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 language | English |
|---|---|
| Pages (from-to) | 921-930 |
| Number of pages | 10 |
| Journal | JAMA Psychiatry |
| Volume | 70 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 2013 |
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ASJC Scopus subject areas
- Psychiatry and Mental health
Cite this
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 journal › Article
}
TY - JOUR
T1 - Converging evidence for the association of functional genetic variation in the serotonin receptor 2a gene with prefrontal function and olanzapine treatment
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
Y1 - 2013
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.
UR - http://www.scopus.com/inward/record.url?scp=84883538421&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84883538421&partnerID=8YFLogxK
U2 - 10.1001/jamapsychiatry.2013.1378
DO - 10.1001/jamapsychiatry.2013.1378
M3 - Article
C2 - 23842608
AN - SCOPUS:84883538421
VL - 70
SP - 921
EP - 930
JO - JAMA Psychiatry
JF - JAMA Psychiatry
SN - 2168-622X
IS - 9
ER -