Converging evidence for the association of functional genetic variation in the serotonin receptor 2a gene with prefrontal function and olanzapine treatment

Giuseppe Blasi, Caterina De Virgilio, Apostolos Papazacharias, Paolo Taurisano, Barbara Gelao, Leonardo Fazio, Gianluca Ursini, Lorenzo Sinibaldi, Ileana Andriola, Rita Masellis, Raffaella Romano, Antonio Rampino, Annabella Di Giorgio, Luciana Lo Bianco, Grazia Caforio, Francesco Piva, Teresa Popolizio, Cesario Bellantuono, Orlando Todarello, Joel E. KleinmanGemma Gadaleta, Daniel R. Weinberger, Alessandro Bertolino

Research output: Contribution to journalArticle

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Abstract

IMPORTANCE: 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. DESIGN: In silico predictions, in vitro, and case-control investigations. SETTING: Academic and clinical facilities. PARTICIPANTS: 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. MAIN OUTCOMES AND MEASURES: 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 AND RELEVANCE: 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.

Original languageEnglish
Pages (from-to)921-930
Number of pages10
JournalJAMA Psychiatry
Volume70
Issue number9
DOIs
Publication statusPublished - 2013

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olanzapine
Receptor, Serotonin, 5-HT2A
Schizophrenia
Short-Term Memory
Genes
Prefrontal Cortex
Computer Simulation
Messenger RNA
Single Nucleotide Polymorphism
Magnetic Resonance Imaging
Endophenotypes
Genetic Databases
Therapeutics
Proteins
Computational Biology
HeLa Cells
Cognition
Antipsychotic Agents
Alleles
Oxygen

ASJC Scopus subject areas

  • Psychiatry and Mental health

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Converging evidence for the association of functional genetic variation in the serotonin receptor 2a gene with prefrontal function and olanzapine treatment. / Blasi, Giuseppe; De Virgilio, Caterina; Papazacharias, Apostolos; Taurisano, Paolo; Gelao, Barbara; Fazio, Leonardo; Ursini, Gianluca; Sinibaldi, Lorenzo; Andriola, Ileana; Masellis, Rita; Romano, Raffaella; Rampino, Antonio; Di Giorgio, Annabella; Lo Bianco, Luciana; Caforio, Grazia; Piva, Francesco; Popolizio, Teresa; Bellantuono, Cesario; Todarello, Orlando; Kleinman, Joel E.; Gadaleta, Gemma; Weinberger, Daniel R.; Bertolino, Alessandro.

In: JAMA Psychiatry, Vol. 70, No. 9, 2013, p. 921-930.

Research output: Contribution to journalArticle

Blasi, G, De Virgilio, C, Papazacharias, A, Taurisano, P, Gelao, B, Fazio, L, Ursini, G, Sinibaldi, L, Andriola, I, Masellis, R, Romano, R, Rampino, A, Di Giorgio, A, Lo Bianco, L, Caforio, G, Piva, F, Popolizio, T, Bellantuono, C, Todarello, O, Kleinman, JE, Gadaleta, G, Weinberger, DR & Bertolino, A 2013, 'Converging evidence for the association of functional genetic variation in the serotonin receptor 2a gene with prefrontal function and olanzapine treatment', JAMA Psychiatry, vol. 70, no. 9, pp. 921-930. https://doi.org/10.1001/jamapsychiatry.2013.1378
Blasi, Giuseppe ; De Virgilio, Caterina ; Papazacharias, Apostolos ; Taurisano, Paolo ; Gelao, Barbara ; Fazio, Leonardo ; Ursini, Gianluca ; Sinibaldi, Lorenzo ; Andriola, Ileana ; Masellis, Rita ; Romano, Raffaella ; Rampino, Antonio ; Di Giorgio, Annabella ; Lo Bianco, Luciana ; Caforio, Grazia ; Piva, Francesco ; Popolizio, Teresa ; Bellantuono, Cesario ; Todarello, Orlando ; Kleinman, Joel E. ; Gadaleta, Gemma ; Weinberger, Daniel R. ; Bertolino, Alessandro. / Converging evidence for the association of functional genetic variation in the serotonin receptor 2a gene with prefrontal function and olanzapine treatment. In: JAMA Psychiatry. 2013 ; Vol. 70, No. 9. pp. 921-930.
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AU - Blasi, Giuseppe

AU - De Virgilio, Caterina

AU - Papazacharias, Apostolos

AU - Taurisano, Paolo

AU - Gelao, Barbara

AU - Fazio, Leonardo

AU - Ursini, Gianluca

AU - Sinibaldi, Lorenzo

AU - Andriola, Ileana

AU - Masellis, Rita

AU - Romano, Raffaella

AU - Rampino, Antonio

AU - Di Giorgio, Annabella

AU - Lo Bianco, Luciana

AU - Caforio, Grazia

AU - Piva, Francesco

AU - Popolizio, Teresa

AU - Bellantuono, Cesario

AU - Todarello, Orlando

AU - Kleinman, Joel E.

AU - Gadaleta, Gemma

AU - Weinberger, Daniel R.

AU - Bertolino, Alessandro

PY - 2013

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N2 - IMPORTANCE: 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. DESIGN: In silico predictions, in vitro, and case-control investigations. SETTING: Academic and clinical facilities. PARTICIPANTS: 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. MAIN OUTCOMES AND MEASURES: 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 AND RELEVANCE: 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.

AB - IMPORTANCE: 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. DESIGN: In silico predictions, in vitro, and case-control investigations. SETTING: Academic and clinical facilities. PARTICIPANTS: 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. MAIN OUTCOMES AND MEASURES: 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 AND RELEVANCE: 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.

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