Genes linked to neuronal communication appear altered in immune cells of patients with depression

Genetic mapping reinforces the systemic nature of the disease and paves the way for developing blood tests that can detect it.

By Maria Fernanda Ziegler  |  Agência FAPESP – Neurons and white blood cells differ greatly in shape, function, and location within the body. However, researchers at the University of São Paulo (USP) in Brazil discovered that certain genes are equally dysregulated in both cell types in people with depression.

This finding not only reinforces the systemic nature of depression, which has repercussions that extend beyond mental health, but also paves the way for future blood tests that can identify the type and severity of depression. The study was published in the journal Scientific Reports.

The research was supported by FAPESP through four projects (18/18886-9, 24/21635-9, 23/07806-2, and 23/06086-6).

"We mapped this network of genes that drives the interaction between the immune and nervous systems. Depression is a systemic phenomenon, meaning it spreads throughout the entire body. And the immune system is one of the systems that decentralizes this condition, spreading it beyond the central nervous system. For that reason, it's not uncommon for a person with depression to exhibit other symptoms, such as skin inflammation or loss of appetite, for example," says Otávio Cabral-Marques, a professor at the USP Medical School (FM-USP) and coordinator of the research.

To arrive at this gene mapping, the scientists analyzed data from more than 3,000 blood samples from public banks in the United States, Germany, and France. Based on the data, they identified changes in gene expression in the white blood cells (defense cells) of patients with major depressive disorder.

Of the 1,383 altered genes, 73 are traditionally associated with synapses, or connections between neurons, including neurotransmitter transmission and the formation of neural connections. In white blood cells, these genes participate in immune and inflammatory pathways throughout the body. Eighteen of these genes enable the consistent differentiation of depressed patients from individuals without the disorder.

Each person has a unique genome that contains the sequence of their entire genetic material. What distinguishes a neuron from a white blood cell or a skin cell from a heart cell is genetic activation – that is, which genes are "turned on" or "turned off" depending on the cell's function, condition, or environment.

"It's a data science study that still needs to be biologically confirmed, but it opens up interesting possibilities for the future development of a panel to identify genes present in immune system cells circulating in the blood that are involved in depression. Since blood is more accessible than brain tissue, the identified genes serve as biological markers of the presence and severity of depression," says Anny Silva Adri, who conducted the study as part of her doctoral research.

A systemic disease

The research group has been investigating the relationship between the immune and neurological systems. In a recent study, they demonstrated the role of a single gene (PAX-6), present in both neurons and white blood cells, as a predictor of depression in an animal model.

"What we've seen in these studies is that there's a very strong connection between the immune and neurological systems created by this network of genes we're investigating. Everything is closely linked, and the division between those systems is merely for educational purposes," says Cabral-Marques.

The researcher points out that the link between peripheral inflammation (in the blood) and central symptoms (in the brain) paves the way for treatments that target inflammation to alleviate depressive symptoms.

Gene mapping revealed a strong link between depression and other diseases. "The analysis suggests that these same genes are involved in vascular and inflammatory comorbidities that are common to depression. Depression isn't confined to the brain but affects the body in an integrated and molecular way," says Adri.

These genes are also associated with bipolar disorder, psychoses, anxiety, hypertension, arterial diseases, inflammatory diseases, and psoriasis. The mapping also identified connections with gastrointestinal symptoms, erectile dysfunction, and complications related to coronavirus.

"Inflammation and molecular dysregulation affect not only the brain but also different organs and systems, amplifying the impact of the disease and suggesting new approaches for diagnosis and treatment," says the researcher.

The article "Systems-level transcriptomic analysis reveals synapse-related gene dysregulation in peripheral leukocytes of MDD patients" can be read at nature.com/articles/s41598-026-39284-y.