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Hotspot in the genome may drive psychosis in schizophrenia and bipolar disorder

May 03, 2019

GRAND RAPIDS, Mich. (May 3, 2019) -- A newly identified epigenetic hotspot for schizophrenia and bipolar disorder may give scientists a fresh path forward for devising more effective treatments and biomarker-based screening strategies.

More than 100 million people worldwide have either schizophrenia or bipolar disorder, which are characterized by periods of hallucinations, delusions and irregular thought processes. They are both associated with overproduction of the neurotransmitter dopamine, a key regulator of reward-seeking behavior, emotional responses, learning and movement, among other functions.

While effective medications do exist, they often have challenging side effects such as apathy, weight gain and uncontrolled movements called dyskinesias that typically are associated with Parkinson's disease. Currently, there are no effective biomarkers for screening and tracking progression of either disorder.

"We've known since the 1970s that the effectiveness of antipsychotic medications is directly related to their ability to block dopamine signaling. However, the exact mechanism that sparks excessive dopamine in the brain and that leads to psychotic symptoms has been unclear," said Viviane Labrie, Ph.D., assistant professor at Van Andel Research Institute (VARI) and corresponding author of the study, which appears in the May 3 edition of Nature Communications. "We now have a biological explanation that could help make a real difference for people with these disorders."

Labrie and her collaborators found a cluster of epigenetic marks that ratchets up dopamine production while simultaneously scrambling the brain's synapses, the information hubs that transmit rapid-fire neural messages responsible for healthy function. The result is a catastrophic shake-up of the brain's organization and chemical balance that fuels symptoms of psychosis.

"What we're seeing is a one-two punch -- the brain is being flooded with too much dopamine and at the same time it is losing these critical neural connections," Labrie said. "Like many other neurological disorders, schizophrenia and bipolar disorder often have early, or prodromal, phases that begin years before obvious symptoms. It is our hope that our findings may lead to new biomarkers to screen for risk, which would then allow for earlier intervention."

The team took a comprehensive, broad look at DNA derived from brain cells of people with either schizophrenia or bipolar disorder and compared them to healthy controls. Their analyses revealed a cluster of epigenetic marks, which switch genes on and off, in an enhancer at a gene called IGF2, a critical regulator of synaptic development. Enhancers are stretches of DNA that help activate genes and can be major players in the development of diseases in the brain and other tissues.

This enhancer also controls the activity of a nearby gene called tyrosine hydroxylase, which produces an enzyme that keeps dopamine in check. When the enhancer is epigenetically switched on, production of dopamine becomes dysregulated, resulting in too much of the chemical in the brain.

Taken together, molecular changes at this site may explain why psychosis brought on by dopamine frequently is accompanied by a disruption of brain synapses, a devastating double-hit that promotes symptoms.

The study controlled for genetic factors, sex, ethnicity, treatment history and lifestyle influences such as smoking, and the results were validated in experimental models of the disease.

"We used cutting-edge computational strategies to understand the events occurring in brain cells that underlie psychiatric disorders," said Shraddha Pai, Ph.D., a postdoctoral fellow at University of Toronto and the study's first author. "Our results were strengthened by additional studies in disease models. This comprehensive approach lends weight to our findings, which we believe will propel additional groundbreaking investigations into this enhancer at the IGF2 gene."
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Other authors include Peipei Li, Ph.D., Bryan Killinger, Ph.D., Lee Marshall, Ph.D., Ji Liao, Ph.D., and Piroska E. Szabó, Ph.D., of Van Andel Research Institute; and Peixin Jia, Ph.D., and Arturas Petronis, M.D., Ph.D., of the Krembil Family Epigenetics Laboratory at the Centre for Addiction and Mental Health. Petronis also is affiliated with Institute of Biotechnology at Vilnius University. Van Andel Research Institute's Pathology and Biorepository Core, Genomics Core and Bioinformatics and Biostatistics Core also contributed to this work. Tissue samples were obtained from the National Institutes of Health NeuroBioBank at the Harvard Brain Tissue Resource Center, the Human Brain and Spinal Fluid Resource Center, the University of Miami Brain Endowment Bank and the University of Pittsburgh Brain Tissue Donation Program.

This work was supported by the U.S. Army Medical Research Materiel Command through the Parkinson's Research Program under award no. W81XWH1810512 (Labrie). Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the U.S. Army.

Research reported in this publication also was supported by the Brain Behavior and Research Foundation award nos. 529941 (Pai) and 23482 (Labrie); Alzheimer's Society of Canada (Labrie); and the Scottish Rite Charitable Foundation of Canada (Labrie). The content is solely the responsibility of the authors and does not necessarily represent the official views of the granting organizations.

ABOUT VAN ANDEL INSTITUTE

Van Andel Institute (VAI) is an independent nonprofit biomedical research and science education organization committed to improving the health and enhancing the lives of current and future generations. Established by Jay and Betty Van Andel in 1996 in Grand Rapids, Michigan, VAI has grown into a premier research and educational institution that supports the work of more than 400 scientists, educators and staff. Van Andel Research Institute (VARI), VAI's research division, is dedicated to determining the epigenetic, genetic, molecular and cellular origins of cancer, Parkinson's and other diseases and translating those findings into effective therapies. The Institute's scientists work in onsite laboratories and participate in collaborative partnerships that span the globe. Learn more about Van Andel Institute at vai.org.

Van Andel Research Institute

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