Humans have been attempting to unravel the mysteries of mental illness since the practice of medicine began. Today, a breakthrough study from an international team of psychiatrists and geneticists jumps our understanding forward considerably.
Their paper, published in Science, found distinct patterns of gene expression in the brains of individuals with autism spectrum disorder (ASD), schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD); diseases that were previously regarded as quite distinct from one another. The work also reveals some of the first tangible differences in the molecular activity between individuals with psychiatric disorders versus those with normal brains.
Follow-up studies aimed at creating targeted medications that reduce symptoms by correcting the underlying atypical gene expression have already begun.
"These findings provide a molecular, pathological signature of these disorders," said senior author Daniel Geschwind in a statement. "The major challenge now is to understand how these changes arose."
Many previous studies have found that people with psychiatric conditions carry abnormal versions of certain genes, confirming the long-held notion that such disorders, or at least a predisposition toward developing them, is inherited. But genes don’t code for behavioral traits or symptoms, they code for proteins that affect the function of our brain circuitry – ultimately impacting behavior in more indirect ways. In addition, people with psychiatric disorders display modified brain function in certain regions only. Because of this, it is believed that development of psychiatric disease involves an interplay between multiple genes and changes in their expression throughout the brain.
To determine which genes are being improperly activated in these patients, Geschwind and his colleagues investigated traces of RNA – transcripts of DNA halfway through the expression process. Cortical tissue donated from 700 deceased individuals with ASD, SCZ, BD, MDD, and alcoholism were analyzed; plus 293 samples from healthy controls and 197 non-neurological disease controls.
Their results showed a striking overlap in altered expression of a handful of abnormal gene versions across ASD, SCZ, BD, and MDD.
Surprisingly, there was very little overlap between alcoholism and the other disorders studied, and bipolar disorder was less closely related to depression than the team hypothesized, given that both are considered mood disorders. Instead, BD brain activity was most comparable with schizophrenia.
"This is not what clinicians would've expected," Kenneth Kendler, a psychiatric geneticist not involved in the study, told Science Mag. "It certainly suggests the idea that these are sharply different kinds of disorders is not valid."
Perhaps the most intriguing revelation came from the discovery that brains with autism, schizophrenia, and bipolar disorder share a unique transcription pattern in a cluster of genes that mediate neuron excitability. In life, people with autism have very few traits in common with these two diseases.
The researchers' next step will be to further investigate the roles of the unusually expressed proteins to see how they affect the actions of certain cell types.
"We show that these molecular changes in the brain are connected to underlying genetic causes, but we don't yet understand the mechanisms by which these genetic factors would lead to these changes," said Geschwind.
Piecing together the total picture of how genes and their relative expression lead to behavior, however, is still quite far off.