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Introduction The heritability of the brain’s structure and function in schizophrenia remains elusive Objectives/Aims To assess the influence of genetic and environmental factors on executive function in schizophrenia. Method A twin-sibling study of 206 subjects; 163 twins, varying in their zygosity and concordance for schizophrenia, and 43 singletons from sibling clusters varying in their concordance for schizophrenia. We assessed performance and regional brain activation using functional magnetic resonance imaging, during a phonological verbal fluency task. Results Patients and their unaffected relatives developed greater activation in the left inferior frontal gyrus, and greater deactivation in the middle temporal gyri bilaterally. These features were maximally evident in subjects with schizophrenia. When the analysis was restricted to the unaffected relatives and healthy controls, a similar pattern was evident. Heritability was greatest in the left hippocampus and the right middle temporal gyrus. Genetic modelling indicated a phenotypic correlation between schizophrenia and increased activity in the inferior frontal gyrus and reduced activity in the left middle temporal gyrus and left hippocampus, which appeared principally due to shared genetic effects. Conclusions Both schizophrenia and its familial vulnerability were associated with altered frontal, parahippocampal and temporal activation during verbal fluency. The altered left inferior frontal activity was particularly associated with schizophrenia, while altered left medial temporal and right middle temporal activity were more heritable. The latter was more intimately linked to the genetic risk for schizophrenia, and thus the better candidate intermediate phenotype.

DTI studies in schizophrenia have consistently reported decreased fractional anisotropy (FA, an index of white matter microstructure) in patients. There is little evidence as to the genetic or environmental determinants of this difference however. Studies of twins with schizophrenia allow us to estimate these influences. We report a cross-sectional case control study of twins with and without schizophrenia.We recruited mono- and di-zygotic twins concordant and discordant for DSM schizophrenia from across the United Kingdom, referred by their treating psychiatrists. We recruited healthy control twins from the Institute of Psychiatry Volunteer Twin Register and by national media advertisements. Clinical diagnoses were confirmed using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version (Spitzer and Endicott, 1978). Zygosity was confirmed by DNA analysis. Eleven pairs of monozygotic twins concordant for schizophrenia, 10 pairs of monozygotic and seven pairs of dizygotic twins discordant for schizophrenia, 24 pairs of healthy monozygotic twins and 20 pairs of healthy dizygotic twins were recruited.Subjects were scanned with an optimized DTI sequence at 1.5T. Scans were warp-corrected, masked, and FA calculated at each voxel. FA maps were then co-registered to a study-specific FA template using SPM2 and group differences calculated on segmented white-matter FA maps using non-parametric XBAM_v3.4.Results are presented of analyses comparing twins with schizophrenia with their well co-twin, linear trend analyses comparing healthy controls with well di and mono-zygotic co-twins, and a heritability analysis of the healthy controls.

Aims:To examine the effect of a polymorphism in the Dopamine Transporter (DAT) gene on brain activation during executive function and, for the first time:1.determine the extent to which this is altered in schizophrenia and2.use a verbal fluency paradigm.This is relevant since:1.DAT plays a key role in the regulation of dopamine, which modulates cortical activation during cognitive tasks and2.a disruption of dopamine function is a fundamental pathophysiological feature of schizophrenia.Method:Functional magnetic resonance imaging was used to measure whole-brain responses during overt verbal fluency in 85 subjects: 44 healthy volunteers and 41 DSM-IV schizophrenia patients. Main effects of genotype and diagnostic group on activation and their interaction were estimated using an ANOVA in SPM5.Results:The 10-repeat allele of the 3'UTR VNTR was associated with greater activation than the 9-repeat allele in the left (Z=4.8; FWEp=0.005) and right (Z=4.2; FWEp=0.057) anterior insula and with decreased activation in the rostral anterior cingulate (Z=4.3 FWEp=0.04) during word generation (versus baseline). These effects were irrespective of diagnostic group but generally more marked in patients. There were also strong trends for groupxgenotype interactions in the left middle frontal gyrus and the left nucleus accumbens. Analysis was controlled for task performance, IQ, antipsychotic medication, psychopathology and demographics.Conclusion:Cortical function during executive tasks is normally modulated by variation in the DAT gene, effect which is dependent on the brain region. DAT's effect may be altered in schizophrenia patients, which may reflect altered central dopamine function.