Common polymorphisms in dopamine related genes combine to produce a “schizophrenia-like” prefrontal hypoactivity
Forty-three healthy adults and 27 people with schizophrenia received an fMRI scan while completing an emotional response inhibition test. Blood samples were collected and DNA was genotyped using Taqman SNP assays. The number of “risk” alleles was tallied in each participant to generate an oligogenic score which was used as a predictor of brain activation. We also tested whether task related brain activity was related to antipsychotic dosage in schizophrenia.
People with schizophrenia showed a significantly reduced activity during inhibition of responses to negative words in left insula, left BA 10, right BA 10, right anterior cingulate, and right BA 9 compared to healthy adults. We detected a significant linear association between increasing prefrontal dopamine risk allele load and reduced activation in the left insula, bilateral BA10, and right BA9 in healthy adults and no such relationship in schizophrenia. We observed a negative association between daily chlorpromazine equivalent dose and dorsolateral prefrontal activation in schizophrenia.
These results provide the first evidence that genetic variation controlling DRD2 receptor characteristics and synaptic dopaminergic availability combine to shape prefrontal cortex neural responses during cognitive-affective challenges. Thus, dopaminergic genes can additively combine in healthy people to produce the hypofrontality endophenotype characteristic of schizophrenia. Antipsychotics could be an overriding environmental factor obscuring dopaminergic genetic effects in schizophrenia.
