The genetics of schizophrenia: an fMRI investigation of endophenotypes in unaffected siblings and an examination of the neuropsychological correlates of COMT val108/158met genotype in patients

Abstract

Schizophrenia is a highly heritable disorder with a prominent genetic component. The search for susceptibility genes that confer liability for schizophrenia has been hampered by the heterogeneous nature of the illness and the complex etiology of the disorder. Identification of endophenotypes with more straightforward genotype-phenotype relationships than complex behavioral symptoms or subjective diagnostic categorizations may assist in identifying susceptibility genes. Abnormal cerebral neurophysiological activity during performance of various cognitive tasks is a promising endophenotype of schizophrenia. The endophenotype approach has been instrumental in identifying at least one candidate susceptibility gene, the COMT val108/158met polymorphism, which is linked to altered mesocortical dopamine function, reduced performance on cognitive tasks that tap frontal lobe functions, and possibly cognitive improvement with atypical antipsychotics in schizophrenia. Two experiments were undertaken to 1) build upon evidence that abnormal cerebral function is a potential endophenotype for schizophrenia, and 2) identify associations between COMT val108/158met genotype, cognition, and cognitive change with clozapine in patients with schizophrenia. In Experiment One, control subjects and unaffected siblings of patients with schizophrenia underwent fMRI while performing a procedural learning task. Compared to controls, unaffected siblings demonstrated less activity in the prefrontal cortex, basal ganglia, and parietal lobe suggesting that dysfunction of these regions may relate to genetic susceptibility for schizophrenia. Experiment Two examined the associations between cognitive function, cognitive improvement with clozapine, and COMT val108/158met genotype in a sample of patients with schizophrenia. The results indicated that patients with the val/val genotype performed worse on tests of executive function and working memory at baseline, and demonstrated less improvement with clozapine on a composite measure of verbal fluency and attention. The present results provide further evidence that neurophysiological abnormalities are related to genetic susceptibility for schizophrenia, add to the growing literature on the relevance of specific genetic polymorphisms to cognitive function, and contribute to the pharmacogenetics of cognitive improvement in schizophrenia.