Scientists Uncover Disharmony in Genes Expressed across Brain Regions in Schizophrenia

Study is first to find that in people with schizophrenia, genes may function differently in different parts of the brain which fail to coordinate with each other.

Baltimore, MD – June 10, 2019 – A postmortem analysis of 900 samples from 551 human brains has revealed that people with schizophrenia exhibit a novel pattern of gene expression in a region that plays a critical role in learning and memory, and lack of cohesion in gene expression across the brain, according to a study from researchers at the Lieber Institute for Brain Development (LIBD) published in the journal Neuron.

The researchers compared gene expression in the brains of people who had suffered from schizophrenia to those who had no psychiatric illness, focusing on an area known as the hippocampus. While scientists have long understood that the hippocampus may be abnormal in patients with schizophrenia, differences in gene expression have been studied in the past principally in a brain region known as the dorsolateral prefrontal cortex (DLPFC)–a part of the brain involved in decision making and executive function that may also influence emotional reactions.

“For the first time we have insight at the molecular level into the role of the hippocampus in schizophrenia, in particular how this region is not coordinating its biology with other brain regions,” said Daniel R. Weinberger, M.D., LIBD CEO & Director. “The different systems of the brain orchestra are out of sync with each other, suggesting new therapeutic strategies for getting things back in tune.”

Lead Investigator Andrew Jaffe, Ph.D., said, “Using a robust cohort of schizophrenic and non-psychiatric controls, we examined brain tissue samples across both the prefrontal cortex and hippocampus. The result is a better understanding of the complex molecular differences of schizophrenia-associated gene expression across different regions of the human brain.” Of note, the scientists discovered that genes related to risk for schizophrenia are not controlled the same way across these regions. To understand the importance of how a gene relates to schizophrenia, it is critical to examine how they are coordinated across brain regions with each other. “Location, location, location matters in the real estate of the brain” said Weinberger.

The study, “Regional Heterogeneity in Gene Expression, Regulation, and Coherence in the Frontal Cortex and Hippocampus across Development and Schizophrenia” appears in the June 4 edition of Neuron.

Hippocampal function is well-characterized in Alzheimer’s disease, but less is known at the molecular level about the region’s role in schizophrenia. To better understand the underlying molecular biology and function of the hippocampus in people with schizophrenia, researchers performed a genome-wide differential gene expression analysis using RNA sequencing (RNA-seq) on postmortem human brains [that had been donated for scientific study]. The study resulted in the largest brain genomic data set on the hippocampus and its relation to schizophrenia to-date.

Researchers at the Lieber Institute worked in partnership with the BrainSeqTM Consortium, a pre-competitive collaboration with seven major pharmaceutical companies. The consortium was established to uncover the genetic origins of brain disorders in order to identify novel therapeutic targets. BrainSeqTM also works to make data freely available to scientists worldwide and all data sets produced in this study are publicly available for future research.

About the Lieber Institute for Brain Development
The mission of the Lieber Institute for Brain Development and the Maltz Research Laboratories is to translate the understanding of basic genetic and molecular mechanisms of schizophrenia and related developmental brain disorders into clinical advances that change the lives of affected individuals. LIBD is an independent, not-for-profit 501(c)(3) organization and a Maryland tax-exempt medical research institute affiliated with the Johns Hopkins University School of Medicine. The Lieber Institute’s brain repository of more than 3,000 human brains is the largest collection of postmortem brains for the study of neuropsychiatric disorders in the world.