Researchers have undertaken a brain proteome-wide association study (PWAS), identifying novel proteins that may be targets for new depression treatments.
Depression is a universal mental illness and a leading cause of disability across the globe. Unfortunately, current treatments for depression are ineffective within a large proportion of individuals. As a result, in this study, published in Nature Neuroscience, researchers explored gene-protein pairs that likely contribute to depression pathogenesis and thus could serve as promising targets.
The team investigated proteins as they are the final products of gene expression and the main functional components of cellular and biological processes. Proteins are also common drug targets and biomarkers. Most depression studies to date have examined genetic, epigenetic and transcriptomic factors, but little research has explored brain proteins directly.
In order to identify potential causal brain proteins, the team hypothesised that specific genetic variants influence depression by altering brain protein expression levels. To explore this, the team integrated depression GWAS results with human brain proteomes to perform a PWAS of depression. They also performed a replication analysis in an independent set of brain proteomic and depression GWAS data from 23andMe.
From this analysis, the researchers identified 19 genes that were consistent with being causal in depression. They were also able to replicate nine of these genes in the independent dataset. The researchers determined that these 19 genes contributed to depression pathogenesis through modulating their brain protein abundance. Meta-analysis of the findings and a replication PWAS analysis, identified 25 brain proteins consistent with being causal in depression, 20 of which were not previously found to associate with depression.
These findings provide promising targets that warrant further investigation, including testing in model systems.
Dr. Thomas Wingo, first author of the study, stated:
“We are very excited to continue to work on these promising targets in our lab but caution that the road leading to new drugs is long and difficult.
We take heart that these findings could also prove useful as biomarkers for depressive symptoms. An effective biomarker – like haemoglobin A1C for diabetes – could help with diagnosis and management of depression.”
Image credit: By kjpargeter – freepik