did not support reverse causation from bone mineral density to sex hormone-binding globulin. Multivariable analyses suggested that this association persisted after adjustment for selected metabolic biomarkers. The other examined exposures did not show consistent evidence of association. These findings provide genetic evidence linking sex hormone-binding globulin to total-body bone mineral density at ages 45-60 years. Further prospective and predictive studies are needed to evaluate its clinical relevance beyond established bone health assessment tools.

Humans↗

PubMed1976

An application of kinship process to the gene frequencies: linkage disequilibrium due to random drift in mendelian genetics with reversible mutation and in molecular genetics.

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Gene Frequency↗

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↗

PubMed2024

MONOCYTES AND B CELLS MEDIATE ALTERATIONS IN THE GENETIC ASSOCIATION BETWEEN PLATELETS AND SEPSIS VIA CLEC SIGNALING PATHWAY.

Background: Sepsis is a life-threatening condition characterized by multiple organ dysfunction. Blood cells abnormalities play a significant role in the onset and progression of sepsis; however, the potential causal relationship between platelets and sepsis remains unclear, as does whether immune cells mediate the interaction between platelets and sepsis. This study aims to explore the potential causal relationship between platelets and sepsis and analyze the mediating effect of immune cells. In addition, cell-to-cell communication was analyzed to explore the interaction between blood cells and immune cells. Material and methods: In this study, genome-wide association study data were utilized to examine the association between blood cells and sepsis. Two-sample Mendelian randomization (MR) and reverse MR were performed to investigate the potential causal relationship between blood cells and sepsis, with a specific focus on the relationship between platelets and sepsis. Subsequently, two-step MR was employed to identify the immune cells that mediate the interaction between platelets and sepsis and to assess their potential mediating effects. Cellchat software was used to analyze cell-to-cell communication. Results: The results of two-sample MR indicated that platelets were negatively correlated with sepsis (OR = 0.976, 95% CI 0.959-0.993, P = 0.005), suggesting that platelets have a protective effect against sepsis. Additionally, reverse MR demonstrated that sepsis had no significant effect on platelets (OR = 0.909, 95% CI 0.156-5.296, P = 0.916). The mediating effect analysis revealed that monocytes and B cells were important mediators in the relationship between platelets and sepsis. Notably, the correlation between platelets and sepsis shifted from negative to positive with the involvement of monocytes and B cells. The number and strength of cell-cell interactions were decreased in sepsis. Monocytes and B cells primarily regulate platelets through the CLEC signaling pathway, contributing to the pathogenesis of sepsis. Conclusion: This study confirmed the protective role of platelets in sepsis. Monocytes and B cells mediate changes in the genetic association between platelets and sepsis. Monocytes and B cells primarily interact with platelets via the CLEC pathway, thereby modulating the genetic association between platelets and sepsis. These findings indicate that thrombocytopenia, especially when accompanied by elevated monocytes and B cells, may serve as a potential marker for sepsis.

Humans↗

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↗

PubMed2026

Genetic interconnections between personality-related phenotypes and psychiatric disorders.

BACKGROUND: Personality-related phenotypes are genetically correlated with psychiatric disorders, but whether these relationships reflect shared genetic loci and differ across individual phenotypes remains unclear. We investigated their shared genetic architecture at the level of specific phenotype-disorder pairs. METHODS: We analyzed genome-wide association study summary statistics for 13 personality-related phenotypes and eight psychiatric disorders in populations of European ancestry. Genetic correlations were evaluated separately for 104 phenotype-disorder pairs using linkage disequilibrium score regression and high-definition likelihood. For pairs supported by both methods, MTAG and CPASSOC were applied separately to identify pleiotropic signals, followed by linkage disequilibrium clumping, Bayesian colocalization, gene prioritization, functional enrichment and bidirectional two-sample Mendelian randomization analyses. No composite personality or psychiatric-disorder phenotype was constructed. RESULTS: Among the 104 evaluated pairs, 77 showed significant positive genetic correlations in both analyses. Joint screening of MTAG and CPASSOC results identified pleiotropic signals in 61 pairs, comprising 1088 independent lead SNV-pair associations and 776 unique SNVs. Bayesian colocalization supported 351 signals across 42 pairs and 284 unique lead SNVs. MAGMA identified 1293 unique genes, of which 379 were prioritized by PoPS and 151 were further supported by SMR. These genes were enriched in brain tissues and biological processes involving nervous system development, synaptic organization and intercellular connectivity. Inverse-variance weighted Mendelian randomization identified 41 forward and 32 reverse associations after false-discovery-rate correction, including 21 pairs with bidirectional evidence. CONCLUSION: These item-resolved analyses identify widespread but heterogeneous genetic sharing between personality-related phenotypes and psychiatric disorders. The findings provide a pair-specific map of shared loci and prioritized genes, while the Mendelian randomization results should be interpreted cautiously because of residual heterogeneity and potential horizontal pleiotropy. Further validation in diverse populations and functional studies is required.

