No association of Disrupted-in-Schizophrenia-1 variation with prefrontal function in patients with schizophrenia and bipolar disorder

The Disrupted-in-Schizophrenia-1 (DISC1) gene has been implicated in both schizophrenia and bipolar disorder by linkage and genetic association studies. Altered prefrontal cortical function is a pathophysiological feature of both disorders, and we have recently shown that variation in DISC1 modulates prefrontal activation in healthy volunteers. Our goal was to examine the influence of the DISC1 polymorphism Cys704Ser on prefrontal function in schizophrenia and bipolar disorder. From 2004 to 2008, patients with schizophrenia (N = 44), patients with bipolar disorder (N = 35) and healthy volunteers (N = 53) were studied using functional magnetic resonance imaging while performing a verbal fluency task. The effect of Cys704Ser on cortical activation was compared between groups as Cys704 carriers vs. Ser704 homozygotes. In contrast to the significant effect on prefrontal activation we had previously found in healthy subjects, no significant effect of Cys704Ser was detected in this or any other region in either the schizophrenia or bipolar groups. When controls were compared with patients with schizophrenia, there was a diagnosis by genotype interaction in the left middle/superior frontal gyrus [family-wise error (FWE) P = 0.002]. In this region, Ser704/ser704 controls activated more than Cys704 carriers, and there was a trend in the opposite direction in schizophrenia patients. In contrast to its effect in healthy subjects, variation in DISC1 Cys704Ser704 genotype was not associated with altered prefrontal activation in patients with schizophrenia or bipolar disorder. The absence of an effect in patients may reflect interactions of the effects of DISC1 genotype with the effects of other genes associated with these disorders, and/or with the effects of the disorders on brain function.