SEARCH · Search PubMed

Results for “mediation analyses”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed2026

How the Social Context and Peer Helping Contribute to Better Alcohol Outcomes Among Sober Living House Residents: Mediation Analyses.

BACKGROUND: Sober Living Houses (SLHs) adopt a social model approach, which emphasizes peer helping. Although SLHs appear to be effective, little is known regarding why. This longitudinal study examined whether higher SLH social model adherence produces better resident outcomes by increasing resident helping. METHODS: Baselines were conducted with 205 residents entering 28 SLHs, with follow-ups through 6 months. Measures included 1-month perceived SLH social model adherence; 2-month help given to and received from SLH residents; and 6-month alcohol use and severity. Analyses were lagged, multivariate mediation models accounting for clustering within SLH. Separate models examined help given and received for each outcome, yielding four model tests. RESULTS: The hypothesized model was unsupported, with all four tests showing nonsignificant indirect effects. However, exploratory post-hoc tests showed significant indirect effects between higher 1-month resident helping and better 6-month alcohol outcomes via higher 1-month SLH social model adherence. Effects held across three of four model tests. CONCLUSIONS: Results suggest that residences adhering to social model principles do not achieve better outcomes by stimulating helping, but rather that more resident helping may foster a supportive SLH social environment, which itself drives better outcomes. Thus, residences might emphasize both resident helping and social model principles.

Sober living↗

PubMed2026

To unveil the causal relationship between immunophenotypes and colorectal cancer using two-sample bidirectional Mendelian randomization and mediation analyses.

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. The mechanisms underlying this trend are not yet fully understood. This study aimed to examine the potential role of genetically predicted immunophenotypes in the development of CRC. A two-sample bidirectional Mendelian randomization study was conducted to explore the relationship between 731 genetically predicted immune cells and CRC. Furthermore, a two-step Mendelian randomization approach was employed to assess the possible mediating effect of immune cells on CRC. The inverse-variance weighted method identified 5 immunophenotypes as significantly inversely associated with CRC risk: the odds ratios for CRC risk associated with activated CD4 regulatory T cells (%CD4 regulatory T cells), CD25++ CD45RA- CD4 nonregulatory T cells (%CD4 + T cells), CD25++ CD45RA- CD4 nonregulatory T cells (%T cells), CD25++ CD8 + T cells (%T cells), and CD64 + CD16 + monocytes were 0.925 (95% CI = 0.874-0.978, P = 6.516 × 10-3), 0.935 (95% CI = 0.878-0.995, P = .035), 0.936 (95% CI = 0.889-0.985, P = .011), 0.863 (95% CI = 0.786-0.948, P = 2.142 × 10-3), and 0.636 (95% CI = 0.519-0.778, P = 1.18 × 10-5), respectively. The mediation analysis indicated that the absolute count of CD25++ CD8 + T cells led to a 33.9% decrease in the risk associated with the percentage of activated CD4 regulatory T cells within CD4 regulatory T cells and CRC. Our analysis revealed that 5 immunophenotypes may be risk factors for CRC. Since other complementary methods have yielded inconsistent results, however, further investigation is necessary.

Colorectal Neoplasms↗

PubMed2025

Serum metabolites characterize hepatic phenotypes and reveal shared pathways: results from population-based imaging.

