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Mental disorders share molecular similarities

UCLA study sheds light on genetic overlap between Autism, schizophrenia, and bipolar disorders...


Most medical disorders have well-defined physical characteristics that can be seen in tissues, organs and body fluids. But psychiatric disorders are only defined by behaviors.

Now, a University of California Los Angeles (UCLA) study appearing Feb. 9 in Science, has found autism, schizophrenia and bipolar disorder share some physical characteristics at the molecular level, specifically in patterns of gene function in the brain. Research also pinpoints important differences in these disorders' gene expression or function.
"These findings provide a molecular, pathological signature of these disorders, which is a large step forward. The major challenge is understanding how these changes arose."

Daniel Geschwind PhD, Professor of Neurology, Psychiatry and Human Genetics, Director of the UCLA Center for Autism Research and Treatment, and senior author.

Researchers know that certain variations in genetic material put people at risk for psychiatric disorders, but DNA alone doesn't tell the whole story. Every cell in the body contains the same DNA. RNA molecules, on the other hand, play a role in gene expression in different parts of the body by "reading" these instructions within DNA and executing their directions.
Extended public review in Science magazine.

Geschwind and the study's lead author, Michael Gandal, reasoned that taking a close look at RNA in human brain tissue would provide a molecular profile of these psychiatric disorders. Gandal is an assistant professor of psychiatry and biobehavioral sciences at UCLA. They analyzed the RNA in 700 tissue samples from the brains of deceased subjects who had autism, schizophrenia, bipolar disorder, major depressive disorder or alcohol abuse disorder, and compared them to samples from brains without psychiatric disorders.
Molecular pathology reflected significant overlap between disorders like autism and schizophrenia, but also specificity as major depression showed molecular changes not seen in the other disorders.

"We show that these molecular changes in the brain are connected to underlying genetic causes, but we don't understand the mechanisms by which these genetic factors would lead to these changes," Geschwind explains. "So, although now we have some understanding of causes, and this new work shows the consequences, we now have to understand the mechanisms by which this comes about, so as to develop the ability to change these outcomes."

Abstract
The predisposition to neuropsychiatric disease involves a complex, polygenic, and pleiotropic genetic architecture. However, little is known about how genetic variants impart brain dysfunction or pathology. We used transcriptomic profiling as a quantitative readout of molecular brain-based phenotypes across five major psychiatric disorders—autism, schizophrenia, bipolar disorder, depression, and alcoholism—compared with matched controls. We identified patterns of shared and distinct gene-expression perturbations across these conditions. The degree of sharing of transcriptional dysregulation is related to polygenic (single-nucleotide polymorphism–based) overlap across disorders, suggesting a substantial causal genetic component. This comprehensive systems-level view of the neurobiological architecture of major neuropsychiatric illness demonstrates pathways of molecular convergence and specificity.

Authors: Geschwind and Gandal, Jillian Haney, Neelroop Parikshak, Virpi Leppa, Gokul Ramaswami, Chris Hartl and Steve Horvath, all of UCLA; Andrew Schork, Vivek Appadurai, Alfonso Buil and Thomas Werge, all of the Institute of Biological Psychiatry, Mental Health Services Copenhagen in Denmark; Chunyu Liu of the University of Illinois at Chicago; Kevin White of the University of Chicago; the CommonMind Consortium; the PsychENCODE Consortium; and the iPSYCH-BROAD Working Group.


The study was supported with funding from the National Institute of Mental Health, the Simons Foundation Autism Research Initiative and the Stephen R. Mallory schizophrenia research award at UCLA.

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Feb 16, 2018   Fetal Timeline   Maternal Timeline   News   News Archive



Cerebral cortex cells reflect both shared and distinctive gene activity patterns in patients
with major mental disorders. Image credit: CNRI/SCIENCE SOURCE


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