Psychiatry research · 2026
Cytomegalovirus-related immune activation and major neuropsychiatric disorders: Mendelian randomization and bulk transcriptomic validation.
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Li Jie, Chen Tailin
Аннотация
BACKGROUND: Cytomegalovirus (CMV) establishes lifelong latency and induces persistent changes in peripheral immunity. Observational links to neuropsychiatric disorders are difficult to interpret because of confounding and reverse causation.
METHODS: We performed two-sample, multivariable, and bidirectional Mendelian randomization (MR) on genetically predicted CMV seropositivity and antigen-specific antibody levels for Parkinson's disease (PD), bipolar disorder (BD), schizophrenia (SCZ), major depressive disorder (MDD), and Alzheimer's disease (AD). Instruments were selected at P < 5 × 10-6 (secondary at P < 5 × 10-7). Multivariable MR (MVMR) sensitivity analysis accounting for age-related genetic structure, pleiotropy/heterogeneity tests, and reverse MR evaluated robustness. Bulk transcriptomic validation tested whether CMV CD14+ late-response and HCMV reactivation-related host signatures were enriched in public PD and BD whole-blood datasets.
RESULTS: Genetically predicted anti-CMV IgG seropositivity was associated with PD (MVMR sensitivity aOR: 1.12, P = 0.020), with directional consistency in a single-instrument secondary analysis (OR: 1.25, P = 0.003). Anti-CMV pp28 antibody levels were associated with BD (aOR: 1.12, P = 0.043). The SCZ signal attenuated after adjustment, and no robust evidence was observed for MDD or AD. Both CMV-related host signatures were significantly enriched among PD-upregulated genes (CMV CD14+ NES = 1.85, FDR = 2.73 × 10-6; HCMV reactivation NES = 2.03, FDR = 9.11 × 10-9); BD showed no robust positive enrichment after covariate adjustment.
CONCLUSIONS: Integrated genetic and transcriptomic evidence prioritizes CMV-related peripheral immune activation as a plausible contributor to PD risk. The pp28-BD signal is hypothesis-generating and requires validation in datasets with direct CMV serostatus.
METHODS: We performed two-sample, multivariable, and bidirectional Mendelian randomization (MR) on genetically predicted CMV seropositivity and antigen-specific antibody levels for Parkinson's disease (PD), bipolar disorder (BD), schizophrenia (SCZ), major depressive disorder (MDD), and Alzheimer's disease (AD). Instruments were selected at P < 5 × 10-6 (secondary at P < 5 × 10-7). Multivariable MR (MVMR) sensitivity analysis accounting for age-related genetic structure, pleiotropy/heterogeneity tests, and reverse MR evaluated robustness. Bulk transcriptomic validation tested whether CMV CD14+ late-response and HCMV reactivation-related host signatures were enriched in public PD and BD whole-blood datasets.
RESULTS: Genetically predicted anti-CMV IgG seropositivity was associated with PD (MVMR sensitivity aOR: 1.12, P = 0.020), with directional consistency in a single-instrument secondary analysis (OR: 1.25, P = 0.003). Anti-CMV pp28 antibody levels were associated with BD (aOR: 1.12, P = 0.043). The SCZ signal attenuated after adjustment, and no robust evidence was observed for MDD or AD. Both CMV-related host signatures were significantly enriched among PD-upregulated genes (CMV CD14+ NES = 1.85, FDR = 2.73 × 10-6; HCMV reactivation NES = 2.03, FDR = 9.11 × 10-9); BD showed no robust positive enrichment after covariate adjustment.
CONCLUSIONS: Integrated genetic and transcriptomic evidence prioritizes CMV-related peripheral immune activation as a plausible contributor to PD risk. The pp28-BD signal is hypothesis-generating and requires validation in datasets with direct CMV serostatus.