BACKGROUND: Steatotic liver disease is a major public health issue, with hepatic iron overload exacerbating fibrotic conditions. This study aimed to identify metabolites associated with hepatic fat and/or iron overload using targeted metabolomics in a population-based cohort. METHODS: We used the cross-sectional KORA-MRI study (N = 376 individuals). Hepatic fat and iron content were derived by magnetic resonance imaging, and serum metabolite concentrations were quantified through targeted metabolomics. Associations between 146 metabolites and 40 indicators with hepatic phenotypes were analyzed, adjusted for confounders, and corrected for multiple testing. Formal pathway analyses and mediation analyses including genetic data were conducted. Performance of metabolomics to diagnose steatosis or hepatic iron overload was evaluated using ROC curves, and compared to the fatty liver index (FLI). RESULTS: Overall, 50.8% of participants (mean age 56.4 years) had hepatic steatosis, and 43.6% iron overload. Twelve unique metabolites/indicators (amino acids, lysophosphatidylcholine, acyl-alkyl-phosphatidylcholine), and sums of branched chain and aromatic amino acids, and five lipids, and ratio of acyl-alkyl-phosphatidylcholines to diacyl-phosphatidylcholines were associated with hepatic fat content. 27 metabolites/indicators, including 25 lipids, were associated with hepatic iron content. Addition of these metabolites to the FLI improved diagnosis of steatosis and iron overload nominally. Glycerophospholipid metabolism, phenylalanine, tyrosine and tryptophan biosynthesis and glycerophospholipid metabolism were shared pathway between steatosis and iron overload. Alanine, isoleucine, glutamine and pimeloylcarnitine (C7-DC) mediated effects between genetic variants and hepatic phenotypes. CONCLUSION: Metabolites were associated with hepatic fat and iron content, shared common pathways, and improved diagnosis of steatosis and iron overload, highlighting the role of iron in hepatic disorders.

Humans↗

PubMed2026

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

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

Humans↗

PubMed2026

Plasma lipid species, immune cell traits, and gastric cancer risk: A Mendelian randomization study.

Plasma lipid composition has been linked to multiple cancers, yet its causal contribution to gastric cancer and the potential intermediary role of immune cells remain unclear. We aimed to clarify these relationships and identify specific lipid and immune cell traits that either protect against or promote gastric cancer. We performed a 2-sample, 2-step Mendelian randomization analysis using summary statistics from large genome-wide association studies of gastric cancer (1423 cases, 3,14,193 controls), plasma lipidomics (179 molecular species), and 731 immune cell phenotypes. Independent, genome-wide significant single-nucleotide variants served as instrumental variables. First, we estimated the causal effects of each plasma lipid on gastric cancer. Then, we explored the potential intermediary role of lipid-associated immune cell traits using a 2-step Mendelian randomization framework. Two lipids - phosphatidylethanolamine (18:0 0:0) and phosphatidylcholine (O-18:0 16:1) - were causally associated with a lower risk of gastric cancer. Three immune cell traits (CD8br and CD8dim %leukocyte, IgD on IgD+ CD38- and CD3 on CD28- CD8br) similarly showed protective effects. In contrast, phosphatidylcholine (O-16:1 18:2), triacylglycerol (49:1), triacylglycerol (56:3), and triacylglycerol (56:4) increased gastric cancer risk, as did immune traits such as TD DN (CD4-CD8-)AC, CD19 on memory B cell, CD28 on CD39+ activated Treg, CD45 on CD4+, CD127 on CD28+DN(CD4-CD8-) and CCR2 on CD14+CD16+ monocyte. Exploratory mediation analyses found no statistically significant evidence that immune cell traits mediated the effects of plasma lipids on gastric cancer risk. Specific phosphatidylethanolamines and phosphatidylcholines confer protection against gastric cancer, whereas several triacylglycerols increase risk. However, exploratory mediation analyses provided no statistically significant evidence that immune cell traits mediated these associations.

Humans↗

PubMed2026

Neighborhood Hostility is Associated With the Relationship Between Park Proximity and Physical Activity Among Youth: National Evidence From Chile.

PURPOSE: Physical inactivity among youth is highly prevalent worldwide. Although proximity to parks and recreational facilities is generally associated with higher physical activity (PA), unsafe or hostile neighborhood environments may limit their use. This study examined whether neighborhood hostility moderates the association between access to recreational facilities and adherence to World Health Organization PA guidelines among Chilean youth. METHODS: This cross-sectional study analyzed data from the 2024 National Physical Activity and Sport Survey of Chile, including 3,477 urban participants stratified into childhood (5-10 years), early adolescence (11-13 years), and late adolescence (14-17 years). Built environment exposures included perceived access to recreational facilities, a cumulative neighborhood hostility score (0-5). Logistic regression models were stratified by age group and adjusted for covariates. Interaction terms assessed moderation by neighborhood hostility, and causal mediation analyses were performed. RESULTS: Adherence to World Health Organization guidelines was low (41.9% in childhood, 43.8% in early adolescence, and 43.9% in late adolescence). Greater distance to recreational facilities was associated with lower odds of meeting activity guidelines. Higher neighborhood hostility was independently associated with lower PA levels. Among adolescents, neighborhood hostility substantially attenuated the association between proximity and activity. Mediation analyses indicated partial mediation, with effective park utilization emerging as the strongest mechanism, accounting for 21.8% of the association (p < .001), followed by psychological motivation (11.9%). DISCUSSION: Proximity to recreational infrastructure alone is insufficient to promote PA in hostile neighborhoods. Policy approaches should integrate infrastructure provision with strategies addressing neighborhood safety and promoting active engagement.

