PROTEOME-WIDE MENDELIAN RANDOMIZATION AND MULTIVARIABLE STUDIES IDENTIFY ADOLESCENT-SPECIFIC PREDICTORS OF TREATMENT-RESISTANT DEPRESSION

Treatment resistance to antidepressants affects a substantial proportion of patients with major depressive disorder and represents a significant public health burden. There is a current paucity of research on the biological underpinnings of treatment-resistant depression (TRD), especially in adolescence, which represents a critical period of mental health development. This study, therefore, leverages a proteome-wide Mendelian randomization framework using protein quantitative locus (pQTL) data and genome-wide association data for TRD to investigate putative age-specific causal associations between plasma protein concentrations and TRD outcomes, identifying potential intervention targets and informing the biological underpinnings of symptoms.
We comprehensively investigated the causal association between circulating proteins and TRD using two-sample Mendelian randomization analysis. Cis-pQTLs were derived separately from an adolescent dataset (HOLBAEK) and two adult datasets (Ferkingstad et al and Sun et al). Genetic associations with TRD were obtained from a large-scale GWAS meta-analysis (Xiong et al). Colocalization, HEIDI, and SMR analyses were performed to prioritize the causal role of candidate proteins. Finally, multivariable Mendelian randomization (MVMR) was used to evaluate age-specific effects.
Genetically predicted levels of 2 proteins, AZGP1 and F12, showed FDR-corrected significant associations with TRD risk, with lower levels linked to greater susceptibility. Both proteins passed all sensitivity checks and displayed significant adolescence-specific effects, highlighting a critical developmental window for exposure. Functional analysis indicated that both proteins are involved in immunometabolic processes. In conclusion, the identification of AZGP1 and F12 as age-specific causal risk factors substantiates the immune-metabolic hypothesis of TRD, highlighting adolescence as a pivotal window for targeted therapeutic intervention.