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.
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 ex...
| Publicado en: | JAMA Psychiatry Vol. 71; no. 10; pp. 1112 - 1121 |
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| Autores principales: | , , , , , , , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
American Medical Association
Oct2014
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=103848831&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 103848831 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 2168622X FT4X jtl: JAMA Psychiatry issn: 2168622X maglogo: N pubinfo: dt: Oct2014 vid: 71 iid: 10 pid: 30 pub: American Medical Association place: Chicago, Illinois artinfo: ui: 103848831 103848831 NLM25162540 2012758018 10.1001/jamapsychiatry.2014.1079 NLM25162540 103848831 ppf: 1112 ppct: 9 formats: tig: atl: 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. aug: au: 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 affil: Lieber Institute for Brain Development, Johns Hopkins University, Baltimore, Maryland. sug: subj: Bipolar Disorder Biochemical Phenomena Depression Proteins Polymorphism, Genetic Schizophrenia Adolescence Adult Age Factors Aged Aged, 80 and Over Bipolar Disorder Metabolism Blotting, Western Brain Embryology Child Child, Preschool Depression Metabolism Female Genes Disease Susceptibility Genotype Infant Infant, Newborn Male Middle Age Parietal Lobe Frontal Lobe RNA Analysis RNA Reverse Transcriptase Polymerase Chain Reaction Schizophrenia Metabolism Sex Factors Young Adult Funding Source Human Adolescent: 13-18 years Adult: 19-44 years Aged: 65+ years Aged, 80 & over Child: 6-12 years Child, Preschool: 2-5 years Infant: 1-23 months Infant, Newborn: birth-1 month Middle Aged: 45-64 years Female Male ab: 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. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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