Working under the umbrella of the PsychENCODE Consortium, the mental health research project established in 2015 by the National Institutes of Health, a team of scientists has uncovered important new insights into the molecular biology of neuropsychiatric disease through two new studies published in a special issue of Science. These investigations, conducted with colleagues from other major research centers, involve the largest single-cell analysis to date of the brains of people with schizophrenia, and a first-of-its-kind population-scale map of the regulatory components of the brain that provides critical insights into the pathogenesis of mental health disorders.
“We desperately need new directions for developing treatments for individuals with schizophrenia and other serious mental health illnesses,” says the senior author of both studies. “We now have the technology and methodology to do a deeper dive than ever before into the biology of neuropsychiatric diseases, and believe that through our latest research we have significantly advanced the field.”
Since the launch of PsychENCODE, dozens of scientists have identified several hundred new risk genes for mental disorders that include schizophrenia, autism spectrum disorder, and bipolar disorder. That body of work has also revealed critical time windows during brain development when these genes can most influence the disease process.
Using a high-resolution dataset of 468,000 single-cell transcriptomes from 140 individuals, researchers looked for cell type-specific schizophrenia-dysregulated genes, pathways, and regulators. The result was a more comprehensive and highly detailed understanding of the molecular alterations associated with schizophrenia—in effect, a reframing of schizophrenia transcriptional pathology.
“While we observed gene change expression within all detected cell types, the majority occurred in neuronal populations and, specifically, more than three-quarters in excitatory neurons, which constitute the bulk of the brain’s neurons,” says the lead author.
“After pinpointing the molecular changes, we were able to look one level up to identify the transcription factors that drive many of those alterations,” explains the author. “That allowed us to identify important upstream regulators that could serve as targets for drug development.”
This study of samples from the brains of individuals with and without neuropsychiatric diseases generated the largest epigenetic analysis to date of the human brain. That, in turn, led to a population-scale map of the regulatory components of the brain and their potential linkage to mental health conditions.
“We can now begin to understand how genetic variation among individuals might affect epigenetic regulation,” says the lead author of the study. “As the field of gene therapy continues to progress, the linkage of risk loci for a wide range of psychiatric and neurological disorders with human brain regulatory regions holds great promise for therapeutic applications.”
Notably, the author adds, genome editing technologies such as CRISPR can potentially target regulatory elements and modify their activity, potentially restoring regulatory mechanisms to a pre-disease state. “The combination of population-scale regulome studies and advances in gene regulation,” he notes, “will undoubtedly provide important new avenues for treating brain disorders in the future.”
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