Common mutations produce typical schizophrenia brain changes

Mutations in dopamine-related genes have a dose-response effect on prefrontal activation during emotional response inhibition in healthy adults, a study shows.

The results support the notion that small, common genetic changes have additive effects on the risk of psychosis.

“In this case, inheritance of only two risk alleles on different chromosomes, both associated with prefrontal functional changes, combined to produce blunted prefrontal brain activation similar to that found in people with schizophrenia,” write Thomas Weickert (University of New South Wales, Sydney, Australia) and co-workers in Translational Psychiatry.

The team looked at the rs4680 mutation in the catechol-O-methyltransferase (COMT) gene, which affects the catabolism of dopamine, and the rs2283265 mutation in the dopamine D2 receptor (DRD2) gene, which influences the ratio of short-to-long DRD2 isoforms in the brain.

A total of 43 healthy adults undertook an emotional response inhibition task, in which they had to respond to words with a neutral meaning while inhibiting responses to emotionally negative words. Functional magnetic resonance imaging revealed five areas of increased activation during this task: the right insula; left middle frontal gyrus; right middle frontal gyrus; right supplementary motor area and right middle frontal gyrus.

Activation of the bilateral middle frontal gyrus and right middle frontal gyrus was related to whether participants were low or high risk in terms of COMT and DRD2 mutations, being significantly higher in those with one or no risk alleles than in those with two or more.

And there was a significant linear relationship between increasing number of risk alleles and reduced activation of the left rostral prefrontal cortex, right rostral prefrontal cortex, right supplementary motor area and right dorsolateral prefrontal cortex during the emotional inhibition task.

The healthy participants had higher activation during this task than 27 patients with schizophrenia. But in contrast with the healthy group, the schizophrenia patients did not have an allelic dose-response.

However, Weickert et al had predicted this effect; all the schizophrenia patients were taking antipyschotics, and the team hypothesised that, if prefrontal activation is mediated partly via DRD2, then the presence of a DRD2 antagonist would overshadow the effects of the risk alleles.

“This suggests that hypofrontality, commonly observed in schizophrenia in the context of antipsychotic treatment, has at least two potential sources: first, inheritance of risk alleles biasing the prefrontal cortex to be underactive during cognitive-affective challenges and, second, as a consequence of DRD2 blockade,” they conclude.

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