No association of ZNF804A rs1344706 with white matter integrity in schizophrenia: a tract-based spatial statistics study

Abstract

Altered brain connectivity has been widely considered as a genetic risk mechanism for schizophrenia. Of the many susceptibility genes identified so far, ZNF804A (rs1344706) is the first common genetic variant associated with schizophrenia on a genome-wide level. Previous fMRI studies have found that carriers of rs1344706 exhibit altered functional connectivity. However, the relationship between ZNF804A and white matter structural connectivity in patients of schizophrenia remains unknown. In this study, 100 patients with schizophrenia and 69 healthy controls were genotyped at the single nucleotide polymorphism rs1344706. Diffusion tensor imaging (DTI) was conducted and analyzed with tract-based spatial statistics. Systematic statistical analysis was conducted on multiple diffusion indices, including fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity. Unpaired two-sample t-test revealed significant differences in fractional anisotropy and diffusivity between schizophrenia and control groups. A two-way ANOVA analysis was conducted to assess the main effects of and the interaction between schizophrenia and ZNF804A. Although significant main effects of the diagnosis of schizophrenia were found on radial diffusivity, no association between the ZNF804A (rs1344706) and white matter connectivity was found in the entire group of subjects or in a selected subgroup of age-matched subjects (n=72).

Fig. 1

TBSS analysis of the effect of schizophrenia and ZNF804A rs1344706 on structural brain connectivity. (a) Unpaired two-sample t-test between schizophrenia and controls based on FA. The top row illustrates the tract-specific statistical significance of the hypothesis that FA of healthy controls is higher than that of schizophrenia in the ALL group. The bottom row shows the results in the SEL group. (b) 2 × 2 ANOVA analysis of the main effect of schizophrenia on the radial diffusivity in white matter fiber tracts in the ALL group. The top row shows the statistical significance maps analyzed based on the second eigenvalue (i.e. the larger radial diffusivity denoted by L2) of the diffusion tensor. The bottom row shows the statistical significance maps based on the third eigenvalue (i.e. the smaller radial diffusivity denoted by L3). Note that the most significant foci found in the SEL group coincide with the unpaired t-test in (a). No significant main effect or interaction was found for ZNF804A rs1344706. The background gray-scale T1-weighted images provide anatomical references. The green color highlights the skeletons of white matter tracts constructed by FSL The “hot” color-scale bar on the right represents the statistical significance (1 − p) with color intensity. These “hot” colors are overlaid on the track skeletons such that brighter voxels represent higher significance (p < 0.05).