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Proteome-Wide Association Study of Depression Homes in on Potential Treatment Targets

NEW YORK — A proteome-wide association study has uncovered new genes that may cause depression when their protein levels change in the brain, including proteins that could be treatment targets. 

Major depressive disorder affects about 264 million people around the global, according to the World Health Organization. While there are treatments for depression, they are only effective in a subset of patients.

Researchers from Emory University School of Medicine conducted a proteome-wide association study to identify brain proteins involved in major depressive disorder. As they reported in Nature Neuroscience on Monday, they uncovered 19 genes whose proteins contribute to the pathogenesis of depression and about two dozen proteins that potentially could be targeted by therapies.

The 19 genes appear to contribute to depression pathogenesis by affecting protein abundance in the brain, which could represent early biological changes that occur in depression, according to senior author Aliza Wingo, a psychiatrist at the Atlanta VA and an associate professor at Emory.

For their study, the researchers combined human brain proteome and SNP-based heritability data from 376 individuals of European ancestry from the Religious Order Study and Rush Memory and Aging Project with summary statistics data from a previous genome-wide association study of depression from a University of Edinburgh-led group.

With this discovery dataset, the team identified 24 genes whose protein abundance levels in the brain were associated with depression. Mendelian randomization analysis suggested that 19 of the genes were likely causal.

A replication analysis using a separate proteomic dataset from the Banner Sun Health Research Institute and a GWAS dataset from 23andMe provided supporting evidence for nine of the 13 genes that could be analyzed in that set. Further, a meta-analysis of the combined discovery and replication datasets uncovered 38 proteins associated with depression, 25 of which Mendelian randomization analysis indicated could be causal for the condition.

Through a subsequent transcriptome-wide association study, 13 of the 19 genes suspected in the proteomic analysis to be causal had mRNA levels association with depression, though only 14 genes could be analyzed.

The researchers further traced the expression of 10 of the 19 genes to particular cell types. For instance, five genes — CACNA2D2, CHD13, CNNM2, NEK4, and SLC25A12 — were highly expressed in inhibitory neurons while three genes — CHD13, CNNM2 and SLC25A12 ­– were somewhat highly expressed in excitatory neurons. Similarly, of the 25 genes highlighted through the meta-analysis, five were enriched in in excitatory neurons, five in inhibitory neurons, and others in other brain cell types.

The proteins uncovered in this analysis, the researchers said, could represent potential targets for treating depression. They noted that drug compounds targeting four of the 19 genes they identified have already been tested in clinical trials for other conditions. For instance, a compound targeting PSMB4 has been tested for glioblastoma multiforme; P2RX7 for rheumatoid arthritis and osteoarthritis; CACNA2D2 for generalized anxiety disorder, fibromyalgia, and neuropathic pain; and EPHB2 for thyroid carcinoma.

Follow-up testing, they added, could shed light on whether these or other genes or proteins might function as treatment targets. "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," first author Thomas Wingo, a neurologist at Emory and the Atlanta VA, said in a statement. "We take heart that these findings could also prove useful as biomarkers for depressive symptoms. An effective biomarker — like hemoglobin A1C for diabetes — could help with diagnosis and management of depression."

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