From Cognition to Genomics: Progress in Schizophrenia Research

This week’s issue of Nature has a special section dedicated to research progress on schizophrenia.i There have been few such issues dedicated to any medical disorder, so this is a landmark for schizophrenia research, a follow-up perhaps to an editorial in Nature at the beginning of this year predicting a “decade for psychiatric disorders”.ii But beyond the mere fact that schizophrenia has been singled out for this distinction, the contents document remarkable progress on a disorder that has been such a conundrum for the past century.

For one thing, schizophrenia can now be described as a brain disorder or, more precisely, as a disorder of brain circuits. With neuroimaging, several of the major nodes in the circuit have been identified, especially within the prefrontal cortex. A major advance has been linking changes in circuit function to cognition and behavior. As a result, we are increasingly focusing on the cognitive deficits of schizophrenia as the core problem, preceding and perhaps leading to the more obvious positive symptoms of hallucinations and delusions.

Another area of unambiguous progress has been genomics. Five years ago the field was frustrated by the lack of replicated findings. With the creation of international consortia sharing data from thousands of patients, we can now see several of the major risk genes. They are not the usual suspects, such as genes involved in dopamine or serotonin neurotransmission. Common variants in genes from the MHC complex, which is important for immune self-recognition, a gene for a transcription factor called TCF4, and several genes that encode synaptic proteins have all been found to confer increased risk. The list is probably not complete as together these explain only a fraction of the genetic risk for the disorder. Many rare variants have also been described in the past year, adding to the known major structural lesions like DISC1 and the 22q11 deletion. These rare events may explain only a small fraction of cases, but as with hypertension and cancer, even rare mutations that cause disease can yield important clues to the pathophysiology underlying more common forms of disease.

From genomics have come clues to the importance of reconceptualizing schizophrenia as a neurodevelopmental disorder. Many of the genetic factors are involved with neurodevelopment; hardly surprising as thousands of genes must be expressed in a carefully choreographed sequence to develop a healthy brain. What is unexpected is that many of the genetic variations associated with schizophrenia appear to disrupt fragments of proteins expressed only in fetal development……

Dr. Thomas Insel
NIMH Director
NIMH’s Director Blog

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