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.

paper Cited Public

Authors: Tao, Ran; Cousijn, Helena; Jaffe, Andrew E; Burnet, Philip W J; Edwards, Freya; Eastwood, Sharon L; Shin, Joo Heon; Lane, Tracy A; Walker, Mary A; Maher, Brady J; Weinberger, Daniel R; Harrison, Paul J; Hyde, Thomas M; Kleinman, Joel E
Year: 2014
Journal: JAMA psychiatry
PMID: 25162540
DOI: 10.1001/jamapsychiatry.2014.1079
PMCID: PMC5894803

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.

Figure 1

Expression Trajectories for ZNF804AE3E4 and ZNF804A Messenger RNA Across the Life SpanLife-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

Diagnostic Effects on Expression of ZNF804A Transcripts in Dorsolateral Prefrontal CortexA, 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

Genotype Effect of rs1344706 on ZNF804AE3E4 Messenger RNA in Human Fetal BrainHomozygotes 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

ZNF804A Immunoreactivity in Human BrainA, 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.

#	Section	Preview
0	Methods — Human Tissue	We studied ZNF804A transcripts in DLPFC from the National Institute of Mental Health (NIMH)/Lieber…
1	Methods — Human Tissue	Gray matter was dissected out, snap frozen, and stored at −80°C prior to RNA extraction, which…
2	Methods — Human Tissue	formalin-fixed, wax-embedded blocks of frontal, temporal, or visual cortex from 5 additional adults…
3	Methods — RNA Sequencing and 5′ Rapid Amplification of Complementary DNA Ends	We used RNA sequencing (RNAseq) to identify potentially new expressed transcripts of ZNF804A and to…
4	Methods — RNA Sequencing and 5′ Rapid Amplification of Complementary DNA Ends	We used the RNAseq read alignment data to design primer pairs to amplify ZNF804A transcripts. We…
5	Methods — RNA Sequencing and 5′ Rapid Amplification of Complementary DNA Ends	After confirming the presence of a truncated transcript of ZNF804A in the commercial fetal and adult…
6	Methods — Quantitative Reverse Transcription–PCR	Based on the results of the RNAseq, 5′ RACE, and end-to-end PCR, we designed primers to…
7	Methods — Western Blotting	Methods, antibodies, and experimental controls are detailed in the eAppendix in the Supplement.…
8	Methods — Immunohistochemistry	Immunohistochemistry was carried out as described in the eAppendix in the Supplement, using the…
9	Methods — Statistical Analysis	Quantitative reverse transcription–PCR analyses were conducted in R version 3.0.1 software (R…
10	Methods — Statistical Analysis	within each diagnosis group. The statistical models for the genotype effect in fetal samples…
11	Methods — Statistical Analysis	For the immunohistochemical study, group comparisons were by unpaired t tests, and the influence of…
12	Results — Identification of a Novel Truncated Transcript of ZNF804A	Using RNAseq, 5′ RACE, end-to-end PCR, and quantitative reverse transcription–PCR, we identified…
13	Results — Effects of Age, Sex, and Other Factors on ZNF804A Transcripts Across the Life Span	Both ZNF804A transcripts were detected across the entire age range (Figure 1), being preferentially…
14	Results — Effects of Age, Sex, and Other Factors on ZNF804A Transcripts Across the Life Span	There was no main effect of sex on either transcript across the life span, but ZNF804A mRNA was more…
15	Results — Both ZNF804A Transcripts Are Associated With Diagnosis	We examined whether the 2 transcripts are differentially expressed in patients with schizophrenia,…
16	Results — Both ZNF804A Transcripts Are Associated With Diagnosis	Expression of ZNF804A mRNA did not correlate with antipsychotic or antidepressant exposure overall…
17	Results — Psychosis Risk SNP rs1344706 Affects Fetal ZNF804AE3E4 mRNA Expression	The SNP rs1344706 did not affect expression of either transcript when all participants were analyzed…
18	Results — Psychosis Risk SNP rs1344706 Affects Fetal ZNF804AE3E4 mRNA Expression	In post hoc comparisons, we also identified 1 genotype-by-diagnosis interaction: in the bipolar…
19	Results — Detection and Distribution of ZNF804A Immunoreactivity	Western blots showed that ZNF804A immunoreactivity is present in adult and fetal brain (Figure 4A…

