In a major new comparative analysis, researchers isolated 25 genes that may play a causal role in depression, paving the way for novel treatments and offering key insights into the origins of the disorder.
The paper, "Brain proteome-wide association study implicates novel proteins in depression pathogenesis," published Monday in Nature Neuroscience, described how researchers isolated the genes by comparing vast datasets from a genome-wide association study with data gathered from human brain tissue samples of 376 participants' proteomes — the full set of proteins expressed in a cell.
Large-scale international data projects have shed light on the genetic basis of diseases such as Alzheimer's, diabetes and glaucoma. But in the Nature Neuroscience analysis, scientists took a more direct approach by examining the proteins that the genes encode, which play a central role in regulating and supporting brain cells.
It's difficult to pin down how genes are expressed by examining the genes in isolation, the researchers said, since regulatory processes at the transcription level — which can't be viewed in the genes themselves — can sometimes shift the eventual abundance of various proteins in cells. 20 of the genes located in the analysis had not been identified in prior investigations into the possible genetic underpinnings of depression.
"Next, we'll see if we can develop some compounds that can manipulate the expression level of those genes and see if that can alleviate the depression," Aliza Wingo, an associate professor of psychiatry and behavioral sciences at Emory University and the senior author of the paper, told The Academic Times. "Current treatments for depression are not adequate. They're effective for less than 50% of patients."
There are already a few medications in the final stages of clinical trials, used for generalized anxiety and rheumatoid arthritis, that target some of the genes cited in the study. According to the researchers, it's possible that those drugs could be repurposed for patients living with depression. In addition, other drugs that target the relevant genes are currently in preliminary clinical trials. Wingo and her colleagues stressed that scientists will need to do further testing to develop medications that target and isolate the genes for which there are currently no medications available.
In order to draw comparisons with data from the genome-wide association study, the researchers gathered proteome data from 376 participants in the Religious Orders Study and Rush Memory and Aging Project — two programs that facilitate postmortem studies of brain tissue from participants who volunteered to offer their brains to science after death. Procuring proteomes in living humans is not yet possible.
Much of the researchers' work, which took about two years to develop, involved integrating data, normalizing results and using statistical inferences to ask questions about genetic trends. The researchers also used the datasets in related projects, such as one that looks into the genetic origins of neurodegenerative diseases like Alzheimer's.
Wingo's work is often rooted in data analysis, but as a practicing psychiatrist, she ultimately applies a human-centric approach to her experiments. "I think having that perspective of a clinician seeing patients contributes to how we ask these research questions," she said. "That's what keeps me going."
The process of identifying problematic proteins is akin to searching for a location on Google Maps, as Thomas Wingo, an associate professor in Emory University's neurology and human genetics department and the first and co-corresponding author of the paper, describes it. One at first sees a picture of the entire globe and must zoom in to find a more precise destination.
"And so right now, we have resolved down to a city level or a state level of the information. But there is a lot more resolution that needs to happen" before scientists can reach street level to see the full picture, Thomas Wingo said.
The problem is magnified by the elusive nature of mental illnesses, since diagnoses are often built off subjective symptoms that may look different in individual patients. Additionally, protein identification can't show how combinations of proteins may augment particular issues in the brain — or how environmental factors may inhibit or induce various genetic disorders. And while isolating genes of interest is vital to our understanding of mental illness, the team cautions that these identification tools do not always reveal the underlying mechanisms that augment protein abundance.
Despite the immense challenges ahead, the researchers say they are motivated by the collaborative, intellectual task of locating and isolating genes and proteins — like solving one of the world's most complex puzzles.
"It's very fulfilling to see the ideas come to fruition, from writing software to actually performing experiments," Thomas Wingo said. "How do you make the most out of what you have on hand? And how do you dream a little bit to figure out, if you could, what would be the ideal thing you would do?"
That means learning how the manipulation of problematic genes and proteins might lead to better outcomes in people with depression. But the proteome datasets took decades to cultivate, as researchers tracked the lives of participants until their time of death. It would likely take decades more to see the effects of experimental interventions built off current research.
"It's a long road to get to that point, so I think that we're very cognizant that this is the dream," added Thomas Wingo.
The study, "Brain proteome-wide association study implicates novel proteins in depression pathogenesis" published April 12 in Nature Neuroscience, was authored by Thomas S. Wingo, Yue Liu, Ekaterina S. Gerasimov, Duc M. Duong, Eric B. Dammer, Adriana Lori, Paul J. Kim, Michael P. Epstein, James J. Lah, Nicholas T. Seyfried, and Allan I. Levey, Emory University; Jake Gockley and Benjamin A. Logsdon, Sage Bionetworks; Kerry J. Ressler, Harvard Medical School; Thomas G. Beach, Banner Sun Health Research Institute; Eric M. Reiman, Banner Alzheimer's Institute; Philip L. De Jager, Columbia University Medical Center; David A. Bennett, Rush University Medical Center; and Aliza P. Wingo, Emory University and Atlanta VA Medical Hospital.