Humans↗

PubMed2026

Multi-omic signatures of genetic mechanisms inform on type 2 diabetes biology and patient heterogeneity.

Type 2 diabetes (T2D) is a heterogeneous disease shaped by genetic pathways related to insulin resistance and β-cell dysfunction, but how this heterogeneity is reflected molecularly remains unclear. We integrated partitioned polygenic scores (pPS) with proteomic and metabolomic profiling to define molecular signatures of T2D and their clinical relevance. We analyzed UK Biobank participants with genomic, proteomic, and metabolomic data. In a disease-free training subset, we used LASSO regression to identify multi-omic signatures associated with each pPS by jointly modeling proteins and metabolites. In an independent testing set, we constructed multi-omic scores and examined their associations with clinical traits and diabetes-related outcomes. Mediation analyses were used to investigate putative causal pathways. Key findings were evaluated in the Multi-Ethnic Study of Atherosclerosis (MESA). We identified distinct multi-omic signatures that capture the molecular architecture of T2D genetic risk across physiological subtypes. Compared with genetic scores alone, multi-omic pPS showed larger effect sizes and better disease discrimination. These scores recapitulated subtype-specific physiology and were associated with T2D risk. The Beta-Cell 2 multi-omic score showed marked stratification for insulin use, which was replicated in MESA, where it also predicted future insulin use. Mediation analyses implicated lipoprotein remodeling and fatty acid metabolism in the Lipodystrophy 1 cluster, accounting for 30-45% of the total effect of pPS on T2D risk. Integrating process-specific genetic risk with circulating multi-omic profiles reveals biologically distinct endotypes of T2D and supports a framework for improved patient stratification and risk assessment.

Journal Article↗

PubMed2026

Clonal Hematopoiesis and Incident Heart Failure.

IMPORTANCE: Clonal hematopoiesis of indeterminate potential (CHIP), the age-related clonal expansion of hematopoietic cells with acquired preleukemic variants, has been associated with cardiometabolic diseases, including heart failure (HF). However, prior studies have lacked power to examine less common CHIP driver variants and have not investigated potential mediators of the CHIP-HF association. OBJECTIVE: To test whether specific CHIP subtypes are associated with incident HF and determine the extent to which CHIP-associated comorbidities mediate this association. DESIGN, SETTING, AND PARTICIPANTS: This was a UK Biobank prospective population-based cohort study of community-dwelling adults in the UK, with enrollment from 2006 to 2010 and follow-up through 2020. Included were participants with whole-exome sequencing (WES) and without prevalent HF, hematologic malignancy, or other CHIP-associated comorbidities (coronary artery disease [CAD], atrial fibrillation [AF], type 2 diabetes [T2D], or chronic kidney disease [CKD]) at baseline. Study data were analyzed from April through October 2025. EXPOSURES: Presence of CHIP and gene-specific CHIP subtypes (DNMT3A, non-DNMT3A, TET2, ASXL1, JAK2, DNA damage repair genes, and spliceosome genes). Mediation analyses examined CHIP-associated comorbidities (CAD, AF, T2D, and CKD). MAIN OUTCOMES AND MEASURES: The primary outcome was incident HF. Cox regression tested associations of CHIP and CHIP subtypes with incident HF, adjusted for age, sex, race, and cardiovascular risk factors. RESULTS: Among 417 616 participants (mean [SD] age, 56.1 [8.1] years; 234 868 female [56.2%]), 7183 (1.7%) developed incident HF over a median (IQR) of 11.1 (10.4-11.8) years of follow-up. CHIP was associated with HF risk (adjusted hazard ratio [aHR], 1.27; 95% CI, 1.15-1.40; P < .001), driven by non-DNMT3A subtypes (aHR, 1.52; 95% CI, 1.33-1.75; P < .001), including associations with TET2, ASXL1, JAK2, and spliceosome CHIP. DNMT3A CHIP was more modestly associated with HF (aHR, 1.15; 95% CI, 1.00-1.31; P = .04). In mediation analyses, development of CAD, AF, T2D, and/or CKD collectively accounted for 28.2% of the association (95% CI, 11.6%-45.4%; P = .001) between non-DNMT3A CHIP and HF. CONCLUSIONS AND RELEVANCE: Results of this cohort study suggest that CHIP, especially non-DNMT3A CHIP, was associated with incident HF. Other CHIP-associated comorbidities explained only a minority of the association between non-DNMT3A CHIP and HF. These findings suggest that CHIP is an HF risk factor and potential therapeutic target.

