Genetic architecture of schizophrenia traced to fetal brain

2 August 2013

Researchers have found that schizophrenia may arise from mutations in networks of genes that orchestrate development of the prefrontal cortex of the brain.

In a collaborative study between multiple centres using the US National Institute of Mental Health (NIMH) genetics repository, researchers combined information about spontaneous mutations associated with non-familial schizophrenia and transcriptomic data showing when and where these genes are active. They found that many were expressed primarily in early fetal development, with a second peak in expression levels in early adulthood – the age at which symptoms of schizophrenia typically manifest.
 
The networks of genes linked with the disease are known to be active during development of the prefrontal cortex of the fetal brain. Notably, the networks formed by genes containing harmful, schizophrenia-associated mutations had more nodes (points of connection) than those in unaffected siblings, or those in affected siblings that contained other mutations not linked with schizophrenia.
 
The findings are consistent with the current neurodevelopmental model of schizophrenia, whereby malfunctions of the prefrontal cortex result in impaired organisation and coordination of information from different regions of the brain that normally direct ‘executive functions’ such as planning, problem-solving, self-regulation, memory and concentration. Deficits in these functions may precede the onset of symptomatic schizophrenia when the brain is fully mature, and could serve as early warning signs.
 
Comment: This study is important in illustrating the complexity of genetics and disease – in this case, the need to consider how mutations affect gene expression in particular locations and at certain times in order to understand how disease arises. The findings are also consistent with current thinking on the fetal / developmental origins of health – that environmental exposures during the prenatal period influence future health.
 
The potential to identify incipient schizophrenia before the onset of symptoms is an interesting one; ideally, this could allow monitoring and the introduction of therapy before the onset of full-blown symptoms, which are highly distressing. On the other hand, it could be harmful to label as schizophrenic teenagers who may display similar impairments without going on to develop the disease.

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