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HOW A SCHIZOPHRENIA “RISK GENE” DISRUPTS BRAIN DEVELOPMENT

 

Working with their very large collection of exquisitely curated and characterized donated human brains, researchers at the Institute seek to identify the mechanisms of action through which genetic variations associated with schizophrenia and other psychiatric illnesses actually cause the illnesses.

Working with their very large collection of exquisitely curated and carefully characterized donated human brains, researchers at the Lieber Institute for Brain Development (LIBD) seek to identify the mechanisms of action through which genetic variations associated with schizophrenia and other psychiatric illnesses actually cause the illnesses. Identifying the mechanisms of action of risk genes—the biological basis of their genetic association with illness—is a critical step toward developing more effective treatments.

In work published in the journal JAMA Psychiatry August 27, 2014, a team led by Joel E. Kleinman, M.D., Ph.D., Associate Director of Clinical Sciences at LIBD, and including six other LIBD Investigators and seven colleagues from the University of Oxford, reports that they have mapped, for the first time, the expression of a gene linked to schizophrenia, known as ZNF804A, across the human life span and identified its potential link to psychosis.

Identifying the mechanisms of action of risk genes—the biological basis of their genetic association with illness—is a critical step toward developing more effective treatments.

The team was able for the first time to confirm that ZNF804A is active in the brain throughout life and that it is most strongly expressed during the prenatal period. This conclusion was based on sampling brain tissue in portions of the prefrontal cortex and the parietal lobe, in 697 donated brains spanning ages 14 weeks (prenatal) to 85 years. Patient donors included individuals diagnosed with schizophrenia, bipolar disorder and major depressive disorder (MDD).

ZNF804A has a known “risk” variant called rs1344706 that has been associated with psychosis, but whose mechanism of action—how it might cause psychosis—has up until now been unexplained. In the current study, the researchers found that the activity, or “expression levels,” of both the gene and its risk variant in the prefrontal cortex region of the brain vary, depending on psychiatric diagnosis. And, most importantly, the team discovered a novel, truncated RNA message produced by the risk variant during fetal brain development (that they have named ZNF804A-E3E4) that they propose is the, until now unexplained, link of ZNF804A to psychosis.

The risk gene’s truncated message—its abnormal instruction for making a protein—was expressed at higher than normal levels in MDD and lower than normal levels in schizophrenia. Activity of the standard version of the gene was unaltered in those two diagnoses but was observed to be below normal in bipolar disorder.

First author Ran Tao, Ph.D., commented that: “This study is another example that the genetic variants increasing the risk for psychiatric disorders involve the expression of specific alternative transcripts which might be critical for early brain development. So to discover and characterize human brain specific alternative transcripts in postmortem human brain specimens, especially during early brain development, are critical for understanding how those genetic variants increase the risk for psychiatric disorders.”