Adult↗

PubMed2026

Plasma Proteomic Signatures of Physical Activity Provide Insights into Biological Impacts and its Protective Role against Dementia.

PURPOSE: Physical activity (PA) and sedentary behavior (SB) are associated with many diseases, including Alzheimer disease and all-cause dementia. However, the specific biological mechanisms through which PA protects against disease are not entirely understood. This study aims to address this gap, with a specific focus on all-cause dementia. METHODS: We first assessed the conventional observational associations of three self-reported and three device-based PA/SB measures with circulating levels of 2911 plasma proteins measured in the UK Biobank ( nmax = 39,160) and assessed functional enrichment of identified proteins. We then used bidirectional Mendelian randomization to further evaluate the evidence for causal relationships of PA/SB with protein levels. Finally, we performed mediation analyses to identify proteins that may mediate the relationship of PA with incident all-cause dementia. RESULTS: Our findings revealed 41 proteins consistently associated with all PA measures and 1027 proteins associated with at least one PA measure. Both conventional observational and Mendelian randomization study designs converged on proteins that appear to increase as a result of PA, including integrins such as ITGAV and ITGAM, as well as MXRA8, CLEC4A, CLEC4M, LPL, and ADGRG2; and on proteins that appear to decrease as a result of PA such as LEP, INHBC, CLMP, PTGDS, ADM, OGN, and PI3; and on proteins that are more responsive to high-intensity PA, such as CA14, CA6, CA4, KIT, and ANGPT2. Functional enrichment analyses revealed processes such as cell-matrix adhesion, integrin-mediated signaling, and collagen binding. Finally, GDF15, ITGAV, ITGAM, ITGA11, HPGDS, GFAP, ADM, AHNAK, and DPP4 were among 21 unique proteins found to mediate the relationship of PA with all-cause dementia, implicating processes such as synaptic plasticity, neurogenesis, and inflammation. CONCLUSIONS: Our results provide insights into how PA affects biological processes and protects against dementia, and provide avenues for future research into the health-promoting effects of PA.

Humans↗

PubMed2026

Psychological consequences of AI-assisted training and the buffering role of mindfulness.

The integration of artificial intelligence (AI) into athletic training is accelerating, yet its psychological implications for athletes remain insufficiently understood. Drawing on the transactional model of stress and the stress-buffering framework of mindfulness, this study examined whether mindfulness training can mitigate adverse psychological responses associated with AI-assisted training. Using a randomized controlled factorial design, 160 collegiate athletes were assigned to AI-assisted training or standard training, with or without concurrent mindfulness intervention, and assessed at baseline, week 4, and week 8. Athletes exposed to AI-assisted training without psychological support exhibited increases in perceived stress and AI dependence over time. In contrast, these stress increases were substantially attenuated when mindfulness training was implemented alongside AI-assisted training. A significant AI × Mindfulness × Time interaction emerged for perceived stress at post-intervention, and difference-in-differences analyses corroborated a robust buffering effect. Mediation analyses further indicated that mindfulness training reduced stress partially through enhancing mindful awareness; a three-wave cross-lagged analysis showed that mindful awareness and stress were reciprocally related over time, with the hypothesized awareness-to-stress pathway remaining robust. Together, these findings suggest that AI-assisted training introduces a distinct form of evaluative pressure, and that mindfulness training may serve as an effective psychological buffer during the adoption of continuous algorithmic performance evaluation systems.

