Psychiatric disorders have many causes, and effective treatments are limited due to the complexity of the brain and the involvement of many genes. Studying genetics and brain-wide analyses can help us better understand these disorders.
Stanford Medicine scientists are creating a “periodic table” for psychiatric disorders to improve understanding and develop targeted treatments. They combined two large databases: one showing genes linked to psychiatric disorders and the other showing which brain cells use these genes the most. This helped identify specific cell types in brain regions related to Schizophrenia.
This new brain-cell classification system confirms previous findings and discovers new cell types that may be involved in psychiatric disorders.
The study confirms that certain brain areas in schizophrenia patients are small or have disrupted nerve-cell signaling. It also identifies new brain-cell types not previously studied and finds cell types common to other psychiatric disorders.
Psychiatric disorders affect at least one-fifth of the population, but the development of treatments has been slow. Understanding which cell types are involved and how they work can help identify potential drugs for conditions like Schizophrenia. The researchers used a noninvasive method relying on computation instead of surgery or imaging.
Studying the brain is challenging because sampling cells deep in the brain usually requires an autopsy. However, the scientists used a noninvasive method that relies on computation instead of surgery or imaging.
They focused on Schizophrenia because it affects about 0.5% of people worldwide, has a strong genetic component, and is more reliably diagnosed than other disorders.
Duncan said, “Schizophrenia is the quintessential psychiatric disorder. Hallucinations mark it (people see or hear things others don’t), delusions (believe themselves to be someone else, often someone famous), and profound difficulties in accomplishing daily activities.”
“It’s devastating. For many, the symptoms are so severe that people with Schizophrenia end up sleeping on the streets.”
The researchers used two main databases. The first one, called GWAS, compared the genomes of many people with and without Schizophrenia. They found 287 genes linked to Schizophrenia.
The second database showed which genes are active in different brain cells and where these cells are located in the brain. It included information from over 3 million cells from autopsied human brains, defining 461 cell types.
By combining these databases, the scientists found 109 cell types associated with Schizophrenia and focused on the 10 most strongly linked to the illness.
The study found two brain cell types in the cerebral cortex linked to Schizophrenia. These cell types control excitatory activity and are located in two different layers of the brain, which appear shrunken in schizophrenia patients.
They also discovered a brain cell type in the retrosplenial cortex, which plays a role in people’s sense of self. This area may be important for psychiatric disorders, as disruption of the sense of self is common in several disorders.
Two schizophrenia-linked cell types are found in the amygdala, which is involved in threat assessment and fear. Two more are in the hippocampus, and one is in the thalamus. These brain structures often show shrinkage in schizophrenic brains.
The researchers aim to use this information to understand psychiatric disorders better and develop new treatments. They plan to refine and expand their model to more disorders, predicting which drugs will work best for individual patients.
Duncan said, “Now we have a roadmap showing specific directions to follow in understanding this disorder. We know exactly which cell types to study further in the lab, we have new drug targets, and we are using genetic information from individual patients to predict what medicine a person should take.”
“It will take six or seven years before scientists have useful clinical applications such as matching patients to therapies.”
“Our study didn’t look at cells in which schizophrenia-associated genes were remarkably underactive. We want to refine our model to include underrepresented genes as well as overrepresented ones so we get an even better understanding of the cell types involved. Plus, we’re expanding the model to more psychiatric disorders. We hope to identify groups whose cell-type profiles are characteristic of specific disorders or subsets of those disorders.”
“That may help us predict or discover which old or new drugs, or combinations of them, will work best for a given patient.”
Journal Reference:
- Duncan, L.E., Li, T., Salem, M., et al. Mapping the cellular etiology of Schizophrenia and complex brain phenotypes. Nat Neurosci (2025). DOI: 10.1038/s41593-024-01834-w
Source: Tech Explorist
