Recent research published in scientific report The white blood cells of people with major depressive disorder show changes in the activity of genes normally associated with brain connectivity, the study suggests. This provides evidence that the biological footprint of depression extends far beyond the brain to the immune system, providing a systemic perspective on the condition.
The study was carried out by a team from the University of São Paulo in Brazil, with support from the São Paulo Research Foundation. The team included Otavio Cabral Marquez, a professor at the University of São Paulo School of Medicine and research coordinator, and Annie Silva Adri, who conducted the study as part of her doctoral research. They focused on how genetic instructions overlap between completely different types of human tissue.
“We mapped a network of genes that drive interactions between the immune system and the nervous system,” Cabral-Marquez says. “Depression is a systemic phenomenon, spreading throughout the body, and the immune system is one of the systems that distributes this condition and extends beyond the central nervous system. Therefore, it is not uncommon for people with depression to exhibit other symptoms, such as skin irritation or loss of appetite.”
Major depressive disorder is a complex mental illness characterized by persistent low mood, loss of interest in daily activities, and a variety of physical symptoms. Because symptoms vary so much from person to person, understanding the biology of the disease requires looking at different systems within the body. Scientists are increasingly focusing on the relationship between the central nervous system and the immune system.
Research groups have spent years investigating this exact overlap between neurological and immune function. “What these studies show is that there is a very strong connection between the immune system and the nervous system that is created by the gene networks that we are studying,” Professor Cabral-Marquez said. “Everything is closely related and the division between these systems is for educational purposes only.”
In the human body, peripheral leukocytes function as the primary white blood cells responsible for protection from disease and disease. These immune cells don’t just float around passively in your bloodstream waiting for infection. They contain many of the same biological components found in the brain, including receptors and enzymes that process neurotransmitters.
Neurotransmitters are chemical messengers that allow nerve cells to communicate across tiny gaps known as synapses. Scientists typically study these molecules in the context of brain signaling, but evidence suggests that these molecules also help direct how white blood cells behave during immune responses. People with depression often show obvious changes in the way their white blood cells process these chemical signals.
Every person has a unique genome that contains the entire genetic sequence. The difference between neurons and white blood cells is gene activation, which determines which specific genes are turned on or off. This activation depends on the specific function, state, or environment of individual cells.
To examine these common inheritance patterns, the authors designed an observational systems biology study that combined multiple existing genetic information databases. They analyzed data from more than 3,000 blood samples held in public banks in the United States, Germany, and France. They collected transcriptomic data from previous high-throughput sequencing studies that shows exactly how often certain genes are turned on or off.
High-throughput sequencing is a laboratory technique that allows scientists to quickly read millions of gene sequences. The final analysis included 1,864 people diagnosed with major depressive disorder and 1,208 healthy people who served as a comparison group. Scientists compared the gene activity in the white blood cells of depressed patients with the gene activity in the white blood cells of healthy people.
Researchers identified 1,383 genes that were altered in the protective cells of patients with major depressive disorder. Seventy-three of these genes are traditionally associated with synapses, including transmitting neurotransmitters and forming neural connections. In white blood cells, these same genes are involved in immune and inflammatory pathways throughout the body.
The researchers then applied a mathematical method called linear discriminant analysis to see whether these genetic changes could reliably distinguish between depressed and healthy patients. This method reduces complex data to find the clearest patterns that distinguish different categories of people. They discovered 18 specific synapse-related genes that consistently differentiate depressed patients from depressed patients.
“Although this is a data science study that still needs to be biologically confirmed, it opens interesting possibilities for the future development of panels to identify genes present in immune system cells circulating in the blood and involved in depression,” Adri says. “Because blood is more accessible than brain tissue, the identified genes serve as biological markers of the presence and severity of depression.”
The scientists also looked at genetic data from seven different brain regions known to be involved in mood regulation. They cross-referenced the altered immune genes with genetic data from areas such as the anterior cingulate cortex and orbitofrontal cortex. Through this comparison, they discovered seven specific synapse-related genes that were altered in both immune cells and brain regions.
To understand the broader health implications of these seven common genes, the authors mapped them against a database of known human diseases. This network analysis revealed that these specific genes were also associated with bipolar disorder, psychosis, anxiety, hypertension, arterial disease, and psoriasis. The mapping also identified associations with gastrointestinal symptoms, erectile dysfunction, and complications associated with the coronavirus.
“This analysis suggests that these same genes are involved in the vascular and inflammatory comorbidities common to depression,” Adri says. “Depression is not limited to the brain; it affects the body in an integrated and molecular manner.”
This molecular overlap provides evidence that genetic disruptions seen in depression may contribute to the physical health problems that often accompany mental disorders. “Inflammation and molecular dysregulation affect not only the brain but also a variety of organs and systems, amplifying the effects of disease and suggesting new approaches for diagnosis and treatment,” Adri says.
Although the findings detail the overlap between the immune system and the brain, the authors caution against exaggerating the biological significance of these genetic patterns. Just because synapse-related genes have been found in white blood cells does not mean that immune cells actually form functional synapses like neurons. This study relies entirely on existing data, meaning it is an exploratory analysis rather than a direct biological experiment.
Because the researchers looked at data collected at one point in time, they cannot determine whether changes in gene activity cause depression, or whether depression causes changes in gene activity. Future studies will need to follow patients over time to see how these genetic profiles change as their depression symptoms worsen or improve. Scientists also need to perform physical experiments in the lab to see exactly what these synapse-related genes are doing inside living white blood cells.
The authors point out that the link between peripheral inflammation in the blood and central symptoms in the brain paves the way for future treatments that target inflammation to alleviate symptoms of depression. By combining different types of biological data, researchers hope to eventually confirm the exact role these common genes play in the human body.
The study, “Systems-level transcriptome analysis reveals synapse-related gene dysregulation in peripheral leukocytes of MDD patients,” was authored by Anny Silva Adri, Adriel Leal Nóbile, Débora Gomes de Albuquerque, Pedro Marçal Barcelos, Fernando Yuri Nery do Vale, Roseane Galdioli Nava, Yohan Lucas G. Correa, and Lena. Friederik Schimke, Luis Fernando Onucci, Rodrigo Dalmolín, Rafael Machado Rezende, Harold Dutra Díaz, Igor Salerno Filgueiras, Otavio Cabral-Marquez.