Humans↗

PubMed2026

Post-Breakup Instagram Surveillance: Attachment Style, Personality Traits, and Breakup Distress as Predictors.

The end of a romantic relationship is one of the most emotionally challenging life events. Social media platforms such as Instagram enable users to monitor an ex-partner, a behavior known as Interpersonal Electronic Surveillance (IES), which may complicate coping. This study examined associations with retrospectively reported IES on Instagram during the first 3 weeks post-breakup, focusing on attachment, personality, and breakup-related emotional distress. Previous studies suggest that higher anxious attachment and emotional distress are related to increased monitoring behaviors on Facebook. The present research extends this approach to Instagram, a popular platform among Generation Z, and additionally examines personality factors. Data from N = 232 participants (aged 18-27 years; 84 percent women), who had experienced a breakup within the past year and followed their ex-partner on Instagram, were collected using a cross-sectional online questionnaire. The survey included standardized measures and self-constructed items. Hierarchical regression analyses including breakup-related variables, mediation analyses, and independent-samples t-tests were conducted. Due to extremely low internal consistency, Agreeableness was excluded from inferential analyses. The analyses indicated that Extraversion was the only personality trait directly associated with increased IES. Attachment styles showed no direct associations after emotional distress was included in the model. Emotional distress emerged as the most consistent factor associated with IES, showing patterns consistent with indirect associations involving Neuroticism and anxious attachment, suggesting a central role of emotional distress in post-breakup surveillance behavior. These findings highlight digital monitoring as a potentially maladaptive coping strategy and underscore the importance of addressing social media use in post-breakup adjustment.

Humans↗

PubMed2026

Family communication patterns and adolescent depressive symptoms: sequential mediating effects of hedonic capacity and anger expression.

OBJECTIVE: Depression is increasingly prevalent among adolescents, highlighting the need to explore its underlying developmental mechanisms to inform effective prevention. This study examined how different family communication patterns longitudinally impact adolescent depressive symptoms, with a focus on the mediating roles of diminished hedonic capacity and anger expression. METHOD: A total of 729 Chinese adolescents from five high schools participated in this two-wave longitudinal study over a six-month period. Participants completed the Family Communication Patterns Scale (FCPS), the Children's Depression Inventory (CDI), the Anhedonia Scale for Adolescents (ASA), and the Children's Inventory of Anger (ChIA). Mediation analyses were conducted using Hayes' PROCESS macro, alongside cross-lagged panel analyses to explore longitudinal effect. RESULTS: Cross-sectional analyses indicated that diminished hedonic capacity and anger experience sequentially mediated the relationship between family communication patterns and adolescent depressive symptoms. Specifically, this mediating effect existed for conversation orientation in junior high school students and female senior high school students, as well as for conformity orientation among female junior and senior high school students. In addition, longitudinal analyses revealed that diminished hedonic capacity mediated the associations at Wave 2. CONCLUSION: Our findings suggest that enhanced hedonic capacity and reduced anger expression may play a key role in the relationship between family communication patterns and adolescent depression, and hedonic capacity should be prioritized in practical interventions. These results support the potential value of interventions that promote positive family communication patterns as a means of mitigating adolescent depression, particularly for families with daughters.

anger expression↗

PubMed2025

GWAS links APOE to neuropsychiatric symptoms in mild cognitive impairment and dementia.

