title: Converging evidence for the association of functional genetic variation in the serotonin receptor 2a gene with prefrontal function and olanzapine treatment.
abstract: OBJECTIVE
  Serotonin (5-hydroxytryptamine) receptor 2a (5-HT2AR) signaling is important for modulation of corticostriatal pathways and prefrontal activity during cognition. Furthermore, newer antipsychotic drugs target 5-HT2AR. A single-nucleotide polymorphism in the 5-HT2AR gene (HTR2A rs6314, C>T; OMIM 182135) has been weakly associated with differential 5-HT2AR signaling and with physiologic as well as behavioral effects.
  
  
  OBJECTIVE
  To use a hierarchical approach to determine the functional effects of this single-nucleotide polymorphism on 5-HT2AR messenger RNA and protein expression, on prefrontal phenotypes linked with genetic risk for schizophrenia, and on treatment with olanzapine.
  
  
  METHODS
  In silico predictions, in vitro, and case-control investigations.
  
  
  METHODS
  Academic and clinical facilities.
  
  
  METHODS
  The postmortem study included 112 brains from healthy individuals; the in vivo investigation included a total sample of 371 healthy individuals and patients with schizophrenia. EXPOSURES Patients received olanzapine monotherapy for 8 weeks.
  
  
  METHODS
  In silico predictions, messenger RNA, and protein expression in postmortem human prefrontal cortex and HeLa cells, functional magnetic resonance imaging prefrontal activity and behavior during working memory and attention in healthy individuals, and response to an 8-week trial of olanzapine treatment in patients with schizophrenia.
  
  
  RESULTS
  Bioinformatic analysis predicted that rs6314 alters patterns of splicing, with possible effects on HTR2A expression. Moreover, the T allele was associated with reduced prefrontal messenger RNA expression in postmortem prefrontal cortex, with reduced protein expression in vitro, inefficient prefrontal blood oxygen level-dependent functional magnetic resonance imaging response during working memory and attentional control processing, and impaired working memory and attention behavior, as well as with attenuated improvement in negative symptoms after olanzapine treatment.
  
  
  CONCLUSIONS
  Our results suggest that HTR2A rs6314 affects 5-HT2AR expression and functionally contributes to genetic modulation of known endophenotypes of schizophrenia-like higher-level cognitive behaviors and related prefrontal activity, as well as response to treatment with olanzapine.
authors.affiliation: Group of Psychiatric Neuroscience, Department of Neuroscience and Sense Organs, Aldo Moro University, Bari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Blasi
authors.forename: Caterina
authors.initials: C
authors.lastname: De Virgilio
authors.forename: Apostolos
authors.initials: A
authors.lastname: Papazacharias
authors.forename: Paolo
authors.initials: P
authors.lastname: Taurisano
authors.forename: Barbara
authors.initials: B
authors.lastname: Gelao
authors.forename: Leonardo
authors.initials: L
authors.lastname: Fazio
authors.forename: Gianluca
authors.initials: G
authors.lastname: Ursini
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Sinibaldi
authors.forename: Ileana
authors.initials: I
authors.lastname: Andriola
authors.forename: Rita
authors.initials: R
authors.lastname: Masellis
authors.forename: Raffaella
authors.initials: R
authors.lastname: Romano
authors.forename: Antonio
authors.initials: A
authors.lastname: Rampino
authors.forename: Annabella
authors.initials: A
authors.lastname: Di Giorgio
authors.forename: Luciana
authors.initials: L
authors.lastname: Lo Bianco
authors.forename: Grazia
authors.initials: G
authors.lastname: Caforio
authors.forename: Francesco
authors.initials: F
authors.lastname: Piva
authors.forename: Teresa
authors.initials: T
authors.lastname: Popolizio
authors.forename: Cesario
authors.initials: C
authors.lastname: Bellantuono
authors.forename: Orlando
authors.initials: O
authors.lastname: Todarello
authors.forename: Joel E
authors.initials: JE
authors.lastname: Kleinman
authors.forename: Gemma
authors.initials: G
authors.lastname: Gadaleta
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bertolino
mesh_terms: D000328:Adult; D000483:Alleles; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology*; D003072:Cognition Disorders / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D058068:Endophenotypes; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D006367:HeLa Cells / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000295:instrumentation / Q000379:methods*; D008297:Male; D000077152:Olanzapine; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics*; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D001569:Benzodiazepines; D000077152:Olanzapine; D044402:Receptor, Serotonin, 5-HT2A; D017367:Selective Serotonin Reuptake Inhibitors