The underlying causes of the debilitating psychiatric disorder schizophrenia remain poorly understood.
In a study published in Genome Research, scientists have performed a powerful gene network analysis that has revealed surprising new insights into how gene regulation and age play a role in schizophrenia.
Researchers are actively working to identify the direct cause of schizophrenia, likely rooted in interactions between genes and the environment that result in abnormal gene expression in the central nervous system. Scientists have been studying expression changes in schizophrenia on an individual gene basis, yet this strategy has explained only a portion of the genetic risk.
In this work, a team of researchers led by Elizabeth Thomas, of the Scripps Research Institute, has taken a novel approach to this problem, performing a gene network-based analysis that revealed surprising insight into schizophrenia development.
The group analyzed gene expression data from the prefrontal cortex, a region of the brain associated with schizophrenia, sampled post mortem from normal individuals and schizophrenia patients ages 19 to 81. However, instead of just looking at genes individually, Thomas and colleagues considered interactions between genes, as well as groups of genes that showed similar patterns of expression to identify dysfunctional cellular pathways in schizophrenia.
"Once gene coexpression networks are identified," said Thomas, "we can then ask how they are affected by factors, such as age or drug treatment, or if they are associated with particular cell types in the brain."
The gene network analysis suggested normal individuals and schizophrenia patients have a unexpectedly similar connectivity between genes, but the most surprising finding was a significant link between aging and gene expression patterns in schizophrenia. The team identified several groups of coexpressed genes that behaved differently in schizophrenia patients compared to normal subjects when age was considered.
A particularly striking age-related difference in coexpression was found in a group of 30 genes related to developmental processes of the nervous system. Normally these genes are turned off as a person ages, but in schizophrenia patients the genes remain active. This critical finding strongly suggests age-related aberrant regulation of genes important for development can explain at least part of the manifestation of schizophrenia.
Thomas explained that these findings help refine the developmental hypothesis of schizophrenia, which states that one or more pathogenic "triggers" occur during critical periods of development to increase risk of the disease. Specifically, this work indicates abnormal gene expression in developmentally related genes might be a significant pathogenic trigger, occurring over a broader time-scale than expected.
"Rather than a pathological trigger occurring at a critical developmental time point," said Thomas, "the trigger is ongoing throughout development and aging."
Furthermore, Thomas noted their study supports early intervention and treatment of schizophrenia. Treatment approaches aimed at averting gene expression changes and altering the course of the disease could be specifically tailored to the patient's age.
This work was supported by the Scripps Translation Science Institute Clinical Translational Science Award, the National Institutes of Health and a Scripps Dickinson Fellowship.