Editors' ChoiceSchizophrenia

Your genes are conspiring against you

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Science Translational Medicine  08 Feb 2017:
Vol. 9, Issue 376, eaam6059
DOI: 10.1126/scitranslmed.aam6059

Abstract

Gene variants in the dopamine receptor D2 expression network predict physiological and clinical features as well as treatment responses in schizophrenia.

For complex neuropsychiatric disorders, such as schizophrenia, there is no reliable biological signature, and clinical description is currently the sole form of diagnosis. The high contribution of genetics in schizophrenia—up to 50%—is due to numerous genetic variants with small individual effects, and their functional relevance is poorly understood. To examine functional readout, a useful approach is to look for gene coexpression networks, groups of genes that have a correlated pattern of expression associated with a certain genetic variant. These networks are likely to reflect biological and molecular pathways altered in the disorder.

In a recent study, Pergola et al. showed that gene coexpression pathways associated with a variant in the gene encoding the dopamine receptor subtype D2 (DRD2), which has previously been linked to schizophrenia, can predict physiological and clinical phenotypes. Using gene expression data from postmortem brain tissue of 249 individuals, they recognized a group of 85 genes that were coexpressed with the DRD2 variant in brain prefrontal cortex, an area affected in the disorder. Based on polymorphisms in eight of these genes, the authors generated a polygenic coexpression index (PCI), representing the genetic contribution to this coexpression, and investigated its potential association with schizophrenia phenotypes, as well as with treatment response. Cognitive dysfunction, including working memory deficits, is a core symptom of the disorder. Genetic variants in DRD2 have been associated with differential working memory performance and activity in the brain prefrontal cortex, a region engaged during tasks that involve working memory. The authors used the n-back test, commonly used for assessment of cognitive abilities, in 368 healthy individuals and 29 schizophrenia patients while they were undergoing functional magnetic resonance imaging to measure brain activity. In this test, subjects are continuously presented with objects and they must indicate when the current object matches the one presented n steps earlier. The authors found that higher PCI was associated with greater prefrontal cortex activity and poorer test performance, as noted by longer reaction times, in both patients and controls. In addition, using an independent sample of 87 patients, they found that greater PCI was correlated with improved response to antipsychotics and clinical outcome. Although the study is limited by using separate groups and small sample sizes, it represents a proof of concept for the development of diagnostic criteria for psychiatric disease based on the association of genetic findings with biological outcomes, such as brain imaging or response to pharmacological treatments.

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