ZNF804A and cortical structure in schizophrenia: in vivo and postmortem studies

Abstract

Recent evidence indicated that the ZNF804A (rs1344706) risk allele A is associated with better cognitive performance in patients with schizophrenia. Moreover, it has been demonstrated that ZNF804A may also be related to relatively intact gray matter volume in patients. To further explore these putatively protective effects, the impact of ZNF804A on cortical thickness and folding was examined in this study. To elucidate potential molecular mechanisms, an allelic-specific gene expression study was also carried out. Magnetic resonance imaging cortical thickness and folding were computed in 55 genotyped patients with schizophrenia and 40 healthy controls. Homozygous risk allele carriers (AA) were compared with AC/CC carriers. ZNF804A gene expression was analyzed in a prefrontal region using postmortem tissue from another cohort of 35 patients. In patients, AA carriers exhibited significantly thicker cortex in prefrontal and temporal regions and less disturbed superior temporal cortical folding, whereas the opposite effect was observed in controls, ie, AA carrier status was associated with thinner cortex and more severe altered cortical folding. Along with this, our expression analysis revealed that the risk allele is associated with lower prefrontal ZNF804A expression in patients, whereas the opposite effect in controls has been observed by prior analyses. In conclusion, our analyses provide convergent support for the hypothesis that the schizophrenia-associated ZNF804A variant mediates protective effects on cortex structure in patients. In particular, the allele-specific expression profile in patients might constitute a molecular mechanism for the observed protective influence of ZNF804A on cortical thickness and folding and potentially other intermediate phenotypes.

Keywords: ZNF804A; cortical folding; cortical thickness; gene expression; psychosis; rs1344706; schizophrenia; susceptibility gene.

Fig. 1.

Cortical statistical maps displaying cortical thickness differences in schizophrenia patients between carriers of AA and AC/CC. In these regions, AA carriers exhibit a significantly thicker cortex compared with AC/CC carriers. Displayed is the lateral and medial surfaces of both hemispheres, (A) left hemisphere and (B) right hemisphere, pial view, and P values corrected for multiple comparisons. Bar diagram illustrates the cortical thickness difference between the genotype groups and mean values exemplarily extracted from the marked (*) cortical region.

Fig. 2.

Cortical statistical maps displaying significant cortical thickness clusters from the ZNF804A genotype × diagnosis interaction analysis between patients with schizophrenia (SZ) and healthy controls (HC). Shown are the surfaces of both hemispheres, (A) left hemisphere and (B) right hemisphere, pial view, and P values corrected for multiple comparisons. Bar diagram illustrates the genotype × diagnosis interaction on cortical thickness and mean values exemplarily extracted from the marked (*) cortical region.

Fig. 3.

Cortical statistical maps displaying significant cortical folding differences in schizophrenia patients between carriers of AA and AC/CC. In this region, AA carriers exhibit a significantly lower cortical folding compared with AC/CC carriers. Displayed is the lateral surface, (A) right hemisphere, pial view, and P values corrected for multiple comparisons. Bar diagram illustrates the cortical folding difference between the genotype groups and mean values extracted from the affected cortical region.

Fig. 4.

Relative ZNF804A gene expression depending on the allelic counts of A and C. Analysis from postmortem prefrontal brain tissue of patients with schizophrenia. P value resulting from unpaired t test with Welch’s correction.