A new analysis has revealed detailed information about genetic variation in brain cells, potentially paving the way for targeted treatments of diseases like schizophrenia and Alzheimer's disease.
The findings, reported on May 23 in Science, are the result of a multi-institutional collaboration known as PsychENCODE. Founded in 2015 by the National Institutes of Health, PsychENCODE aims to uncover new insights into the genomic influences on neuropsychiatric diseases. This study was published alongside related studies in Science, Science Advances, and Science Translational Medicine.
Mark Gerstein, the Albert L. Williams Professor of Biomedical Informatics at Yale School of Medicine and senior author of the new study, highlighted the significant link between genetics and the likelihood of developing neuropsychiatric diseases. "The correlations between genetics and your susceptibility to disease are much higher for brain diseases than for cancer or heart disease," Gerstein said. "If your parents have schizophrenia, you're much more likely to get it than you are to get heart disease if your parents have the disease. There is a very large heritability for these brain-related conditions."
However, the mechanisms through which genetic variation leads to these diseases remain unclear. "We want to understand the mechanism," Gerstein explained. "What is that gene variant doing in the brain?"
In their study, researchers aimed to better understand genetic variation across individual brain cell types. They performed several types of single-cell experiments on over 2.8 million cells from the brains of 388 people, including healthy individuals and those with schizophrenia, bipolar disorder, autism spectrum disorder, post-traumatic stress disorder, and Alzheimer's disease.
From this pool, researchers identified 28 different cell types and examined gene expression and regulation within them. One key analysis linked gene expression to variants in "upstream" regulatory regions, which can influence a gene's expression. "That's useful because if you have a variant of interest, you can now link it to a gene," Gerstein said. "And that's really powerful because it helps you interpret the variants. It helps you understand what effect they're having in the brain. And because we looked across cell types, our data also allow you to connect that variant to an individual cell type of action."
The researchers found that gene variability was higher across cell types than across individuals, particularly for genes associated with neurotransmitters and drug targets. This finding suggests that drugs targeting specific cell types are more likely to be effective across different genetic backgrounds.
Using their data, the researchers mapped genetic regulatory networks within cell types and communication networks between cells, integrating these networks into a machine learning model. This model could predict whether an individual had a brain disease based on their genetic information and highlight the relevant genes and cell types involved in the prediction.
The model also allowed researchers to introduce genetic changes and observe their effects on the network and an individual's health, offering potential applications in drug design and evaluation.
Together, these findings could support precision-medicine approaches for neuropsychiatric diseases. The PsychENCODE consortium has made its results and models available to other researchers, aiming to facilitate further discoveries in the field. "Our vision is that researchers interested in a particular gene or variant can use our resources to better understand what it's doing in the brain or to perhaps identify new candidate drug targets to investigate more," Gerstein concluded.
More: https://medicalxpress.com/news/2024-05-tracking-cellular-genetic-roots-neuropsychiatric.html
