Expression of ZNF804A in human brain and alterations in schizophrenia, bipolar disorder, and major depressive disorder: a novel transcript fetally regulated by the psychosis risk variant rs1344706 - PubMed (original) (raw)

. 2014 Oct;71(10):1112-20.

doi: 10.1001/jamapsychiatry.2014.1079.

Helena Cousijn 2, Andrew E Jaffe 1, Philip W J Burnet 2, Freya Edwards 2, Sharon L Eastwood 2, Joo Heon Shin 1, Tracy A Lane 2, Mary A Walker 2, Brady J Maher 1, Daniel R Weinberger 1, Paul J Harrison 2, Thomas M Hyde 1, Joel E Kleinman 1

Affiliations

Expression of ZNF804A in human brain and alterations in schizophrenia, bipolar disorder, and major depressive disorder: a novel transcript fetally regulated by the psychosis risk variant rs1344706

Ran Tao et al. JAMA Psychiatry. 2014 Oct.

Abstract

Importance: The single-nucleotide polymorphism rs1344706 in the zinc finger protein 804A gene (ZNF804A) shows genome-wide association with schizophrenia and bipolar disorder. Little is known regarding the expression of ZNF804A and the functionality of rs1344706.

Objectives: To characterize ZNF804A expression in human brain and to investigate how it changes across the life span and how it is affected by rs1344706, schizophrenia, bipolar disorder, and major depressive disorder.

Design, setting, and participants: Molecular and immunochemical methods were used to study ZNF804A messenger RNA (mRNA) and ZNF804A protein, respectively. ZNF804A transcripts were investigated using next-generation sequencing and polymerase chain reaction-based methods, and ZNF804A protein was investigated using Western blots and immunohistochemistry. Samples of dorsolateral prefrontal cortex and inferior parietal lobe tissue were interrogated from 697 participants between 14 weeks' gestational age and age 85 years, including patients with schizophrenia, bipolar disorder, or major depressive disorder.

Main outcomes and measures: Quantitative measurements of ZNF804A mRNA and immunoreactivity, and the effect of diagnosis and rs1344706 genotype.

Results: ZNF804A was expressed across the life span, with highest expression prenatally. An abundant and developmentally regulated truncated ZNF804A transcript was identified, missing exons 1 and 2 (ZNF804AE3E4) and predicted to encode a protein lacking the zinc finger domain. rs1344706 influenced expression of ZNF804AE3E4 mRNA in fetal brain (P = .02). In contrast, full-length ZNF804A showed no association with genotype (P > .05). ZNF804AE3E4 mRNA expression was decreased in patients with schizophrenia (P = .006) and increased in those with major depressive disorder (P < .001), and there was a genotype-by-diagnosis interaction in bipolar disorder (P = .002). ZNF804A immunoreactivity was detected in fetal and adult human cerebral cortex. It was localized primarily to pyramidal neurons, with cytoplasmic as well as dendritic and nuclear staining. No differences in ZNF804A-immunoreactive neurons were seen in schizophrenia or related to rs1344706 (P > .05).

Conclusions and relevance: rs1344706 influences the expression of ZNF804AE3E4, a novel splice variant. The effect is limited to fetal brain and to this isoform. It may be part of the mechanism by which allelic variation in ZNF804A affects risk of psychosis. ZNF804A is translated in human brain, where its functions may extend beyond its predicted role as a transcription factor.

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Conflict of interest statement

Conflict of Interest Disclosures: None reported.

Figures

Figure 1

Figure 1. Expression Trajectories for ZNF804AE3E4 and ZNF804A Messenger RNA Across the Life Span

Life-span expression trajectories for the novel truncated transcript isoform ZNF804AE3E4 (A) and full-length ZNF804A (B) messenger RNA in human dorsolateral prefrontal cortex. Circles indicate observed data; lines, smoothing spline within each age stage.

Figure 2

Figure 2. Diagnostic Effects on Expression of ZNF804A Transcripts in Dorsolateral Prefrontal Cortex

A, ZNF804AE3E4 messenger RNA (mRNA) shows elevated expression in major depressive disorder (MDD) but decreased expression in schizophrenia and no change in bipolar disorder compared with controls. B, Full-length ZNF804A mRNA shows decreased expression in bipolar disorder and no change in schizophrenia and MDD. C, Ratio of ZNF804AE3E4 to ZNF804A mRNA. Compared with controls, the ratio is greater (ie, relative increase in ZNF804AE3E4 mRNA) in bipolar disorder and MDD but lower in schizophrenia. Boxes indicate interquartile range; horizontal lines in boxes, median; and whiskers, 1.5 × interquartile range. The postmortem brain samples involved are from the National Institute of Mental Health/Lieber Institute for Brain Development series (Table). a P < .01 for each diagnostic group vs controls in 1 linear model (see Methods). b P < .001 for each diagnostic group vs controls in 1 linear model (see Methods). c P < .05 for each diagnostic group vs controls in 1 linear model (see Methods).

Figure 3

Figure 3. Genotype Effect of rs1344706 on ZNF804AE3E4 Messenger RNA in Human Fetal Brain

Homozygotes for the risk T allele are compared with GG homozygotes and TG heterozygotes (A) and with G carriers (B). Homozygotes for the risk T allele have lower expression than G carriers or TG heterozygotes. Center horizontal lines indicate mean; error bars, standard deviation. a P < .05.

Figure 4

Figure 4. ZNF804A Immunoreactivity in Human Brain

A, Western blot. Lane 1 is HEK293 cells transfected with ZNF804A; lane 2, nontransfected HEK293 cells; lane 3, fetal cortex; and lanes 4 and 5, adult frontal cortex. eFigure 3 in the Supplement shows a full-length blot and the β-actin loading control, and eFigure 4 in the Supplement shows the D-14 blocking peptide control and a blot using a different anti-ZNF804A antibody. B, ZNF804A immunoreactivity through the inferior parietal cortex. Roman numerals indicate the cortical layers; WM, white matter. C, Layer III of the inferior parietal cortex (scale bar = 100 μm). D, Pyramidal neurons in layer III of the temporal cortex (scale bar = 10 μm). E, Layer III of the inferior parietal cortex with Nissl counterstain (scale bar = 10 μm). F, Frontal cortex of a neonate (scale bar = 10 μm). eFigure 5 in the Supplement shows the immunohistochemistry peptide block control.

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