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New Model Helps Unravel Complex Psychiatric Disorders Such As Autism and Schizophrenia

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New Mannequin Helps Unravel Advanced Psychiatric Problems Such As Autism and Schizophrenia

The analysis focuses on mapping cis-regulatory parts in human neurons which may be linked to the heredity of psychiatric problems.

A Mount Sinai stem cell mannequin could possibly make clear the advanced biology behind sure psychiatric problems.

To map illness danger variants in human neurons, researchers on the Icahn Faculty of Medication at Mount Sinai used a singular stem cell mannequin. This work may assist make clear the organic mechanisms behind neuropsychiatric illnesses equivalent to autism and schizophrenia.

Nan Yang

Nan Yang, Ph.D., assistant professor of neuroscience. Credit score: Mount Sinai Well being System

The group’s in vitro cell mannequin, not too long ago printed within the journal Cell Stories, was created to allow future researchers to raised perceive illness mechanisms involving genome-wide affiliation research (GWAS) that characterize numerous danger alleles (frequent genetic variants conferring danger) for psychiatric problems. This examine may assist develop higher diagnostic strategies to identify psychological issues years earlier than sufferers’ signs manifest.

The analysis focuses on figuring out cis-regulatory components in human neurons which may be linked to the heritability of psychiatric problems. Cis-regulatory components, which embody enhancers and promoters, are non-coding[{” 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 Typically, researchers can only use postmortem brain samples where the neurons are no longer active.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 Alzheimer’s Disease within the Mount Sinai Health System. “That means improving our diagnostic capabilities, predicting clinical trajectories, and identifying presymptomatic points of therapeutic intervention for psychiatric disorders.”

By characterizing cell-type specific and activity-regulated gene expression patterns in human cell-derived neurons, Dr. Yang believes her team’s study can greatly benefit the research community. “Our data can guide choosing relevant cell types of experimental conditions to further elucidate molecular mechanisms of disease across the genome,” she points out. “And that could lead to the development of biomarkers that might detect neuropsychiatric disorders years before they manifest themselves in patients, while there is still time to delay or possibly prevent them.”

Reference: “Mapping cis-regulatory elements in human neurons links psychiatric disease heritability and activity-regulated transcriptional programs” by Carlos Sanchez-Priego, Ruiqi Hu, Linda L. Boshans, Matthew Lalli, Justyna A. Janas, Sarah E. Williams, Zhiqiang Dong and Nan Yang, 31 May 2022, Cell Reports.
DOI: 10.1016/j.celrep.2022.110877



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