Brain proteome-wide association study implicates novel proteins in depression pathogenesis.

Abstract

Depression is a common condition but current treatments for depression are only effective in a subset of individuals. To identify novel treatment targets, we integrated depression GWAS results (N=500,199) with human brain proteomes (N=376) to perform a proteome-wide association study (PWAS) of depression, followed by Mendelian randomization. We identified 19 genes consistent with being causal in depression, acting via their cis-regulated brain protein abundance. We replicated 9 of these genes using an independent depression GWAS (N=307,353) and human brain proteomic dataset (N=152). Eleven of these 19 genes also had their cis-regulated mRNA levels associated with depression based on integration of the depression GWAS with human brain transcriptomes (N=888). Meta-analysis of the discovery and replication PWAS identified 25 brain proteins consistent with being causal in depression, and 20 were not previously implicated in depression by GWAS. Together, these findings provide novel promising brain protein targets for further mechanistic and therapeutic studies.