Name	Type
ACTB	gene
adults	cohort
African American	cohort
antidepressants	drug
antipsychotics	drug
anti-ZNF804A antibody local	drug
Asian	cohort
B2M local	gene
bacteria local	cohort
bipolar disorder	phenotype
blocking peptide local	drug
brain	anatomy
canonical ZNF804A transcript local	variant
control group	cohort
control participants	cohort
diagnosis	phenotype
diagnostic group local	phenotype
dlPFC	anatomy
fetal brain	anatomy
Fetal samples local	cohort
frontal cortex	anatomy
Full-length ZNF804A local	variant
G carriers local	variant
GLB1 local	gene
HEK293 cells	cohort
Hispanic participants local	cohort
human brain	anatomy
inferior parietal lobe	anatomy
lamina III local	anatomy
lamina III pyramidal neurons local	anatomy
major depressive disorder	phenotype
men	cohort
neonates	cohort
neurodevelopmental psychiatric disorders local	phenotype
newly identified ZNF804A transcript local	variant
NIMH/Lieber Institute for Brain Development series local	cohort
nonpsychiatric controls local	cohort
P-13 mouse antibody local	drug
participants	cohort
patient group	cohort
PMI	phenotype
poly(A)+ mRNA local	drug
primary visual cortex	anatomy
psychiatric disorders	phenotype
psychosis	phenotype
pyramidal neurons	anatomy
RIN	phenotype
RNAseq	drug
rodent neural progenitors local	anatomy
rs1344706	variant
schizophrenia	phenotype
sex	phenotype
Stanley Medical Research Institute series local	cohort
temporal cortex	anatomy
TT homozygotes local	variant
white participants	cohort
whole brain	anatomy
women	cohort
ZNF804A	gene
ZNF804AE3E4 local	gene
ZNF804AE3E4 local	variant
ZNF804AE3E4/ZNF804A mRNA ratio local	variant
ZNF804A full-length transcript local	variant
ZNF804A truncated transcript local	variant

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In this knowledge base

Title	Year	PMID
Expression quantitative trait loci in the developing human brain and their enrichment in neuropsychiatric disorders.	2018	30419947
Methylation QTLs in the developing brain and their enrichment in schizophrenia risk loci.	2016	26619357
Replication of ZNF804A gene variant associations with risk of heroin addiction.	2015	26382569

External

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The DPYSL2 gene connects mTOR and schizophrenia.	Pham X et al.	—	2016	→
Translating Genetic Risk Loci Into Molecular Risk Mechanisms for Schizophrenia.	Bray NJ et al.	—	2016	→
ZNF804A Genetic Variation Confers Risk to Bipolar Disorder.	Zhang C et al.	—	2016	→
ZNF804A variants confer risk for heroin addiction and affect decision making and gray matter volume in heroin abusers.	Sun Y et al.	—	2016	→
Associations between the schizophrenia susceptibility gene ZNF804A and clinical outcomes in psychosis.	Wickramasinghe A et al.	—	2015	→
Bioinformatic analyses and conceptual synthesis of evidence linking ZNF804A to risk for schizophrenia and bipolar disorder.	Hess JL et al.	—	2015	→
BrainSeq: Neurogenomics to Drive Novel Target Discovery for Neuropsychiatric Disorders.	BrainSeq: A Human Brain Genomics Consortium. Electronic address: drweinberger@libd.org et al.	—	2015	→
CHRNA7 and CHRFAM7A mRNAs: co-localized and their expression levels altered in the postmortem dorsolateral prefrontal cortex in major psychiatric disorders.	Kunii Y et al.	—	2015	→
Modulation of hippocampal theta and hippocampal-prefrontal cortex function by a schizophrenia risk gene.	Cousijn H et al.	—	2015	→
Oxidative stress and cognition amongst adults without dementia or stroke: Implications for mechanistic and therapeutic research in psychiatric disorders.	Newton DF et al.	—	2015	→
Postnatal neurodevelopmental expression and glutamate-dependent regulation of the ZNF804A rodent homologue.	Chang EH et al.	—	2015	→
Recent genetic findings in schizophrenia and their therapeutic relevance.	Harrison PJ	—	2015	→
Replication of ZNF804A gene variant associations with risk of heroin addiction.	Hancock DB et al.	—	2015	→
The Rat Homolog of the Schizophrenia Susceptibility Gene ZNF804A Is Highly Expressed during Brain Development, Particularly in Growth Cones.	Hinna KH et al.	—	2015	→
No effect of schizophrenia risk genes MIR137, TCF4, and ZNF804A on macroscopic brain structure.	Cousijn H et al.	—	2014	→
Prenatal expression patterns of genes associated with neuropsychiatric disorders.	Birnbaum R et al.	—	2014	→
What causes aberrant salience in schizophrenia? A role for impaired short-term habituation and the GRIA1 (GluA1) AMPA receptor subunit.	Barkus C et al.	—	2014	→