Neural mechanisms of a genome-wide supported psychosis variant.

A polymorphism within ZNF804A (rs1344706), the first variant to achieve genome-wide significance for schizophrenia, has been shown by this study to alter brain connectivity. Altered brain connectivity is a feature of schizophrenia, and a likely neural mechanism by which illness risk is genetically increased.

Studies combining genetics and functional magnetic resonance imaging (fMRI) can further develop our understanding of brain functions and mental diseases. Where a genetic variant has been statistically associated with illness risk, such as ZNF804A, the first to achieve genome-wide significance for schizophrenia, brain imaging can provide clues as to its biological function. In the present study, conducted in a sample of 115 German healthy subjects, association between indices of functional brain connectivity and ZNF804A genotype was explored. During fMRI two paradigms were employed: (1) an n-back task which assesses working memory functions was designed to activate prefrontal cortex; and (2) an emotional face matching task was used to elicit emotional responses and obtain amygdala activation. Differences in regional brain activation and functional connectivity between the regions around the most activated voxel in each task and the whole brain activation were used as a measure of differences associated with genotype. With respect to the working memory performance task, the risk polymorphism was detected to be associated with altered right dorsolateral prefrontal coupling. Secondly, the hippocampus was uncoupled in non-risk allele homozygotes, but showed dose-dependent increased connectivity in risk allele carriers. Moreover, the risk allele predicted extensive increases of connectivity from amygdala to hippocampus, orbitofrontal cortex, and medial prefrontal cortex in the face matching task. The authors concluded that decreased dorsolateral connectivity could contribute to schizophrenia, whereas increased connectivity from amygdala to other brain regions might be related to bipolar disorder. The study elegantly shows how genetic imaging data in healthy controls can generate and support hypotheses on psychiatric disease models. The rs1344706 variant is functionally relevant in healthy subjects; further studies need to examine whether this same variant also impacts cognitive as well as emotional processing in patients with schizophrenia. The strength of the study is its large sample size, which allows a statistically solid data analysis. The results may stimulate further studies in imaging genetics in patients with schizophrenia that investigate the effect of this polymorphism on altered prefrontal cortex function. We fully recommend the article to the readership.