We have recently completed a ten year longitudinal study of brain structure and function in a group of individuals at high risk of schizophrenia for familial reasons, and have taken blood for genetic analyses. We can therefore study the effects of recently discovered candidate genes for schizophrenia in a large well characterised cohort of those at risk, including some who went on to become ill, but without illness related potential confounders such as antipsychotic medication.

162 initially healthy people aged 15-25 at high genetic risk of schizophrenia, because they had at least one close relative with the disorder, were recruited and examined with structural MRI and functional MRI. The development of psychotic symptoms and/or schizophrenia itself was monitored at serial assessments, which most participants had at 18-24 month intervals over up to 10 years.

21 developed schizophrenia during the study and an additional 66 subjects had psychotic symptoms at one or more assessments. 78 of the subjects were genotyped. Single nucleotide polymorphisms in the Brain Derived Neurotrophic Factor (BNDF) and D-amino acid oxidase (DAO) genes were associated with abnormalities of frontal and temporal function in the high risk cohort as a whole. A risk allele (SNP8NRG243177) in the Neuregulin 1 (NRG1) promoter region, on the other hand, was associated with psychotic symptoms, decreased premorbid IQ and decreased activation of pre-frontal and temporal lobe regions. The Val(158)Met polymorphism in the Catechol-O-MethylTransferase (COMT) gene predicted schizophrenia in this cohort in a dose-dependent manner. It was also associated with reduced gray matter density and BOLD signal in anterior cingulate cortex.

These patterns of altered brain structure and function have previously been associated with schizophrenia in this and other samples. In the Scottish population, BDNF and DAO may have trait effects, while the NRG1 variant appears to be a risk factor for an extended or intermediate phenotype and the COMT Val allele is associated with an increased risk of schizophrenia. This genetic background may provide a mechanistic framework in which to study the effects of environmental risk factors, perhaps particularly in subjects at increased familial risk.