There is impressive and growing evidence for the involvement of several specific genetic risk factors in the aetiopathogenesis of schizophrenia and/or bipolar disorder. Examining the relationship of well established genes to brain imaging abnormalities is arguably the best currently available method of examining these effects in vivo. Ideally, this would be done in large well characterised cohorts of patients and also in those at risk but without illness or illness related potential confounders such as antipsychotic medication. We have recently completed a ten year longitudinal study of brain structure, function, and risk of developing schizophrenia in a group of individuals at high risk of schizophrenia for familial reasons. In a sample of young and initially healthy people at high genetic risk of schizophrenia, blood was taken and assays conducted for a small number of these best replicated risk factors for schizophrenia. Here we will discuss the effects of the Val(158)Met polymorphism in the Catechol-O-MethylTransferase (COMT) and the effects of a variant in the human Neuregulin 1 (NRG1) promoter region in subjects at high risk of schizophrenia on: (i) brain structure as measured with structural magnetic resonance imaging (sMRI), (ii) brain function as indexed with key neuropsychological tests and functional MRI, and (iii) the development of psychotic symptoms and/or schizophrenia itself. The COMT Val allele increased the risk of schizophrenia in this cohort in a dose-dependent manner. Subjects with the COMT Val allele had reduced gray matter density in anterior cingulate cortex. In addition, there was evidence of increased fMRI activation in lateral prefrontal cortex and anterior and posterior cingulate, with increasing task difficulty in those with the COMT Val allele despite a similar level of performance. The risk allele in the NRG1 promoter region, on the other hand, was associated with the development of psychotic symptoms, decreased premorbid IQ and decreased activation of pre-frontal and temporal lobe regions. These patterns of altered brain structure and function have previously been associated with schizophrenia in this and other samples. In the Scottish population, the NRG1 gene appears to be a risk factor for an extended or intermediate phenotype while the COMT Val allele is associated with an increased risk of schizophrenia in subjects at increased familial risk. Determining how these and other risk factors interact will require studies which are an order of magnitude larger and establishing these will require collaborative clinical, genetic and multi-centre imaging research networks.