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Mendelian randomization and transcriptome analysis reveal depression-driven regulatory patterns of the immune
Zihao Zhou1, Xiaotongning Yu1, Yani Jin1
1School of Life Sciences, Jining Medical University, Rizhao, China.
Insights
Major depressive disorder (MDD) significantly increases the risk of myocardial infarction (MI) and heart failure (HF) without reverse causation. This study identifies key genes and immune subtypes linking MDD to CVD, paving the way for targeted therapies.
Area of Science:
- Cardiovascular Science
- Psychiatry
- Immunology
Background:
- Major depressive disorder (MDD) and cardiovascular diseases (CVD) represent significant, interconnected global health challenges.
- The precise causal links and immune mechanisms connecting MDD to myocardial infarction (MI) and heart failure (HF) require further elucidation.
Purpose of the Study:
- To investigate the directional causal relationship between MDD and the risk of MI and HF using genetic evidence.
- To identify immune-determined molecular signatures and gene expression patterns underlying MDD-associated CVD.
- To develop diagnostic gene panels and immune endotypes for MDD-CVD subtypes.
Main Methods:
- Bidirectional two-sample Mendelian randomization (MR) applied to large-scale genome-wide association studies (GWAS) for MDD, MI, and HF.
- Replication analysis using NHANES data with logistic regression and restricted cubic splines.
- Integration of multi-cohort transcriptomics (peripheral blood and cardiac tissue) with bioinformatics analyses (LASSO, CIBERSORT, ssGSEA, consensus clustering, GSVA).
Main Results:
- MR analyses confirmed a directional effect of MDD on increased risk of MI and HF, with no evidence of reverse causation.
- Depression severity showed a nonlinear, dose-dependent association with MI and HF risk.
- Six robust biomarkers were identified, and risk-score models demonstrated high accuracy in discriminating MI and HF in peripheral blood.
- Consensus clustering revealed two distinct CVD subtypes associated with MDD: 'homeostatic/pro-fibrotic' and 'inflammatory-metabolic'.
Conclusions:
- Genetic and multi-omic data strongly support a directional link between MDD and elevated MI/HF risk.
- Reproducible blood-based gene panels and immune endotypes were identified, dissecting distinct MDD-CVD substructures.
- These findings offer potential targets for precision immunomodulatory therapies for cardio-depressive comorbidity.
Background:
Major depressive disorder (MDD) and cardiovascular diseases (CVD) are mutually amplifying global health burdens, yet the causal directions and immune-determined molecular substructures that link MDD to myocardial infarction (MI) and heart failure (HF) remain poorly resolved.
Methods:
Bidirectional two-sample Mendelian randomization (MR) was applied to large-scale GWAS (1.35 million MDD; 361 K MI; 977 K HF) followed by replication in 11,004 NHANES 2005-2020 participants using restricted cubic splines and multivariable logistic regression. Multi-cohort transcriptomics (peripheral blood microarray n = 447; in-house RNA-seq n = 14; left-ventricular tissue from dilated cardiomyopathy (DCM) patients (n = 332) were integrated to identify MDD-driven expression signatures. LASSO regression, CIBERSORT, ssGSEA, consensus clustering and GSVA were employed to derive diagnostic gene panels and immune endotypes.
Results:
MR analyses provided genetic evidence consistent with a directional effect of MDD on MI (IVW β = 0.01, P = 4.6 × 10⁻6) and HF (IVW β = 0.19, P = 1.3 × 10⁻6) without reverse causation. Depression (PHQ-9 ≥ 10) has a dose-dependent nonlinear association with MI and HF (P<0.0001), with adjusted odds ratios (OR) of 1.80 (95% CI: 1.07-3.05) and 2.41 (95% CI: 1.45-4.00), respectively. A total of 202 MDD-related genes were identified through integrated transcriptomic analysis. After cross validation with the MI/HF dataset, six robust biomarkers (TMEM43, C1orf174, L3MBTL4, OR52N4, SLC25A20, MISP3) were screened. Risk-score models discriminated MI (AUC = 0.90-1.00) and HF (AUC = 0.95) in peripheral blood, but HF discrimination in cardiac tissue was modest (AUC = 0.60). Consensus clustering on 184 MDD-correlated genes stratified each CVD into two reproducible subtypes: a "homeostatic/pro-fibrotic" cluster enriched for ribosomal and cell-cycle pathways and an "inflammatory-metabolic" cluster characterized by NF-κB, TNF-α, IL-6, complement and coagulation activation.
Conclusions:
Genetic, epidemiological, and multi-omic evidence supports a directional association between MDD and increased risk of MI and HF. We deliver reproducible blood-based gene panels and immune endotypes that dissect biologically distinct MDD-CVD substructures, offering actionable targets for precision immunomodulatory therapy in cardio-depressive comorbidity.
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