A kynurenine immune-metabolic subtype of depression defined by childhood maltreatment and IDO2: Evidence from multi-omics profiling.
Major depressive disorder (MDD) is a complex disorder caused by genetic and environmental factors. Previous evidence implicates a potential depression subtype from interaction between childhood maltreatment (CM) and kynurenine pathway (KP) gene. Here, we investigated the top-down multi-omics KP alterations for this subtype.
A total of 142 patients with MDD receiving monotherapy were included. Individuals carrying IDO2 rs2340953 TT genotype and reporting CM were classified as IDO2-CM group, whereas the remaining patients were categorized as non-IDO2-CM group. Plasma KP metabolites, DNA methylation, KP-related protein, and inflammatory protein were profiled. Group differences were examined using regression models adjusting for relevant covariates.
Thirty patients met criteria for the IDO2-CM group. Compared with non-IDO2-CM, IDO2-CM individuals exhibited significantly poorer response rate to antidepressant at weeks 4 and 8. Metabolite analyses revealed a significantly elevated quinolinic acid (QA)/kynurenine (KYN) ratio and QA/kynurenic acid (KYNA) ratio in IDO2-CM group (β = 0.086, SE = 0.042, P = 0.023; β = 0.164, SE = 0.045, P = 0.0006). Epigenetic analyses of KP genes demonstrated coordinated methylation shifts favoring QA production (hypomethylation of KMO and AFMID; hypermethylation of ACMSD) and suppression of KYNA related enzymes (hypermethylation of CCBL1, CCBL2, AADAT, and GOT2). Proteomic profiling identified reduced circulating levels of KYNU and VCAM1 in IDO2-CM group.
CM interacting with IDO2 genotype defines a biologically distinct MDD subtype characterized by poor antidepressant response and convergent multi-omics evidence of KP bias toward neurotoxic metabolism. These findings support a stratification strategy and highlight the KP as a potential target for precision treatment in depression.
A total of 142 patients with MDD receiving monotherapy were included. Individuals carrying IDO2 rs2340953 TT genotype and reporting CM were classified as IDO2-CM group, whereas the remaining patients were categorized as non-IDO2-CM group. Plasma KP metabolites, DNA methylation, KP-related protein, and inflammatory protein were profiled. Group differences were examined using regression models adjusting for relevant covariates.
Thirty patients met criteria for the IDO2-CM group. Compared with non-IDO2-CM, IDO2-CM individuals exhibited significantly poorer response rate to antidepressant at weeks 4 and 8. Metabolite analyses revealed a significantly elevated quinolinic acid (QA)/kynurenine (KYN) ratio and QA/kynurenic acid (KYNA) ratio in IDO2-CM group (β = 0.086, SE = 0.042, P = 0.023; β = 0.164, SE = 0.045, P = 0.0006). Epigenetic analyses of KP genes demonstrated coordinated methylation shifts favoring QA production (hypomethylation of KMO and AFMID; hypermethylation of ACMSD) and suppression of KYNA related enzymes (hypermethylation of CCBL1, CCBL2, AADAT, and GOT2). Proteomic profiling identified reduced circulating levels of KYNU and VCAM1 in IDO2-CM group.
CM interacting with IDO2 genotype defines a biologically distinct MDD subtype characterized by poor antidepressant response and convergent multi-omics evidence of KP bias toward neurotoxic metabolism. These findings support a stratification strategy and highlight the KP as a potential target for precision treatment in depression.
Authors
Sun Sun, Su Su, Kang Kang, Zhao Zhao, Bai Bai, Guo Guo, Wang Wang, Lu Lu, Zhang Zhang, Feng Feng, Sun Sun, Yue Yue
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