PSMB4: a potential biomarker and therapeutic target for depression, perspective from integration analysis of depression GWAS data and human plasma proteome

Abstract

Abstract Depression is a common and severe mental disorder that affects more than 300 million people worldwide. While it is known to have a moderate genetic component, identifying specific genes that contribute to the disorder has been challenging. Previous Genome-wide association studies (GWASs) have identified over 100 genomic loci that are significantly associated with depression. But finding useful therapeutic targets and diagnostic biomarkers from this information has proven difficult. To address this challenge, I conducted a plasma protein proteome-wide association study (PWAS) for depression, using human plasma protein QTL (pQTL) and depression GWAS data. I identified four proteins that were significantly associated with depression: BTN3A3 (P value = 6.41 × 10−06), PSMB4 (P value = 1.42 × 10−05), TIMP4 (P value = 3.77 × 10−05), and ITIH1 (P value = 7.86 × 10−05). Specifically, I found that BTN3A3 and PSMB4 play a causal role in depression, as confirmed by colocalization and Mendelian Randomization (MR) analysis. Interestingly, I also discovered that PSMB4 was significantly associated with depression in both the brain proteome studies and the plasma PWAS results, which suggests that it may be a particularly promising candidate for further study. Overall, this work has identified 4 new risk proteins for depression and highlights the potential of plasma proteome data for uncovering novel therapeutic targets and diagnostic biomarkers.