title: Variation in psychosis gene ZNF804A is associated with a refined schizotypy phenotype but not neurocognitive performance in a large young male population.
abstract: Genetic variability within the ZNF804A gene has been recently found to be associated with schizophrenia and bipolar disorder, although the pathways by which this gene may confer risk remain largely unknown. We set out to investigate whether common ZNF804A variants affect psychosis-related intermediate phenotypes such as cognitive performance dependent on prefrontal and frontotemporal brain function, schizotypal traits, and attenuated psychotic experiences in a large young male population. Association analyses were performed using all 4 available self-rated schizotypy questionnaires and cognitive data retrospectively drawn from the Athens Study of Psychosis Proneness and Incidence of Schizophrenia (ASPIS). DNA samples from 1507 healthy young men undergoing induction to military training were genotyped for 4 previously studied polymorphic markers in the ZNF804A gene locus. Single-marker analysis revealed significant associations between 2 recently identified candidate schizophrenia susceptibility variants (rs1344706 and rs7597593) and a refined positive schizotypy phenotype characterized primarily by self-rated paranoia/ideas of reference. Nominal associations were noted with all positive, but not negative, schizotypy related factors. ZNF804A genotype effect on paranoia was confirmed at the haplotype level. No significant associations were noted with central indexes of sustained attention or working memory performance. In this study, ZNF804A variation was associated with a population-based self-rated schizotypy phenotype previously suggested to preferentially reflect genetic liability to psychosis and defined by a tendency to misinterpret otherwise neutral social cues and perceptual experiences in one's immediate environment, as personally relevant and significant information. This suggests a novel route by which schizophrenia-implicated ZNF804A genetic variation may confer risk to clinical psychosis at the general population level.
authors.affiliation: *To whom correspondence should be addressed; Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, The University of Western Australia and North Metropolitan Health Service-Mental Health, Gascoyne House, John XXIII Avenue, Mt Claremont, WA 6010, Perth, Australia; tel: (08)9347-6439, fax: (08)9384-5128, e-mail: nikos.stefanis@uwa.edu.au.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Stefanis
authors.forename: Alex
authors.initials: A
authors.lastname: Hatzimanolis
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Avramopoulos
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Smyrnis
authors.forename: Ioannis
authors.initials: I
authors.lastname: Evdokimidis
authors.forename: Costas N
authors.initials: CN
authors.lastname: Stefanis
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.forename: Richard E
authors.initials: RE
authors.lastname: Straub
mesh_terms: D000293:Adolescent; D000328:Adult; D003072:Cognition Disorders / Q000175:diagnosis / Q000235:genetics*; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006115:Greece / Q000453:epidemiology; D006239:Haplotypes; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics*; D008297:Male; D010259:Paranoid Disorders / Q000175:diagnosis / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011569:Psychiatric Status Rating Scales; D011618:Psychotic Disorders / Q000175:diagnosis / Q000235:genetics; D012189:Retrospective Studies; D012569:Schizotypal Personality Disorder / Q000175:diagnosis / Q000235:genetics*; D055815:Young Adult
chemical_list: D005819:Genetic Markers; D051741:Kruppel-Like Transcription Factors; C540527:ZNF804A protein, human