Colocalization↗

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↗

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

Causal Relationship Between Ischemic Stroke and Vascular Dementia: A Mendelian Randomization Study.

Ischemic stroke (IS) is a major cause of disability and mortality worldwide, and vascular dementia (VaD) is a common dementia subtype associated with cerebrovascular injury. Observational studies have suggested a relationship between IS and VaD, but these studies are vulnerable to confounding and reverse causality. This protocol describes a reproducible two-sample Mendelian randomization (MR) workflow for evaluating the potential causal association between IS and VaD using publicly available genome-wide association study (GWAS) summary statistics. Genetic instruments associated with IS were extracted from a public GWAS dataset, and outcome associations for VaD were obtained from a public VaD GWAS dataset. The corresponding dataset IDs are provided in the Protocol section. After outcome matching and allele harmonization, 51 single-nucleotide polymorphisms (SNPs) were retained for the final MR analysis. The workflow includes instrumental variable selection, linkage disequilibrium clumping, allele harmonization, instrument strength assessment, inverse variance weighted (IVW) analysis, weighted median analysis, MR-Egger analysis, heterogeneity testing, horizontal pleiotropy assessment, and leave-one-out sensitivity analysis. In the representative analysis, the IVW method showed a positive association between genetically predicted IS and VaD risk, and the weighted median method yielded a directionally concordant result. The MR-Egger estimate was directionally consistent but did not reach statistical significance. Therefore, these findings should be interpreted as suggestive evidence of a possible causal effect, rather than definitive proof of causality. This protocol may help researchers apply a transparent and reproducible MR workflow to investigate cerebrovascular disease-related outcomes using public GWAS data.

Humans↗

PubMed2026

The impact for causal associations between common diseases and inflammatory bowel disease: a disease-wide bidirectional Mendelian randomization study.

OBJECTIVES: Observational studies on associations between various diseases and inflammatory bowel disease (IBD) are often limited by confounding and reverse causation. We aimed to assess potential causal relationships between a wide range of diseases and IBD, including Crohn's disease (CD) and ulcerative colitis (UC). METHODS: We performed a comprehensive bidirectional Mendelian randomization (MR) analysis of 104 common diseases and IBD traits using the generalized summary-data-based MR (GSMR) approach. Genome-wide association study (GWAS) summary statistics for diseases were obtained from the MRC Integrative Epidemiology Unit, and IBD data from the International IBD Genetics Consortium. Summary-data-based MR (SMR) integrating GWAS and expression quantitative trait locus data was applied to identify pleiotropic genes associated with IBD. RESULTS: MR analyses identified 38, 34, and 52 exposures significantly associated with IBD, UC, and CD, respectively. Childhood- and adult-onset asthma showed distinct causal effects on UC and CD. Reverse MR indicated associations between IBD traits and 15 diseases, including multiple sclerosis. SMR identified RGS14 and CARD9 as pleiotropic genes linked to IBD, suggesting shared genetic mechanisms with asthma and multiple sclerosis. CONCLUSIONS: These findings provide evidence for causal links and shared immune-related genetic mechanisms underlying IBD, highlighting potential targets for future research.

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

Causal relationships between psoriasis and coronary artery disease: A two-sample Mendelian randomization study.

Previous studies have revealed a potential association between psoriasis and coronary artery disease (CAD). However, the causal relationship between the 2 remains unclear. This study aims to assess the causal link between psoriasis and CAD, which encompasses coronary heart disease, myocardial infarction, and angina pectoris. After obtaining genome-wide association studies data on psoriasis and CAD, we selected appropriate single nucleotide polymorphisms for Mendelian randomization (MR) analysis. The inverse-variance weighted method was used as the main analytical method. The inverse-variance weighted method indicated that psoriasis was associated with a higher risk of CAD (odds ratio = 11.538, 95% confidence interval = 4.498-29.595, P < .001), and coronary heart disease (odds ratio = 1.080, 95% confidence interval = 1.031-1.132, P = .001). Reverse MR analyses did not show causal effects of CAD on psoriasis. This study shows a significant causal association between psoriasis and incidence of CAD. However, there is no reverse causal association between CAD and psoriasis.

