New model helps untangle complex psychiatric disorders such as autism and schizophrenia

The research focuses on mapping cis-regulatory components in human neurons that may be linked to the heredity of psychiatric disorders.

A Mount Sinai stem cell model may be able to shed light on the complex biology behind certain psychiatric disorders.

To map disease risk variants in human neurons, researchers at the Icahn School of Medicine at Mount Sinai used a unique stem cell model. This work could help shed light on the biological mechanisms behind neuropsychiatric diseases such as autism and schizophrenia.

Nan Yang

Nan Yang, Ph.D., assistant professor of neuroscience. Credit: Mount Sinai Health System

The group’s in vitro cell model, recently published in the journal Cell Reports, was created to enable future researchers to better understand disease mechanisms involving genome-wide association studies (GWAS) that characterize various risk alleles (common genetic variants conferring risk) for psychiatric disorders. This study could help develop better diagnostic methods to spot mental problems years before patients’ symptoms manifest.

The research focuses on identifying cis-regulatory elements in human neurons that may be linked to the heritability of psychiatric disorders. Cis-regulatory elements, which include enhancers and promoters, are non-coding

DNA
DNA, or deoxyribonucleic acid, is a molecule made up of two long strands of nucleotides that wrap around each other to form a double helix. It is the hereditary material in humans and almost all other organisms that carries genetic instructions for development, functioning, growth and reproduction. Almost all cells in a person’s body have the same DNA. Most DNA is found in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA).

” data-gt-translate-attributes=”[{” attribute=””>DNA regions that control the expression of genes and are essential parts of the genetic regulatory network. A considerable enrichment of common variants in the cis-regulatory elements, including those linked to bipolar disorder, schizophrenia, and autism spectrum disorder, has been found in previous genetic investigations.

“While common risk variants can shed light on the underlying molecular mechanism, identifying causal variants remains challenging for scientists,” says Nan Yang, Ph.D., Assistant Professor of Neuroscience at the Icahn School of Medicine of Mount Sinai, and senior author of the study. “That’s because cis-regulatory elements, particularly the enhancers, vary across cell types and activity states. Typically, researchers can only use postmortem brain samples where the neurons are no longer active. As a result, they are likely to miss enhancers that only respond to stimulation. Our approach is to map cis-regulatory elements in human neurons derived from pluripotent stem cells. That allows us to replicate neurons in the human brain that can be affected by different types of neuropsychiatric disease, and conduct mechanistic studies of human genetic variants that are inaccessible from other types of human samples.”

In recent years, GWAS have identified hundreds of gene regions associated with psychiatric disease, though understanding disease pathophysiology has been elusive. The functional genomics approach Dr. Yang and her team developed uses stem cell models that can help resolve the impact of patient-specific variants across cell types, genetic backgrounds, and environmental conditions. This unique approach effectively lays a foundation to translate risk variants to genes, genes to pathways, and pathways to circuits that reveal the synergistic relationship between disease risk factors within and between the cell types in the brain.

“Our research attempts to decode and transfer highly complex genetic insights into medically actionable information,” says Dr. Yang, who is a member of the Black Family Stem Cell Institute, The Friedman Brain Institute, and The Ronald M. Loeb Center for


#model #helps #untangle #complex #psychiatric #disorders #autism #schizophrenia