A genetic correlation between cognitive performance and OA and RA, with colocalization analysis identifying shared genetic factors, highlights the need for integrated interventions targeting cognitive function and joint health.
Abstract
This study aimed to investigate the relationship between cognitive performance and the pathogenesis of osteoarthritis (OA) and rheumatoid arthritis (RA), emphasizing the role of plasma metabolites and proteins. Using National Health and Nutrition Examination Survey 2011 to 2014 data, cognitive functions of participants aged >60 years were evaluated, examining their correlation with OA and RA. Covariates, including demographics and health-related factors, were included. Genetic causality was determined using Mendelian randomization with single-nucleotide polymorphisms from the UK Biobank and other datasets. Linkage disequilibrium score regression and colocalization analyses were performed to validate genetic correlations and identify shared genetic variants. Cognitive performance was assessed in 387 and 237 OA and RA patients, respectively, compared with 1569 controls. OA patients had significantly lower Consortium to Establish a Registry for Alzheimer’s Disease-4 cognitive scores (odds ratio [OR]: 0.962, P = .001), while RA patients had lower digit symbol substitution test scores (OR: 0.980, P = .001). Mendelian randomization revealed a negative causal association between cognitive performance and OA (OR: 0.767, P = .001) and RA (OR: 0.712, P = .006). Plasma components, including bone sialoprotein 2, NKP44, and the metabolite X-11478, were causally linked to cognitive performance. Mediation analysis identified mediators, including FGR and 6CKine. Linkage disequilibrium score regression revealed a genetic correlation between cognitive performance and OA and RA, with colocalization analysis identifying shared genetic factors. GDF5 and TRAIP were associated with OA, and EHMT2 with RA. Cognitive factors, influenced by plasma components, may influence OA and RA onset. This relationship highlights the need for integrated interventions targeting cognitive function and joint health.
Genetic evidence supporting a causal role for depression in the etiology of late-onset AD is provided, a link not observed for other major psychiatric disorders tested and highlighted the specific importance of managing depression as a potential strategy for mitigating AD risk.
This study investigated the causal relationship between cognitive function and knee osteoarthritis (KOA) and whether body mass index (BMI) mediates this effect. A bidirectional Mendelian randomization (MR) analysis was conducted using genome-wide association study summary statistics. The primary analysis used the inverse-variance weighted method, with MR-Egger, weighted median, robust adjusted profile score, and MR-PRESSO applied for sensitivity analyses. Forward MR analyses showed a significant inverse causal effect of cognitive function on KOA risk, with intelligence (OR = 0.843, 95% CI: 0.755–0.941, P = .002) and cognitive performance (OR = 0.850, 95% CI: 0.771–0.937, P = .001) associated with reduced risk. Reverse MR analyses found no evidence that KOA causally affects cognitive function (Intelligence: β = −0.020, 95% CI:−0.048 to 0.008, P = .167; Cognitive performance: β = −0.006, 95% CI:−0.032–0.020, P = .661). Mediation analysis showed that BMI partially mediated the effect of intelligence on KOA (indirect β = −0.047, 95% CI:−0.110 to−0.006, P = .023), accounting for 27.29% of the total effect. In conclusion, these findings support a unidirectional causal effect of cognitive function on KOA, partially mediated by BMI, highlighting the relevance of cognitive function and weight management in high-risk individuals.
ABSTRACT Arthritis may influence neurodegenerative risk, but directionality and mediators remain unclear. This study integrates population survival analysis, Mendelian randomization, transcriptomic mapping, and mouse perturbation to map osteoarthritis (OA)/rheumatoid arthritis (RA) links with five neurodegenerative outcomes and prioritize mediators. In 310 162 European‐ancestry UK Biobank participants, Cox models associate OA with higher risks of Alzheimer's disease (AD; hazard ratio: 1.13, 95% confidence interval: 1.04–1.22), Parkinson's disease (PD; 1.10, 1.00–1.21), and disorders of autonomic nervous system (DANS; 1.36, 1.06–1.74), and RA with higher AD risk (1.37, 1.13–1.67) (all p < 0.05), but not incident PD. Mendelian randomization prioritizes a modest protective genetic effect of RA on PD (odds ratio: 0.93, 0.88–0.99; p = 0.015), without reverse causation. Transcriptome‐wide association and colocalization analyses identify shared RA–PD genes and prioritize Ring Finger Protein 40 (RNF40). In a collagen‐induced arthritis (CIA) and 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model, CIA attenuates dopaminergic injury, whereas systemic Rnf40 knockdown alleviates arthritis but exacerbates Parkinsonian pathology. Endogenous RNF40 is induced in arthritic joints but remains stable in midbrain. These cross‐layer data define arthritis–neurodegeneration connections and nominate RNF40 as a context‐dependent joint–brain candidate linking inflammatory arthritis with dopaminergic vulnerability.
