Using living neural cells and DNA sequencing, scientists have identified how genetic variants influence the risk of neurological and psychiatric disorders, including schizophrenia and autism. These variants act like switches, turning genes on or off depending on cellular pathways. This research offers new insights into the biological mechanisms behind psychiatric disorders and could lead to personalized treatments based on genetic profiles.
Scientists have known for years that certain genetic variants, subtle differences in the DNA code between different people, have some impact on the development of neurological and psychiatric disorders, such as schizophrenia, autism and bipolar disorder.
However, understanding exactly how these variants contribute to these conditions has long been a challenge.
Researchers at the University of North Carolina (UNC) recently made progress on this issue using an approach that combines living cells and DNA sequencing.
They took a close look at the human genome in order to identify which specific genetic variants may be involved in increasing the risk of developing these disorders.
The team, led by Jason Stein, PhD, professor of genetics, used living human brain cells as a model to study how these variants work. The study was published in the journal Nature Neuroscience.
Most of our genome does not code for proteins, which are the molecules responsible for nearly all biological functions in our bodies. Only 3% of human DNA is responsible for creating these proteins.
The remainder, about 97%, is made up of noncoding regions, where many of the variants associated with psychiatric disorders are located. These regions, often likened to “light switches,” can turn coding genes on or off, but understanding their exact role is complex.
One reason is that these noncoding variants have a context-dependent function, meaning they can only act when certain specific biological pathways are active. This means that their effects can only be observed when cells are actively functioning, such as brain cells responding to stimuli.
Stein’s team set out to explore this phenomenon by stimulating a specific pathway called the canonical Wnt pathway, which plays a crucial role in brain development.
They used cells from 82 donors and analyzed how chromatin (the structure that surrounds DNA) changes and how genes are expressed after this activation.
Through these analyses, they found genetic variants that directly affect brain development pathways and were able to identify hundreds of regulatory genomic elements that influence gene function in response to stimulation.
The study also revealed that these regulatory elements are associated with genes that may influence the development of disorders such as schizophrenia and bipolar disorder.
The findings suggest that many of these genetic variants influence brain development from an early age and may affect both adult brain function and behavior.
These new insights provide a stronger foundation for understanding how genetic alterations may predispose some people to psychiatric conditions.
With this new approach, scientists are closer to identifying potential targets for future treatments, aimed at reducing the risk of developing these conditions or improving treatment options for patients.
In summary, this study demonstrates the importance of exploring the “non-coding” regions of the genome, which act as crucial regulators of genes, and how specific variants in these areas may play a significant role in the development of psychiatric disorders.
Similarly, future applications of this approach could be used to prescribe psychiatric treatments based on an individual’s genetics.
READ MORE:
Stimulating Wnt signaling reveals context-dependent genetic effects on gene regulation in primary human neural progenitors
Matoba, N., Le, B.D., Valone, J.M. et al.
Nat Neurosci (2024).
Abstract:
Gene regulatory effects have been difficult to detect at many non-coding loci associated with brain-related traits, likely because some genetic variants have distinct functions in specific contexts. To explore context-dependent gene regulation, we measured chromatin accessibility and gene expression after activation of the canonical Wnt pathway in primary human neural progenitors (n = 82 donors). We found that TCF/LEF motifs and brain-structure-associated and neuropsychiatric-disorder-associated variants were enriched within Wnt-responsive regulatory elements. Genetically influenced regulatory elements were enriched in genomic regions under positive selection along the human lineage. Wnt pathway stimulation increased detection of genetically influenced regulatory elements/genes by 66%/53% and enabled identification of 397 regulatory elements primed to regulate gene expression. Stimulation also increased identification of shared genetic effects on molecular and complex brain traits by up to 70%, suggesting that genetic variant function during neurodevelopmental patterning can lead to differences in adult brain and behavioral traits.