Polymorphisms in the COMT and MAOA genes and their consequences for Clinical, Neuropsychological and Neuroimaging dimensions in a population at High Risk of Schizophrenia

Schizophrenia is a severe an enduring psychiatric condition occurring in around 1% of the general population. In addition to clinical symptoms, sufferers show neuropsychological deficits. Neuroimaging changes including deficits in frontal and temporal lobe structures can be seen in subjects with the condition. Of the many aetiological perspectives of Schizophrenia the heritability of the illness and the role of excess of the neurotransmitter dopamine are important. Dopamine is degraded by two enzymes COMT and MAOA. Thus mutations in the genes controlling the effectiveness of these enzymes may render subjects with a hyperdopaminergic state. This thesis will concentrate on two specific Single Nucleotide Polymorphisms in the MAOA and COMT genes and their consequences on the clinical, neuropsychological and neuroimaging phenotype. The study population for this thesis will be taken from the Edinburgh High Risk Study. This is a prospective cohort of individuals at high risk of schizophrenia due to having two or more relatives with the condition. It is in this population that the effects of the genes may be studied without the contaminating effects of psychotropic medication or other illness factors. The results from this thesis show that COMT genotype can be related to structural and functional neuroimaging changes. Additionally MAOA genotype appears to have a significant effect on affective symptoms and neuropsychological traits. These findings suggest a mechanism for how a hyperdopaminergic state may impact on the Schizophrenia Phenotype