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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.
- Source :
-
JAMA psychiatry [JAMA Psychiatry] 2013 Sep; Vol. 70 (9), pp. 921-30. - Publication Year :
- 2013
-
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.<br />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.<br />Design: In silico predictions, in vitro, and case-control investigations.<br />Setting: Academic and clinical facilities.<br />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.<br />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.<br />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.<br />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.
- Subjects :
- Adult
Alleles
Cognition Disorders drug therapy
Cognition Disorders genetics
Cognition Disorders metabolism
Endophenotypes
Female
HeLa Cells metabolism
Humans
Magnetic Resonance Imaging instrumentation
Male
Olanzapine
Prefrontal Cortex drug effects
Prefrontal Cortex physiopathology
Schizophrenia drug therapy
Schizophrenia genetics
Schizophrenia physiopathology
Selective Serotonin Reuptake Inhibitors pharmacology
Young Adult
Antipsychotic Agents pharmacology
Benzodiazepines pharmacology
Genetic Variation genetics
Magnetic Resonance Imaging methods
Prefrontal Cortex metabolism
Receptor, Serotonin, 5-HT2A genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2168-6238
- Volume :
- 70
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- JAMA psychiatry
- Publication Type :
- Academic Journal
- Accession number :
- 23842608
- Full Text :
- https://doi.org/10.1001/jamapsychiatry.2013.1378