The effect of psychosis associated CACNA1C, and its epistasis with ZNF804A, on brain function.

CACNA1C-rs1006737 and ZNF804A-rs1344706 polymorphisms are among the most robustly associated with schizophrenia (SCZ) and bipolar disorder (BD), and recently with brain phenotypes. As these patients show abnormal verbal fluency (VF) and related brain activation, we asked whether the latter was affected by these polymorphisms (alone and in interaction)-to better understand how they might induce risk. We recently reported effects on functional VF-related (for ZNF804A-rs1344706) and structural (for both) connectivity. We genotyped and fMRI-scanned 54 SCZ, 40 BD and 80 controls during VF. With SPM, we assessed the main effect of CACNA1C-rs1006737, and its interaction with ZNF804A-rs1344706, and their interaction with diagnosis, on regional brain activation and functional connectivity (psychophysiological interactions-PPI). Using public data, we reported effects of CACNA1C-rs1006737 and diagnosis on brain expression. The CACNA1C-rs1006737 risk allele was associated with increased activation, particularly in the bilateral prefronto-temporal cortex and thalamus; decreased PPI, especially in the left temporal cortex; and gene expression in white matter and the cerebellum. We also found unprecedented evidence for epistasis (interaction between genetic polymorphisms) in the caudate nucleus, thalamus, and cingulate and temporal cortical activation; and CACNA1C up-regulation in SCZ and BD parietal cortices. Some effects were dependent on BD/SCZ diagnosis. All imaging results were whole-brain, voxel-wise, and familywise-error corrected. Our results support evidence implicating CACNA1C and ZNF804A in BD and SCZ, adding novel imaging evidence in clinical populations, and of epistasis-which needs further replication. Further scrutiny of the inherent neurobiological mechanisms may disclose their potential as putative drug targets.

The impact of psychosis genome-wide associated ZNF804A variation on verbal fluency connectivity.

Schizophrenia (SCZ) and bipolar disorder (BD) have high heritability. Genome-wide association studies (GWAS) have identified ZNF804A as a significant risk gene for both illnesses. A validation of this finding at the brain systems-level is imperative as there is still little understanding of how it heightens risk. Based in part on our recent findings of an effect on widespread decreased white matter microstructural fractional anisotropy (putatively a proxy of its integrity), particularly strong in SCZ, we asked whether the risk allele has a detrimental effect on regional brain activation and functional connectivity during a type of cognitive processing which is, together with its neural correlates, impaired in BD and SCZ: verbal fluency. Functional MRI and genotype data was collected from 80 healthy volunteers, and 54 SCZ and 40 BD patients. A standard multifactorial analysis of variance using statistical parametric mapping and significance correction of FWE p < 0.05 was used. We found the GWAS risk allele A was associated with decreased positive functional coupling between the left precentral gyrus/inferior frontal gyrus (i.e. the most highly recruited area for the task) and: 1) the left inferior frontal gyrus, and 2) the left posterior cingulate gyrus, encompassing the precuneus; both as a main effect across controls and psychosis patients. Such association of the risk allele with reduced functional connectivity (with no area where the opposite main effect was detected), converges with findings in other tasks, our previous finding of its widespread impact on brain white matter microstructure, and with the dysconnectivity hypothesis of SCZ.