Atlas provides genetic insights into schizophrenia
A new single-cell atlas of the prefrontal cortex could help develop more effective schizophrenia treatments.
Researchers led by study first author Brad Ruzicka (McLean Hospital, MA, USA), have developed a single-cell atlas for a region of the brain known to be implicated in schizophrenia. The atlas shows how genes linked to schizophrenia affect specific cells within the brain, which could help develop more effective, targeted treatments for schizophrenia.
Schizophrenia impacts around 24 million individuals, about 1 in 300 people, globally and is frequently associated with significant distress and impairment in many areas of life. The condition is complex, with varying presentations that have made it challenging to understand its underlying mechanisms and develop effective treatments.
To better understand schizophrenia, the researchers used single-cell RNA sequencing to measure transcriptomic changes in postmortem tissue from 140 individuals across two independent cohorts. They then developed a single-cell resolution atlas of the prefrontal cortex across subjects with and without schizophrenia.
“We discovered which cell types express genes associated with schizophrenia risk differently, which biological functions are impacted within those cells, and which transcription factors are important for these changes,” explained Ruzicka.
The researchers found that excitatory neurons were the most affected cell group, with transcriptional changes implicating neurodevelopment- and synapse-related pathways. They also found that known genetic risk factors for schizophrenia are linked to changes in specific neuronal populations, indicating the interaction between rare and common genomic variants.
Using the atlas, the researchers were able to identify two distinct subpopulations of individuals with schizophrenia, marked by the expression of specific excitatory and inhibitory neuronal cell states.
The study also suggests potential links between schizophrenia pathology and processes such as neurodevelopment, synaptic signaling, and transcriptional regulation, with key transcriptional regulators associated with both schizophrenia and neurodevelopmental disorders identified.
“This work advances understanding of schizophrenia pathophysiology at greater detail across both the complex landscape of cells within the brain, and the diverse experiences of people with this disease,” said Ruzicka. “Our increased mechanistic understanding of schizophrenia provides avenues for future research to unravel the genetic and environmental underpinnings of this complex disease so we can provide our patients better care.”
The team is now investigating other regions of the brain, as well as other psychiatric disorders, such as bipolar disorder.