INTRODUCTION: Neuropsychiatric symptoms in dementia (NPS) collectively refer to behavioral and psychological symptoms affecting individuals with mild cognitive impairment (MCI) or Alzheimer's disease or related dementia (ADRD). NPS are among the most troubling aspects of living with dementia and their treatments have limited efficacy. We aim to investigate genetic variants contributing to NPS to identify new therapeutic targets. METHODS: We performed a genome-wide association study (GWAS) for nine NPS domains measured by the NPI-Q in 12,800 participants of European ancestry with MCI or ADRD recruited by Alzheimer's disease research centers across the U.S. RESULTS: We found genome-wide significant signals for agitation, anxiety, apathy, delusions, and hallucinations in the APOE locus that were driven by the APOE ε4 allele. We replicated these findings in two independent datasets. Mediation analyses revealed that MCI/ADRD severity only partially mediated the GWAS signals, except for apathy. DISCUSSION: These findings suggest the APOE ε4 allele influences NPS independently of and beyond its effect on ADRD.

Journal Article↗

PubMed2025

Differential DNA methylation in blood as potential mediator of the association between ambient PM 2.5 and cerebrospinal fluid biomarkers of Alzheimer's disease among a cognitively normal population-based cohort.

INTRODUCTION: Fine particulate matter (PM 2.5 ) is a known risk factor for Alzheimer's disease (AD), with emerging evidence linking PM 2.5 exposure to cerebrospinal fluid (CSF) biomarkers in pre-clinical stages. However, the role of DNA methylation (DNAm) as potential mediator in this relationship among cognitively normal individuals remains largely unexplored. METHODS: In 535 cognitively normal individuals, we assessed genome-wide blood DNAm, CSF Aβ 42 concentrations, and residential PM 2.5 exposure in the year preceding blood collection. Multi-stage comprehensive mediation analyses were conducted. RESULTS: Nine CpG sites mediated the PM 2.5 -Aβ42 association, with significant natural indirect effects (NIEs) for eight CpGs, mediating 14-43% of the effect. The joint NIE for all nine CpGs was -0.115 (95% CI: -0.215, -0.101) per 1 ug/m 3 increase in PM 2.5 exposure. Six CpGs are annotated to genes implicated in neuroinflammatory pathways. DISCUSSION: Our findings suggest that differential DNAm, particularly in neuroinflammation-related genes, mediates PM 2.5 toxicity in AD's pre-clinical stage.

Journal Article↗

PubMed2026

Urban heat island and risk of rheumatoid arthritis: Insights from genetic predisposition and proteomics.

BACKGROUND: Urban heat island (UHI) exposure is an increasingly common consequence of urbanization and climate warming, but its association with rheumatoid arthritis (RA) risk remains unclear. OBJECTIVE: To investigate the association between UHI exposure and incident RA, and to further assess the roles of genetic susceptibility and plasma proteomic profiles in this association. METHODS: This study included 400,628 urban residents with UHI exposure data and free of RA at baseline. Cox proportional hazards models were used to evaluate the association between UHI exposure and incident RA. Polygenic risk scores were used to assess effect modification by genetic susceptibility. Proteomic analyses identified candidate proteins and enriched pathways underlying the association. Mendelian randomization, colocalization, and mediation analyses assessed causal relevance and mediation. RESULTS: Over a median follow-up of 14.05 years, 5397 incident RA cases were documented. Each standard-deviation increase in UHI exposure was associated with a 17% higher risk of RA. This association was more pronounced among older adults and individuals with lower socioeconomic status. An additive interaction was observed between UHI exposure and genetic risk for RA. Proteomic analyses suggested that this association may involve not only canonical immune-inflammatory pathways, but also hypoxia response and protein transport, with CD40, VCAM1, and SUGP1 emerging as potential molecular mediators. CONCLUSIONS: UHI exposure may be a modifiable environmental risk factor for RA and provide new insights into the biological mechanisms underlying this association.

Humans↗

PubMed2025

S-GMAS: Genome-Wide Mediation Analysis With Brain Subcortical Shape Mediators.

