Several linkage and genetic association studies have implicated the disrupted-in-schizophrenia-1 (DISC1) gene as influencing susceptibility to schizophrenia, and bipolar disorder,1 but relatively little is known about its effect on brain function. DISC1 is expressed in centrosomes, mitochondria, the cytoplasm of postsynaptic spines, and actin stress fibers of cerebral cortical neurons.1 It interacts with proteins involved in cell division, cytoskeletal organization and intracellular transport, including PDE4B, which has been linked to learning and memory, and Ndel1, a key regulator of neuronal migration and a putative target of anti-psychotic drugs.1 Knockdown of DISC1 perturbs neurite outgrowth in vitro,1, 2 and cortical neuronal migration and dendritic arborization in vivo.1 Over-expression of DISC1 leads to enhanced neurite growth in vitro,1 whereas expression of mutant human DISC1 in mice is associated with behavioural abnormalities, ventricular enlargement and attenuation of cortical neurite outgrowth.3
Abnormal pre-frontal function is a robust pathophysiological feature of psychotic disorders, and may underlie many of the associated symptoms and cognitive deficits.4 A risk gene for these disorders would therefore be expected to influence pre-frontal function. We used functional neuroimaging to test the hypothesis that DISC1 would significantly influence pre-frontal function in healthy volunteers. Functional magnetic resonance imaging was employed to measure regional brain activation during a verbal fluency task, a classical test of pre-frontal function which requires the generation of words from letter cues.5 Execution of this task is normally associated with prominent pre-frontal activation, particularly in the left hemisphere.5 In patients with psychotic disorders, task performance is impaired and pre-frontal activation is altered.4 We scanned 53 healthy volunteers consisting of 27 Cys704 carriers (including 7 Cys704 homozygotes) and 26 Ser704 homozygotes (Supplementary Table S1; Supplementary Materials and Methods). Demographic features (intelligence quotient, years of education, gender, handedness and ethnicity) were not different between genotype groups (at P<0.05) except for age (F=4.27, P=0.044) which was therefore used as a covariate of no interest. Subjects articulated responses out loud, permitting on-line recording of task performance. We selected the Ser704Cys polymorphism, encoded by the rs821616 single-nucleotide polymorphism (SNP), as this coding and non-synonymous SNP is the only one that has been shown to have a functional impact at the molecular level.6 Furthermore, in genetic association studies the Ser704Cys polymorphism has been associated with schizophrenia,7 whereas neuroimaging studies suggest that it has effects on the structure or function of brain regions that have been implicated in psychotic disorders, such as the frontal white matter,6 the anterior cingulate gyrus,6 and the hippocampus.8
We found that both Ser704 homozygotes and Cys704 carriers showed bilateral activation in the pre-frontal cortex during the verbal fluency task, with greater engagement of the left hemisphere than the right (Supplementary Table S2 and Figure S1). However, activation in Ser704/Ser704 subjects was greater than in Cys704 carriers (Supplementary Table S3; Figure 1), particularly in the left middle (Z-score=4.3; family-wise error, FWEp=0.056; false discovery rate, FDRp=0.01) and the left superior frontal gyri (Z-score=5.0; FWEp=0.003; FDRp=0.006), where the difference between genotypes was highly significant, surviving correction for multiple comparisons (at P<0.05). At the voxel where this effect was maximal (−28, 48 and 14), genotype accounted for 13% of the inter-individual variance (R2=0.13, F=14.90; P=0.0002). The differences in activation were independent of task demand. Additional differences were evident in the homologous part of the superior frontal gyrus in the right hemisphere (Figure 1), and the left inferior frontal and cingulate cortex, thalamus and caudate nucleus (Supplementary Table S3). These differences survived FDR but not FWE correction (at P<0.05). There were no areas that were significantly more activated in Cys704 carriers than Ser704/Ser704 subjects. To confirm that the Cys704/Cys704 genotype was relevant to the findings, we then repeated the analysis after removing the heterozygotes from the Cys704 carriers. Ser704 homozygotes again displayed greater pre-frontal activation, with significant differences in the left middle and inferior frontal gyri, and in the right inferior frontal gyrus (at FWEp<0.05 and FDRp<0.05).
The differences in activation are not attributable to an effect of genotype on task performance, as there was no difference in the number of erroneous responses between genotype groups (Supplementary Table S1) and the analysis was restricted to images associated with correct responses. The greater pre-frontal activation in Ser704/Ser704 subjects in the context of equal task performance can be interpreted as a manifestation of less efficient pre-frontal function, with more activation required to achieve the same behavioural output.9 This is consistent with the association of Ser704 with an increased risk for schizophrenia7 and impaired declarative memory in patients with schizophrenia.7 The Ser704 polymorphism has also been associated with alterations in anterior cingulate volume,6 frontal white matter integrity6 and the structure and function of the hippocampus.7 However, although the hippocampal effects were in the same direction as is seen in schizophrenia, the opposite applied to the effects on cingulate volume and frontal white matter integrity. The present study also detected effects of Ser704Cys on activation in regions other than the pre-frontal cortex, including the cingulate cortex, striatum and thalamus. As well as Ser704Cys, other polymorphisms in DISC1 may affect brain function; indeed DISC1 haplotypes8 and the DISC1 Leu607Phe (rs6675281) polymorphism10 have also been associated with altered pre-frontal grey matter density or volume.
In summary, we have presented the first evidence that DISC1 modulates pre-frontal function in humans. This is consistent with the critical role of this region in the pathophysiology of psychotic disorders and genetic data implicating it as a major risk gene for schizophrenia and bipolar illness.
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Anxiogenic-like behavior and deficient attention/working memory in rats expressing the human DISC1 gene
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