This work leveraged two-sample Mendelian randomization 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 and identified three lipids with robust causal effects.
Abstract
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.
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.
Yanggang Hong, Feng Chen, Yi Wang et al.· iScience· 0 citations
Knee osteoarthritis (KOA) is a prevalent degenerative joint disease with limited treatment options, and the regulatory roles of plasma proteins and metabolites in its pathogenesis remain largely unclear. To explore the causal relationships and correlations among plasma proteins, plasma metabolites, and KOA, we constructed a regulatory network integrating these 3 components. We selected a total of 4907 plasma proteins as exposure variables, 1400 plasma metabolites as mediating variables, and KOA as the outcome variable in this study. We employed inverse variance weighting as the primary analytical approach and performed pleiotropy and heterogeneity tests to guarantee the robustness of the results; additionally, we conducted reverse Mendelian randomization analysis to validate the rationality of the exclusion restriction assumption. Subsequently, we implemented mediation analysis for plasma proteins exhibiting a significant causal association with KOA. Inverse variance weighting analysis identified 2 plasma proteins with significant causal associations with KOA: insulin-like growth factor-binding protein 3 was positively correlated with KOA susceptibility (β = 0.065, odds ratio = 1.067, P = .004, 95% confidence interval: 1.021–1.115), whereas collagen type XVIII alpha 1 chain was negatively correlated with KOA (β = −0.111, odds ratio = 0.895, P = .005, 95% confidence interval: 0.830–0.966); no reverse causal relationships were detected for either protein. Mediation effect analysis revealed 20 plasma metabolites with significant mediating associations with KOA; notably, insulin-like growth factor-binding protein 3 could downregulate the levels of N-acetylmethionine and 2-O-methylascorbic acid, thereby promoting the progression of KOA. Collectively, the identified causal associations and mediating effects provide a theoretical foundation and research orientation for the development of KOA therapeutic strategies targeting plasma proteins.
Hai-Bo Zheng, P. Zeng, Xian-Qiu Li et al.· Medicine· 0 citations
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.
Yuan-Bi Wang, Wen Wen, Han-Sheng Chen et al.· Journal of Affective Disorde...· 0 citations
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.
BACKGROUND
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Lipid metabolism is closely related to neuronal function and energy homeostasis, but the genetic association between specific lipid species and ALS risk remains unclear.
OBJECTIVE
This study aimed to investigate the potential causal associations between genetically predicted lipid species and ALS risk using a two-sample Mendelian randomization (MR) approach.
METHODS
Summary-level GWAS data for 179 lipid species were obtained from 7,174 Finnish participants in the GeneRISK cohort. ALS GWAS data included 29,612 ALS cases and 122,656 controls. The inverse variance weighted (IVW) method was used as the primary MR approach, supplemented by MR-Egger, weighted median, weighted mode, and simple mode analyses. False discovery rate (FDR) correction was applied across all lipid traits based on IVW P values. Sensitivity analyses were conducted to assess heterogeneity, horizontal pleiotropy, and robustness.
RESULTS
After FDR correction, genetically predicted higher levels of diacylglycerol (DAG) (18:1_18:1), phosphatidylcholine (PC) (16:1_18:1), PC (18:0_18:1), phosphatidylethanolamine (PE) (O-16:1_18:2), and several triacylglycerol (TAG) species were associated with increased ALS risk. Phosphatidylinositol (PI) (16:0_18:1) showed only a nominal protective association and did not remain significant after FDR correction. Sensitivity analyses did not indicate substantial heterogeneity or horizontal pleiotropy.
CONCLUSION
This MR study provides genetic evidence supporting potential associations between specific lipid species and ALS risk. These findings highlight lipid metabolism as a relevant pathway in ALS susceptibility.
Houwen Zhang, Chunrong Li, Jialin Yu et al.· Orphanet Journal of Rare Dis...· 0 citations
An atlas of brain IDPs associated with bipolar disorder is established, by integrating epidemiological and genetic evidence, and candidate IDPs that were consistently associated with BD are highlighted across complementary analyses.
Wenzhuo Yang, Lin Pan, Haoqun Xie et al.· BMC Medicine· 0 citations
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