Exploring causal plasma protein level ratios and potential drug targets for depression: A proteomics Mendelian randomization study

Background
The rising prevalence of depression imposes a heavy burden on individuals and society. Due to the complex pathogenesis of depression, there is a need to explore new diagnostic and prognostic biomarkers, as well as drug targets.
Methods
This study selected single nucleotide polymorphisms (SNPs) associated with depression and 2821 plasma protein level ratios to serve as instrumental variables (IVs). We employed a two-sample Mendelian randomization (MR) analysis and supplemented the sensitivity analysis with bidirectional MR analysis and Bayesian co-localization. Additionally, we utilized DrugBank to identify the targets and conducted a protein–protein interaction network analysis.
Results
Mendelian randomization analysis revealed that increased ADH4/GSTA1 (OR = 0.95; 95 % CI, 0.92–0.98; P = 0.0027), ADH4/KYNU (OR = 0.94; 95 % CI, 0.89–0.99; P = 0.0364), and ROBO2/SCARF2 (OR = 0.95; 95 % CI, 0.90–0.99; P = 0.0268) were associated with a decreased risk of depression, while elevated CD40/CD40LG (OR = 1.06; 95 % CI, 1.01–1.10; P = 0.0046), CD40/F11R (OR = 1.05; 95 % CI, 1.02–1.09; P = 0.0003), PLA2G15/PRCP (OR = 1.05; 95 % CI, 1.01–1.09; P = 0.0143), and PPP1R2/USP8 (OR = 1.04; 95 % CI, 1.00–1.08; P = 0.0385) were associated with an increased risk of depression. ADH4, GSTA1, CD40, CD40LG, F11R, PLA2G15, PPP1R2, USP8, and SCARF2 were identified as associated with therapeutic targets of existing depression medications, warranting further exploration.
Conclusion
This study is the first to identify a causal relationship between the plasma protein level ratios and depression using MR analysis. These discoveries offer new perspectives for exploring the diagnosis, prognosis, and therapeutic targets of depression.