title: 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.
abstract: OBJECTIVE
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Ran
authors.initials: R
authors.lastname: Tao
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, United Kingdom.
authors.forename: Helena
authors.initials: H
authors.lastname: Cousijn
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Jaffe
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, United Kingdom.
authors.forename: Philip W J
authors.initials: PW
authors.lastname: Burnet
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, United Kingdom.
authors.forename: Freya
authors.initials: F
authors.lastname: Edwards
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, United Kingdom.
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Eastwood
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Joo Heon
authors.initials: JH
authors.lastname: Shin
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, United Kingdom.
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Lane
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, United Kingdom.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Walker
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Brady J
authors.initials: BJ
authors.lastname: Maher
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.affiliation: Department of Psychiatry, University of Oxford, Oxford, United Kingdom.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Harrison
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Hyde
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Joel E
authors.initials: JE
authors.lastname: Kleinman
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001714:Bipolar Disorder / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000196:embryology; D001923:Brain Chemistry; D002648:Child; D002675:Child, Preschool; D003865:Major Depressive Disorder / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D051741:Kruppel-Like Transcription Factors / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D010296:Parietal Lobe / Q000737:chemistry; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017397:Prefrontal Cortex / Q000737:chemistry; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism; D012737:Sex Factors; D055815:Young Adult
chemical_list: D051741:Kruppel-Like Transcription Factors; D020033:Protein Isoforms; D012333:RNA, Messenger; C540527:ZNF804A protein, human