Plasma Metabolomic and Proteomic Profiling of the Mechanisms Underlying the Cumulative Impact of Co-occurring Psychiatric Disorders on Atopic Dermatitis

Association of pre-clinical depressive symptoms and its plasma metabolomic signature with Parkinson’s disease: a community-based longitudinal study

Accumulating evidence has suggested that depression is associated with an increased risk of Parkinson’s disease (PD), yet whether pre-clinical depressive symptoms in PD development and the potential mediating effects of metabolomic profiles remain unclear. We aimed to examine the association between depressive symptoms and PD risk, evaluate effect modification by genetic susceptibility, and assess metabolomic mediation. This prospective study included 451,922 PD-free participants from the UK Biobank. Depressive symptoms were collected by a 2-item Patient Health Questionnaire (range, 0–6; ≥3 indicates possible depressive disorder) at baseline. Identification of PD was based on medical records. PD-related polygenic risk score (PRS PD ), which incorporates established genes for PD based on external GWAS meta-analyses, was tertiled as low, moderate, and high. Baseline plasma metabolites were quantified via NMR spectroscopy from blood samples. Data were analyzed using Cox regression. Over a median follow-up of 14.6 years, 3108 (0.7%) participants developed PD. Higher depressive symptom severity showed linear association with PD risk (hazard ratio [HR]: 1.11, 95% confidence interval: 1.07–1.15). Participants with possible depressive disorder had 36% higher PD risk (HR: 1.36, 1.15–1.61). Those with both possible depressive disorder and high genetic risk had the highest PD risk (HR 2.15, 1.74–2.65; P for interaction = 0.028). Metabolomic signature, incorporating fatty acids and lipoproteins, accounted for 15% (model-based proportion) of the depressive symptoms-PD association. Pre-clinical depressive symptoms are associated with a moderately increased risk of PD, particularly among people with a high genetic susceptibility to PD. Metabolomic profiles account for a significant portion of this relationship.

Metabolomic signatures and causal effects of circulating metabolites on age-related cataract.

The proteomic and metabolomic signature of inherited chromosomally integrated HHV‐6 and its role in all‐cause dementia and mortality risk: The UK Biobank study

Abstract OBJECTIVE To examine associations of inherited chromosomally integrated human herpesvirus 6 (iciHHV‐6) with incident dementia and mortality, characterize proteomic and metabolomic correlates of carrier status, and evaluate whether these biomarkers relate to dementia and mortality risk. METHODS We analyzed UK Biobank participants ≥50 years of age with plasma metabolomics (N = 138,676) and proteomics (N ≤ 15,416) data and ≈15 years of follow‐up. Cox proportional hazards models adjusted for key confounding factors evaluated associations of iciHHV‐6 with dementia and mortality. Multivariable linear models assessed iciHHV‐6 associations with metabolomic and proteomic profiles. Mediation and interaction were evaluated using structural equation models and Cox models with biomarker interactions. Least absolute shrinkage and selection operator regression identified independent proteomic and metabolomic predictors using imputed biomarker data. RESULTS iciHHV‐6 was associated with higher dementia risk (hazard ratio [HR] = 1.32), particularly among women (HR = 1.66) and individuals with elevated Alzheimer's disease polygenic risk (HR = 1.49). Branched‐chain amino acids (leucine and isoleucine) were elevated among carriers without mediating dementia risk. Proteomic analyses identified 126 nominally associated iciHHV‐6–related proteins, many of which (Neurofilament Light Chain (NEFL), Glial Fibrillary Acidic Protein (GFAP), Yes‐Associated Protein 1 (YAP1), Sialic Acid‐binding Immunoglobulin‐like Lectin 5 (SIGLEC5), Interleukin 19 (IL19), A Disintegrin And Metalloproteinase with Thrombospondin Motifs 16 (ADAMTS16), Sphingomyelin Phosphodiesterase 1 (SMPD1)) were also associated with dementia and/or mortality. Exploratory pathway analyses suggested enrichment of proteins related to immune regulation and post‐translational modification. Predictive models identified NEFL, GFAP, Vascular Endothelial Growth Factor A (VEGF), Brevican (BCAN), remnant cholesterol, and polyunsaturated fatty acids as dementia predictors (area under the curve [AUC] = 0.83), whereas NEFL, Growth Differentiation Factor 15 (GDF15) Latent Transforming Growth Factor Beta Binding Protein 2 (LTBP2), Ectodysplasin A2 Receptor (EDA2R) and Advanced Glycosylation End‐product Specific Receptor (AGER) predicted mortality (AUC = 0.70). DISCUSSION iciHHV‐6 was associated with increased dementia risk, particularly among women and genetically susceptible individuals, with neuroimmune and metabolic biomarker profiles potentially relevant to brain aging and mortality risk.

C-reactive protein polygenic risk is associated with obesity-related traits in schizophrenia spectrum disorders

