Findings support an immunometabolic interpretation in which EBV-related immune responses and plasma metabolite remodeling may be relevant to depression vulnerability, and they prioritize candidate metabolites and pathways for future mechanistic and clinical investigation.
Abstract
Depression is a major contributor to global disability, yet its underlying biological mechanisms remain incompletely understood. Immune activation and metabolic alterations, particularly involving lipid metabolism, have been implicated, but their roles in depression remain unclear. We used large-scale genome-wide association study (GWAS) summary statistics to examine the relationships among antibody responses, plasma metabolites, and depression. Mendelian randomization (MR) was applied to evaluate genetically predicted associations of antibody traits and metabolites with depression risk. Generalized summary-data-based Mendelian randomization (GSMR) was used as a complementary analysis, and two-step mediation analyses were performed to assess whether selected metabolites were compatible with mediating immune-related effects on depression. Higher Epstein-Barr virus (EBV) ZEBRA antibody levels were associated with increased depression risk, whereas arachidonate-enriched metabolites tended to show inverse associations with depression and several linoleoyl-related metabolites showed positive associations. Mediation analyses suggested that 1,2-dilinoleoyl-GPC showed a positive indirect effect, whereas 1-arachidonylglycerol showed a negative indirect effect. Two glycerolipid ratios also showed indirect effects consistent with partial mediation. Complementary GSMR analyses showed directionally concordant results for the principal associations. Overall, these findings support an immunometabolic interpretation in which EBV-related immune responses and plasma metabolite remodeling may be relevant to depression vulnerability, and they prioritize candidate metabolites and pathways for future mechanistic and clinical investigation.
To investigate the causal relevance of melatonin metabolism, which provides the biological basis for circulating melatonin levels, to specific depression symptom subtypes, we performed a targeted systematic review of melatonin metabolism pathways in the human brain and liver. Using two-sample Mendelian randomization (MR), we assessed the causal effects of metabolism pathways and/or individual genes on major depressive disorder (MDD) and nine symptom subtypes derived from Patient Health Questionnaire-9 (PHQ-9). Instrumental variables (IVs) were expression quantitative trait loci (eQTL) for eight individual genes, one synthesis route, and three degradation routes. Results were assessed using Bayesian colocalization and phenome-wide association analyses. At the pathway-level, the genetically proxied synthesis-route signal was associated with PHQ-9 Assessment 5 (PHQ9A5, OR: 0.89, 95% CI: 0.85-0.93), but sensitivity analyses suggested this association was primarily driven by TPH1 and may reflect serotonin-related biology. In contrast, higher brain melatonin degradation raised the risk of both PHQ9A1 (OR: 1.03, 95% CI: 1.02-1.04) and PHQ9A7 (OR: 1.03, 95% CI: 1.02-1.03). Within degradation, up-regulation of the kynurenine sub-pathway increased the odds of PHQ9A3 (OR: 1.05, 95% CI: 1.02-1.07), PHQ9A4 (OR = 1.04, 95% CI: 1.02-1.06) and PHQ9A7 (OR: 1.05, 95% CI: 1.02-1.07). Gene-level analyses were largely concordant, except for SULT1A1, whose higher expression was genetically protective for PHQ9A3 but risk-increased for PHQ9A1 and PHQ9A4. Overall, these results demonstrate that melatonin metabolism exerts symptom-specific and pathway-specific causal effects on depression. A stratified view of melatonin's role may help optimize the application of exogenous melatonin supplementation.
Yuanbi Wang, Wen Wen, Hansheng Chen et al.· Journal of Affective Disorde...· 0 citations
Anxiety disorders represent a major psychiatric burden, yet their molecular underpinnings remain poorly understood. While observational studies have linked circulating lipids and proteins to mental health, causal inference is hampered by confounding and reverse causation. Here, we leveraged two-sample Mendelian randomization (MR) to systematically evaluate the causal effects of 179 plasma lipid species and 4,907 plasma proteins on anxiety disorders, using two large-scale independent GWAS datasets for replication. Significant findings from the primary inverse variance weighted analysis were validated using Bayesian Weighted MR and MR Robust Adjusted Profile Score methods to mitigate potential pleiotropy. Sensitivity analyses and reverse MR assessed robustness and directionality. Mediation analyses further explored whether protein signatures mediate lipid-anxiety associations. We identified three lipids with robust causal effects, with sterol ester (27:1/20:5) consistently conferring a protective effect across both cohorts. Additionally, 31 proteins showed significant causal links to anxiety. Notably, the protective effect of sterol ester (27:1/20:5) was partially mediated by the upregulation of SERPINA4 and ICT1, both of which exhibited protective associations. Our findings provide genetic evidence for causal roles of the plasma lipidome and proteome in anxiety disorders, and unveil a specific lipid-protein-anxiety pathway that may offer novel biomarkers and therapeutic targets. These results underscore the value of integrating multi-omic MR to dissect psychiatric disease mechanisms.
Jiahui He, Zehan Zhang, Yanan Wang et al.· Behavioural Brain Research· 0 citations
Chronic kidney disease (CKD) is a major global health concern with a multifactorial pathogenesis. Emerging evidence suggests that the gut microbiota and its metabolic products contribute to CKD development. However, robust evidence supporting metabolites as causal mediators in this pathway remains limited. We aimed to investigate causal relationships and mediating effects linking gut microbiota, circulating metabolites, and CKD.
Two-sample Mendelian randomization (MR) analyses were conducted using summary statistics from large-scale genome-wide association studies (GWAS) on gut microbiota, plasma metabolites, and CKD-related outcomes. Independent single-nucleotide polymorphisms strongly associated with each exposure were selected as instrumental variables. The inverse-variance weighted method served as the primary analysis, complemented by four additional MR approaches. Heterogeneity and pleiotropy were assessed using Cochran’s Q test, the MR-Egger intercept, and MR-PRESSO. Mediation analysis quantified the proportion of microbiota–CKD effects mediated by specific metabolites.
MR analyses identified causal associations among multiple gut microbial pathways, circulating metabolites, and CKD-related traits. Mediation analysis revealed that argininate partially mediated the effect of the microbial pathway PWY-6629 on the urinary albumin-to-creatinine ratio (UACR), accounting for 22% of the total effect. A one–standard-deviation increase in genetically predicted PWY-6629 activity was associated with a 1.3% increase in UACR, mediated through a 7.9% reduction in argininate levels. Conversely, higher genetically predicted argininate levels were associated with a 3.7% reduction in UACR.
This study provides genetic evidence that gut microbiota influence CKD risk partially through circulating metabolites, highlighting the gut microbiota–metabolite–CKD axis as a potential therapeutic target.
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.