Researchers use brain cells in a dish to study genetic origins of schizophrenia

A study in Biological Psychiatry establishes an in vitro model of human neuron development to investigate genetic risk for psychiatric disease


Philadelphia, October 16, 2018

A study in Biological Psychiatry has established a new analytical method for investigating the complex genetic origins of mental illnesses using brain cells that are grown in a dish from human embryonic stem cells. Researchers at the University of California Los Angeles examined the process in which new neurons are designated for certain roles, and found that changes in gene expression over the course of neural development were significantly associated with genetic risk for schizophrenia.

“Our approach allowed us to model how multiple regions in the genome that increase risk for psychiatric disorders act in concert to affect molecular and cellular function that is relevant for neurodevelopment. This is exciting as it provides a novel framework to study genetic risk of psychiatric disease and shows that we can capture parts of the heritability of schizophrenia in a lab model system,” said first author and PhD candidate Anil Ori, MSc.

Studying the disease biology and heritability of schizophrenia in model systems is challenging because of the genetic complexity of psychiatric illnesses. “[Large-scale population studies] have shown that psychiatric disorders are heritable traits in which hundreds if not thousands of genes throughout the human genome contribute to disease risk,” said senior author Roel Ophoff, PhD. This accumulation of many small gene effects is referred to as polygenic risk.

“The translation of polygenic risk to neurobiology is one of the major scientific challenges for psychiatry in this era. This paper highlights a novel approach to begin this work,” said John Krystal, MD, Editor of Biological Psychiatry.

The new approach embraced the polygenic nature of schizophrenia by tracking changes in gene expression as human neural stem cells developed. By integrating the gene expression profiles with genome-wide schizophrenia risk data, first author Anil Ori and colleagues found that the differentially expressed genes during development were associated with schizophrenia polygenic risk. They replicated this finding in the study using a different sample.

According to the authors, the findings will help researchers narrow down the core disease processes that contribute to disease risk. In the study, the genes primarily responsible for the association with disease risk were involved in synaptic function—the means by which cells communicate and transmit signals through the brain.

“Establishing this platform for further study has great potential benefit,” said Mr. Ori. Now that the study has established in vitro neural development as a model for psychiatric disease, researchers can tweak the model to investigate how different environments might affect disease risk, and use this to understand the biology of mental illnesses.

“As large-scale genetic studies of psychiatric disorders will continue to expand, our study provides a valuable genomic tool to help investigate and understand how risk that is distributed across the genome contributes to the etiology of psychiatric disorders,” said Dr. Ophoff.

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Notes for editors
The article is "A longitudinal model of human neuronal differentiation for functional investigation of schizophrenia polygenic risk," by Anil P. S. Ori, Merel H. M. Bot, Remco T. Molenhuis, Loes M. Olde Loohuis, and Roel A. Ophoff (https://doi.org/10.1016/j.biopsych.2018.08.019). It appears in Biological Psychiatry, published by Elsevier.

Copies of this paper are available to credentialed journalists upon request; please contact Rhiannon Bugno at Biol.Psych@UTSouthwestern.edu or +1 214 648 0880. Journalists wishing to interview the authors may contact Roel Ophoff at Ophoff@ucla.edu or Anil Ori at AOri@mednet.ucla.edu.

The authors’ affiliations and disclosures of financial and conflicts of interests are available in the article.

John H. Krystal, MD, is Chairman of the Department of Psychiatry at the Yale University School of Medicine, Chief of Psychiatry at Yale-New Haven Hospital, and a research psychiatrist at the VA Connecticut Healthcare System. His disclosures of financial and conflicts of interests are available here.

About Biological Psychiatry
Biological Psychiatry is the official journal of the Society of Biological Psychiatry, whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal publishes both basic and clinical contributions from all disciplines and research areas relevant to the pathophysiology and treatment of major psychiatric disorders.

The journal publishes novel results of original research which represent an important new lead or significant impact on the field, particularly those addressing genetic and environmental risk factors, neural circuitry and neurochemistry, and important new therapeutic approaches. Reviews and commentaries that focus on topics of current research and interest are also encouraged.

Biological Psychiatry is one of the most selective and highly cited journals in the field of psychiatric neuroscience. It is ranked 6th out of 142 Psychiatry titles and 9th out of 261 Neurosciences titles in the Journal Citations Reports® published by Thomson Reuters. The 2017 Impact Factor score for Biological Psychiatry is 11.982. www.sobp.org/journal

About Elsevier
Elsevier is a global information analytics business that helps institutions and professionals advance healthcare, open science and improve performance for the benefit of humanity. Elsevier provides digital solutions and tools in the areas of strategic research management, R&D performance, clinical decision support and professional education, including ScienceDirect, Scopus, SciVal, ClinicalKey and Sherpath. Elsevier publishes over 2,500 digitized journals, including The Lancet and Cell, more than 38,000 e-book titles and many iconic reference works, including Gray's Anatomy. Elsevier is part of RELX Group, a global provider of information and analytics for professionals and business customers across industries. www.elsevier.com

Media contact
Rhiannon Bugno, Editorial Office
Biological Psychiatry
+1 214 648 0880
Biol.Psych@UTSouthwestern.edu