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

The discovery PWAS identified 19 proteins consistent with being causal in depression.This figure shows the Manhattan plot of the 19 proteins identified in the discovery PWAS of depression using FUSION, followed by SMR and HEIDI. These 19 genes likely contribute to depression pathogenesis via their cis-regulated brain protein abundances.

Protein-protein interaction (PPI) network and pathways among the 25 potentially causal proteins in depression from the meta-analysis of the discovery and replication PWAS of depression. The lines represent physical PPI. The thickness of the lines is proportional to the evidence for the PPI. Community 1 includes CTNND1, CSE1L, SLC25A12, and PSMB4. Community 2 includes LYRM4 and GMPPB. Enrichment of pathways was determined using a hypergenometric test with bonforroni adjustment for for multiple testing correction.

Bar graph of single-cell type enrichment for the A. Causal genes in depression from the discovery PWAS (n=19), and B. Causal genes in depression from the meta-analysis of the discovery and replication PWAS (n=25). The plot shows the average log fold change (x-axis) for each gene (y-axis) with evidence of significant enrichment within a particular brain cell-type (color of bar). A gene can be enriched in more than one cell type and only positive log fold change is plotted for simplicity. Enrichment is tested based on expression of the gene in a particular cell type versus in all other cell types using Wilcoxon rank sum test adjusted for 17,775 genes. The underlying data were from human brain single nuclei RNA-sequencing from the dPFC, and the full statistics are presented in Supplementary Table 16.