Expression and neural correlates of schizophrenia risk gene ZNF804A

Thesis

Genome wide association studies have provided evidence for a significant association between ZNF804A (zinc finger protein 804A) - specifically the intronic single nucleotide polymorphism (SNP) rs1344706 - and schizophrenia, but little is known about the function of the gene or the effects of the SNP. By studying post-mortem human brain tissue, I characterised ZNF804A immunoreactivity in adult and foetal human brain and investigated effects of diagnosis and rs1344706 genotype on ZNF804A mRNA and protein expression. Secondly, I looked in a large sample of healthy volunteers (n=922) at the effects of rs1344706 on brain structure using volumetry and voxel based morphometry (VBM). Furthermore, I recruited healthy volunteers who were either homozygous for the risk allele or homozygous for the non-risk allele (n=50). They participated in magnetoencephalography (MEG) and magnetic resonance (MR) sessions in which brain activity was measured during a working memory task, a visual processing task, and rest. Using magnetic resonance spectroscopy, also neurotransmitter levels were assessed. The experiments conducted for this thesis showed for the first time that ZNF804A immunoreactivity can be detected in both foetal and adult human brain and that it is mainly localised to layer III pyramidal cells, with a granular subcellular distribution throughout the cytoplasm. No effect of rs1344706 on mRNA and protein expression was found. In our structural MRI study, rs1344706 did not affect macroscopic brain structure as measured by volumetry and VBM, and given the large sample size, this seems a convincing negative. However, we did find that rs1344706 alters prefrontal-hippocampal connectivity, with increased connectivity being observed in risk homozygotes. Additionally, using MEG, we found an effect of ZNF804A genotype on hippocampal connectivity in the theta band (4-8Hz), with non-risk homozygotes displaying more connectivity. This finding provides a first clue as to the mechanisms that might underlie the previously observed effects of rs1344706 on prefrontal-hippocampal connectivity. Future studies will need to elucidate the actual function of the ZNF804A protein, in order to bridge the gap between the molecular and neuroimaging findings described in this thesis.

Authors: Cousijn, H

• Publication date: 2013
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: Oxford University, UK
• Language: English
• Keywords: risk gene; ZNF804A; human brain tissue; schizophrenia; neuroimaging
• Subjects: Neuroscience