Background Patients with schizophrenia spectrum disorders (SSDs) are at increased risk of cardiometabolic dysregulations, which substantially contribute to cardiovascular morbidity and reduced life expectancy. Chronic low-grade inflammation is a key factor in the development of cardiometabolic outcomes. Polygenic risk scores (PRS) for inflammatory biomarkers like for C-reactive protein (CRP) and interleukin 6 (IL-6) may help clarify the genetic contribution to this risk, yet evidence in SSDs populations remains limited. Methods We investigated the associations of PRSes for CRP and IL6 with cardiometabolic outcomes in 671 patients with SSDs from the longitudinal Dutch Genetic Risk and Outcome in Psychosis (GROUP) study. Seven PRSCRP and seven PRSIL-6 were constructed using clumping and threshold method at seven P-value thresholds (Pt_x) based on large, independent genome-wide association studies. We examined 11 cardiometabolic outcomes measured at three years after diagnosis, including body mass index (BMI), waist circumference (WC), lipid levels, blood pressures, glycaemic markers, and a metabolic composite score. Linear regression models adjusted for age, sex, and population substructure tested the associations between PRSes, with multiple testing correction and bootstrapping for validation. Regression coefficients (βP-threshold) and 95% confidence intervals and unadjusted R2 (variance explained) were reported. Sensitivity analyses were conducted by further adjusting for smoking and antipsychotic medication use. Results Higher standardized PRSCRP was significantly associated with increased BMI (βPt_0.5 = 0.64, 95%CI=0.21-1.02, Pbootstapping = 0.003) and WC (βPt_0.5 = 2.25, 1.00-3.53, Pbootstapping < 0.001), explaining up to 1.85% variance in BMI, and 2.52% in WC. Nominal associations were also observed between PRSCRP and triglycerides (TG) levels (βPt_0.2 = 0.13, 0.01-0.26, Pbootstapping = 0.036), and metabolic composite score (βPt_0.2 = 0.14, 0.04-0.24, Pbootstapping = 0.006), and between PRSIL-6 and HbA1c level (βPt_5e06=-0.66, -1.26 to -0.05, Pbootstapping = 0.033); however these associations did not remain significant after correction for multiple testing. Conclusions Higher genetic susceptibility for low grade inflammation as captured by PRSCRP is modestly but robustly associated with increased levels of obesity-related traits in SSDs independent from antipsychotics use. These results support CRP-related genetics pathways as potential contributors to risk of cardiometabolic vulnerability in SSDs and may inform genetic-based personalized risk stratification and prevention strategies in SSDs patients.

Plasma metabolomic signatures of migraine in 479,760 adults

Summary Migraine has been linked to metabolic and vascular factors, and previous metabolomic studies have implicated HDL-related alterations, but large-scale prospective evidence remains limited. We analyzed 251 baseline plasma metabolites measured by nuclear magnetic resonance in 479,760 UK Biobank participants, including 6,724 incident hospital-diagnosed migraine cases during follow-up. Prospective and cross-sectional analyses replicated and extended a coherent lipid and lipoprotein pattern: HDL-related measures were generally inversely associated with hospital-diagnosed migraine, whereas triglyceride-rich and VLDL-related measures showed positive associations. Repeated least absolute shrinkage and selection operator (LASSO) analysis prioritized 12 metabolite features, which were further examined in exploratory analyses of brain structural imaging phenotypes, migraine polygenic risk, and affective and sleep-related traits. These findings provide large-scale prospective evidence supporting a structured plasma metabolomic profile associated with hospital-diagnosed migraine and contextualize systemic lipid and lipoprotein metabolism as a relevant domain for future mechanistic and translational studies of migraine-related metabolic variation.

The Impact of Omega Fatty Acids on DKD: A Multimodal Study Integrating Mendelian Randomization, Proteomic Mediation Analysis, and Meta‐Analysis

Diabetic kidney disease (DKD), a significant microvascular complication of diabetes, is escalating the global disease burden. Research suggests free fatty acids, particularly specific polyunsaturated fatty acids, may influence DKD development and progression through anti‐inflammatory and antioxidant mechanisms. However, existing evidence remains controversial, and the precise underlying mechanisms are still unclear. We performed a two‐sample Mendelian randomization (MR) analysis leveraging genome‐wide association study data and plasma proteomic panels. A two‐step protein‐mediated MR framework and Reactome pathway enrichment were employed to identify mediators and elucidate biological pathways. Subsequently, we conducted a meta‐analysis of clinical studies to comprehensively evaluate the impact of omega‐3 supplementation on DKD patients. Genetically predicted higher plasma omega‐3 fatty acid levels were causally associated with reduced DKD risk (odds ratio [OR] = 0.869, 95% confidence interval [CI]: 0.772–0.978, p = 0.020), while omega‐6 fatty acids showed no significant causal association (OR = 0.895, 95% CI: 0.731–1.096, p = 0.283). Fourteen plasma proteins showed nominally significant evidence of partial mediation, with consistent mediation directions and mediation proportions ranging from 2.10% to 29.80%. Potential mediators included neuronal pentraxin‐2, hemoglobin subunit theta‐1, and periostin. Enrichment analysis highlighted Notch signaling, apoptosis regulation, and chronic inflammatory pathways as core processes. Meta‐analysis of 12 randomized controlled trials (474 participants) showed that omega‐3 supplementation significantly reduced triglycerides (mean difference [MD] = −0.27 mmol/L, 95% CI: −0.35 to −0.20, p < 0.00001), systolic blood pressure (MD = −4.50 mmHg, 95% CI: −7.57 to −1.42, p = 0.004), and kidney injury molecule‐1 (MD = −1.74 pg/mL, 95% CI: −2.58 to −0.89, p < 0.0001), while increasing high‐density lipoprotein cholesterol (MD = 0.14 mmol/L, 95% CI: 0.04–0.23, p = 0.004). No significant improvements in albumin‐to‐creatinine ratio or estimated glomerular filtration rate were observed. Genetic evidence demonstrates that elevated omega‐3 fatty acid levels may causally reduce DKD risk, with this protective effect possibly partially mediated by plasma proteins. The meta‐analysis findings confirm that omega‐3 supplementation effectively ameliorates lipid profiles, systolic blood pressure, and early renal impairment in DKD cases. Dietary omega‐3 supplementation may offer a protective effect against DKD, though this association requires further validation.