Emory Study Identifies Genes and Proteins Linked to Depression

Emory Study Identifies Genes and Proteins Linked to Depression
DNA (Deoxyribonucleic acid) strand, computer artwork. (DNA

A research study led by Emory University School of Medicine has identified 19 genes and 25 brain proteins that could cause depression, which the team hopes will help in the search for new treatments.

The researchers used a new approach combining genome wide association study (GWAS) data with human brain proteomic data to do a proteome wide association study (PWAS).

Depression is thought to impact more than 300 million people around the world and is a significant public health problem. Although treatments are available, they do not work for many people affected by the condition.

One way to identify new treatment targets is to look for gene variants or abnormal proteins that could be targeted to treat the symptoms. With this in mind, Aliza Wingo, M.D., a researcher at Emory University School of Medicine and psychiatrist at Atlanta Veterans Affairs Medical Center, and colleagues carried out a combined genomic and proteomic study.

To do this, they used results from a GWAS study looking for variants associated with depression in 500,199 individuals combined with brain proteome data from 376 individuals to carry out a PWAS study to find proteins linked to the neurological condition.

“Depression studies have examined genetic, epigenetic and transcriptomic factors, but far fewer studies have examined brain proteins directly,” write Wingo and co-authors in a paper describing the work published in the journal Nature Neuroscience.

Overall, variants in 19 genes were identified as having a link to depression, but only 9 of these associations were strongly replicated and three partly replicated (in the protein analysis but not the genomic analysis) in a separate cohort of 307,353 individuals and a separate proteomic dataset including 152 individuals.

The researchers used two techniques known as functional summary-based imputation (FUSION) and summary data-based Mendelian randomization (SMR). FUSION allows researchers to identify genes with cis-regulated brain protein levels linked to depression and SMR looks at whether there is a link between the proteins, gene variants and symptoms of depression.

Overall, 11 of the 19 genes identified in the original GWAS had cis-regulated brain protein levels associated with depression. In the replication cohort, 5 of the genes — CNNM2, FAHD2B, HIBADH, SLC25A12 and CDH13 – also had protein associations with depression.

As a result of the PWAS, the team found 25 proteins that had links with depression, 20 of which had not previous been identified in earlier GWAS studies.

A number of the genes and proteins identified play roles in maintaining and promoting neuronal synapses. For example, the B3GLCT protein stabilizes another protein that triggers the formation of synapses. Decreased levels of this protein could therefore contribute to depressive symptoms. Other roles for the proteins discovered by the research team include: magnesium homeostasis, glycosylation, neuronal apoptosis and cell adhesion.

“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,” said Thomas Wingo, M.D., also a researcher at Emory University School of Medicine and first author on the study, who runs a joint lab with Aliza Wingo.

“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.”