Causal pathways linking DNA methylation, ANKK1 expression, and immune cells in major depressive disorder
Qinghua Guo, Yong Wang, Libo Guo, Shaomei ShangAbstract
Objectives:
To investigate potential causal pathways linking druggable gene expression, DNA methylation, immune cell traits, and major depressive disorder (MDD), with a particular focus on the core symptom dimensions of depressed mood and anhedonia.
Methods:
We performed a multistep Mendelian randomization (MR) analysis using genomic, epigenetic, and immunologic data sets to prioritize druggable genes associated with MDD. A total of 4,479 druggable genes were screened using 2-sample MR, with gene expression as the exposure and MDD and its core symptom phenotypes (MDD1: depressed mood; MDD2: anhedonia) as outcomes. Mediation MR was used to explore upstream regulation through DNA methylation and downstream effects through immune cell activity.
Results:
ANKK1 emerged as the most consistently prioritized candidate gene associated with both MDD1 and MDD2 and was further supported by summary-data-based MR. DNA methylation at cg05590274 mediated 65.54% of the effect of ANKK1 on MDD1 and 46.52% on MDD2. In addition, the association of ANKK1 with depressed mood was partially mediated (22.42%) by double-negative (DN) (CD4⁻CD8⁻) natural killer T (NKT) cells, suggesting a potential gene–immune regulatory pathway in depressive symptomatology.
Conclusions:
These findings prioritize ANKK1 as a candidate target linked to depressive symptom dimensions through DNA methylation and immune-related pathways, while further functional validation is required.