Psoriasis↗

PubMed2025

Association of cancers with the occurrence and 28-day mortality of sepsis: a mendelian randomization and mediator analysis.

Observational studies have indicated an association between cancer and the occurrence of sepsis, with an increased risk of mortality in cancer-related sepsis. However, whether a causal relationship exists between the two remains unknown. Summary statistics of thirteen cancers from the largest available genome-wide association studies (GWAS) of GWAS catalog and FinnGen biobank were extracted for the MR analysis. GWAS data for sepsis and its 28-day mortality were obtained from MRC-IEU. Univariable, multivariable, and reverse MR analyses were employed to explore potential associations between cancers and sepsis and its 28-day mortality. Moreover, a two-step mediation MR analysis was performed to investigate independent positive causal relationships between cancers and sepsis and its 28-day mortality. In univariable Mendelian randomization (MR) analysis, significant causal relationships were found between genetically predicted lung cancer (OR = 1.17, 95% CI = 1.08-1.26, adjusted p = 0.001), squamous cell lung carcinoma (OR = 1.10, 95% CI = 1.02-1.18, adjusted p = 0.042), lung adenocarcinoma (OR = 1.12, 95% CI = 1.03-1.21, adjusted p = 0.032), small cell lung carcinoma (OR = 1.07, 95% CI = 1.02-1.12, adjusted p = 0.031), and sepsis. Subsequent multivariable MR analysis revealed that these three types of lung cancer were independently associated with the risk of sepsis. Additionally, a causal relationship was found between lung cancer and 28-day mortality from sepsis, while no causal link was observed between non-solid tumors and the onset or death of sepsis. Reverse MR analysis did not indicate a potential for sepsis to trigger the onset of cancers. Furthermore, TRAIL was found to have promotive effects on the occurrence and mortality of sepsis. Lung cancer causally correlates with increased sepsis occurrence and 28-day mortality, as evidenced by Mendelian Randomization analysis. Genetic predispositions enhance this risk, underscoring the potential of genetic profiling to guide early, precise sepsis interventions in these patients.

Humans↗

PubMed2025

Exploring the shared genetic basis of attention-deficit/hyperactivity disorder and obstructive sleep apnea: A multi-omics analysis.

BACKGROUND: Observational studies have suggested an association between attention-deficit/hyperactivity disorder (ADHD) and obstructive sleep apnea (OSA), but these findings are often inconsistent due to potential biases from medication use, and varying diagnostic criteria. Genetic analyses can help mitigate these confounding factors, providing additional evidence. METHODS: This study evaluated the genetic correlations between ADHD and OSA using Genome-wide association study (GWAS) summary data, applying linkage disequilibrium score regression (LDSC) and SUPER GeNetic cOVariance Analyzer (SUPERGNOVA). Cross-trait association and colocalization analysis identify potential pleiotropic loci. Tissue enrichment analysis and gene-level analysis of shared genes between OSA and ADHD was conducted. Additionally, bidirectional Mendelian randomization was used to assess potential causal relationships. RESULTS: We found significant genetic correlations between ADHD and OSA (rg = 0.309, p = 3.252E-27), and identified 8 novel pleiotropic loci through cross-trait association analysis. Tissue enrichment analysis showed that these shared genes were primarily concentrated in brain tissues, particularly in deep gray matter regions, and were associated with immune and inflammatory pathways. Forward Mendelian Randomization analysis showed that ADHD was significantly associated with the risk of OSA (OR 1.070, 95 % CI 1.013-1.130, p = 0.016), and reverse analysis showed that OSA was significantly associated with the risk of ADHD (OR 1.240, 95 % CI 1.106-1.390, p = 2.213E-4). CONCLUSION: The findings of this study show a significant positive genetic correlation between ADHD and OSA and each is a risk factor for the other. Inflammation in specific brain regions may be the underlying mechanism for their comorbidity.

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↗