Mediation analysis is widely utilized in neuroscience to investigate the role of brain image phenotypes in the neurological pathways from genetic exposures to clinical outcomes. However, it is still difficult to conduct mediation analyses with whole genome-wide exposures and brain subcortical shape mediators due to several challenges including (i) large-scale genetic exposures, that is, millions of single-nucleotide polymorphisms (SNPs); (ii) nonlinear Hilbert space for shape mediators; and (iii) statistical inference on the direct and indirect effects. To tackle these challenges, this paper proposes a genome-wide mediation analysis framework with brain subcortical shape mediators. First, to address the issue caused by the high dimensionality in genetic exposures, a fast genome-wide association analysis is conducted to discover potential genetic variants with significant genetic effects on the clinical outcome. Second, the square-root velocity function representations are extracted from the brain subcortical shapes, which fall in an unconstrained linear Hilbert subspace. Third, to identify the underlying causal pathways from the detected SNPs to the clinical outcome implicitly through the shape mediators, we utilize a shape mediation analysis framework consisting of a shape-on-scalar model and a scalar-on-shape model. Furthermore, the bootstrap resampling approach is adopted to investigate both global and spatial significant mediation effects. Finally, our framework is applied to the corpus callosum shape data from the Alzheimer's Disease Neuroimaging Initiative.

Humans↗

PubMed2026

Sugar-sweetened beverage consumption and incident depression: an exploratory multi-omics analysis of candidate biological mediators.

BACKGROUND: Depression is a leading cause of mental and physical disability globally, with its onset and progression influenced by a complex interplay of dietary, psychological, and biological factors. Recent research suggests a link between sugar-sweetened beverage (SSB) consumption and depression risk, although the potential biological pathways underlying this association remain poorly understood. METHODS: This study utilized data from 192,045 participants in the UK Biobank to examine the prospective association between SSB consumption and incident depression using Cox proportional hazards models. SSBs were defined as the sum of five beverage categories assessed via the Oxford WebQ 24-hour dietary recall. Directional consistency of the association was further examined across three external supporting datasets encompassing diverse populations: NHANES, YRBSS, and the Lianyungang Municipal School Health and Risk Factor Surveillance Study Dataset. We further investigated whether proteins, metabolites, inflammatory markers, and brain imaging phenotypes may serve as candidate mediators statistically consistent with mediation of the SSB-depression association. RESULTS: High SSB consumption was associated with an 18% higher risk of incident depression compared with non-consumers (HR = 1.18; 95% CI: 1.11-1.25), with consistent directional associations observed across external supporting datasets. A plasma proteomic signature comprising 229 proteins was constructed using elastic net regularization and was associated with an increased risk of incident depression. Exploratory mediation analyses identified 72 proteins, 36 metabolites, and 5 inflammatory markers as candidate mediators, with IL1RN showing the strongest protein-level candidate mediating effect (9.6%), and Unsaturation and neutrophil count showing the strongest metabolite- and inflammatory marker-level effects, respectively. CONCLUSIONS: This study provides preliminary evidence that proteins, metabolites, and inflammatory markers may serve as candidate mediators statistically consistent with mediation of the association between SSB consumption and incident depression. These findings are exploratory and hypothesis-generating, and future experimental studies are needed to validate these candidate pathways and assess their potential as targets for dietary interventions in depression prevention.

Humans↗

PubMed2025

Mediating effects of waist circumference and BMI on the association between meal frequency and mortality.

OBJECTIVE: To examine the potential indirect effect of meal frequency on mortality via obesity indices. DESIGN: Prospective cohort study. SETTING: Korean Genome and Epidemiology Study. PARTICIPANTS: This cohort study involved 148 438 South Korean adults aged 40 years and older. RESULTS: Meal frequency at the baseline survey was assessed using a validated FFQ. Outcomes included all-cause mortality, cancer mortality and CVD mortality. Cox proportional hazards regression models were employed to examine the relationship between meal frequency and the risk of mortality. Mediation analyses were performed with changes in obesity indices (BMI and weight circumference (WC)) as mediators. In comparison to the three-time group, the once-per-day and four-times-per-day groups had a higher risk for all-cause mortality. The irregular frequency group had a higher risk for CVD mortality. Both once-per-day and four-times-per-day groups exhibited higher risks for cancer mortality. The effect of meal frequency on all-cause mortality was partially mediated by WC. For specific-cause mortality, similar mediation effects were found. CONCLUSIONS: The data suggests that three meals per day have a lower mortality and longer life expectancy compared with other meal frequencies. Increased waist circumference partially mediates this effect. These findings support the implementation of a strategy that addresses meal frequency and weight reduction together.

Humans↗