Jinwen Wang, Wen-Hui Xie, Lei Yang et al.· Advancement of science· 0 citations
Objectives This study is aimed at comprehensively understanding genetically causal associations between some platelet indices (PIs) and rheumatoid arthritis (RA). Methods Genetic summary statistics for the 4 types of PIs and RA were derived from Neale Lab, FinnGen, and MRC‐IEU consortium. Two‐sample Mendelian randomization (TSMR) analysis was utilized to infer the bidirectional causality with the implementation of the inverse‐variance weighted (IVW), weighted median (WM), weighted mode, and MR‐Egger methods. Sensitivity analysis with leave‐one‐out method was conducted to assess the robustness of the observed causal estimates. Results TSMR results indicated that the genetically‐determined plateletcrit (PCT) had a causal association with the higher risk of RA (odds ratio [OR] = 1.13, 95% confidence interval [CI]: 1.01, 1.29, p = 0.012) and seropositive RA (OR = 1.03, 95% CI: 1.01, 1.21, p = 0.003). Both WM method and sensitivity analysis supported that the observed causal estimates were reliable. In the reverse MR analysis, genetic susceptibility leading to RA (Beta [se] = −0.012 [0.006], p = 0.037) was causally related to the decrease in mean platelet volume (MPV). Conclusions Our study reveals a positive causal association between PCT and the risk of RA, and that genetic susceptibility to RA is causally associated with a reduced MPV. This provides a reference for further studies on the exploration of mechanisms of platelets in the pathogenesis of RA.
Xu-Yan Shen, Jiaying Sun, Xin Wang et al.· International Journal of Gen...· 0 citations
OBJECTIVE
Chronic obstructive pulmonary disease (COPD) poses a major global health burden, but its relationship with serum uric acid (SUA) remains controversial. This study combined meta-analysis and Mendelian randomization (MR) to evaluate the observational association and potential causal relationship between SUA and COPD.
METHODS
We systematically searched PubMed, Embase, Web of Science, CNKI, and Wanfang Data for observational studies comparing SUA levels between COPD patients and healthy controls published up to December 2025. Meta-analysis was performed using a random-effects model to calculate mean differences (MD) and 95% confidence intervals (CI), followed by subgroup analyses. This meta-analysis has been registered with PROSPERO under the registration number CRD420251234511. Two-sample bidirectional MR analysis was conducted using publicly available GWAS summary data, with inverse variance weighting (IVW) as the primary method, supplemented by weighted median, MR-Egger regression, and sensitivity analyses.
RESULTS
The meta-analysis included 22 studies, comprising a total of 3739 COPD patients and 2778 healthy controls. Results showed that SUA levels were significantly higher in stable COPD patients compared to healthy controls (MD: 1.19 mg/dL, 95% CI: 0.83-1.55, P < 0.00001). Patients with acute exacerbation of COPD (AECOPD) exhibited even higher uric acid levels (MD: 1.30 mg/dL, 95% CI: 0.36-2.24, P < 0.00001), and SUA levels were significantly higher in severe COPD patients compared to those with mild-to-moderate COPD (MD: 1.18 mg/dL, 95% CI: 0.76-1.60, P = 0.02). Bidirectional MR analysis revealed that genetically predicted higher SUA levels were causally associated with reduced COPD risk (IVW: OR: 0.883, 95% CI: 0.811-0.961, P = 0.004). Reverse MR analysis found no significant causal effect of COPD on uric acid levels (P > 0.05). Sensitivity analyses supported the robustness of the MR findings.
CONCLUSION
Observational evidence indicated elevated SUA in COPD, especially during exacerbations, while genetically predicted higher SUA showed a modest protective effect. These findings suggest a complex, dual role of uric acid. However, observational associations may be confounded by reverse causality, and the MR estimates-derived from East Asian populations-are method-sensitive. Current evidence does not yet support altering uric acid management in COPD, and further prospective and interventional studies across diverse populations are warranted.
Aiju Su, Yunpeng Xu, Xue Han et al.· BMC Pulmonary Medicine· 0 citations
The potential causal relationship between hip osteoarthritis (HOA) and pancreatic cancer (PC) is not well understood. To investigate this, our study utilized a two-sample Mendelian randomization (MR) method to examine a possible causal link between HOA and an increased risk of PC. Genome-wide association study summary data for both HOA and PC were sourced from the Integrative Epidemiology Unit OpenGWAS database (https://gwas.mrcieu.ac.uk/datasets/). The single-nucleotide polymorphisms associated with these conditions at a statistically significant level (P value <5 × 10−8) were identified as instrumental variables for subsequent analysis. We conducted bidirectional two-sample MR analyses employing inverse-variance weighting (IVW), weighted median, MR-Egger regression, and weighted mode methods. The robustness of the findings was assessed through sensitivity testing. The IVW analysis indicated that HOA elevated the risk of PC (odds ratio = 1.788; 95% confidence interval: 1.166–2.742; P = .008). Conversely, in the reverse MR analysis, the IVW analysis provided no evidence that PC increased the risk of HOA (odds ratio = 1.016; 95% confidence interval: 0.973–1.060; P = .475). In addition, the weighted mode, weighted median, and MR-Egger regression methods did not uncover a causal relationship. There was no heterogeneity or horizontal pleiotropy among the instrumental variables. The “leave-one-out” analysis revealed that no single-nucleotide polymorphism significantly influenced the overall results. Genetically predicted HOA is significantly associated with an increased risk of PC. However, we found no evidence that PC leads to an increased risk of HOA.
Wei Li, Bo Hu, H. Zhuang· Medicine· 0 citations
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