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Original Investigation |

Converging Evidence for the Association of Functional Genetic Variation in the Serotonin Receptor 2a Gene With Prefrontal Function and Olanzapine Treatment

Giuseppe Blasi, MD, PhD1; Caterina De Virgilio, PhD2; Apostolos Papazacharias, MD1; Paolo Taurisano, PhD1; Barbara Gelao, PhD1; Leonardo Fazio, PhD, MD1; Gianluca Ursini, MD1; Lorenzo Sinibaldi, MD, PhD3; Ileana Andriola, MD1; Rita Masellis, PhD1; Raffaella Romano, PhD1; Antonio Rampino, MD1; Annabella Di Giorgio, MD, PhD3; Luciana Lo Bianco, PhD1,4; Grazia Caforio, MD, PhD1; Francesco Piva, Eng, PhD5; Teresa Popolizio, MD3; Cesario Bellantuono, MD4; Orlando Todarello, MD6; Joel E. Kleinman, MD, PhD7; Gemma Gadaleta, PhD2; Daniel R. Weinberger, MD8; Alessandro Bertolino, MD, PhD1
[+] Author Affiliations
1Group of Psychiatric Neuroscience, Department of Neuroscience and Sense Organs, Aldo Moro University, Bari, Italy
2Department of Biochemistry and Molecular Biology Ernesto Quagliariello, Aldo Moro University, Bari, Italy
3Istituto di Ricovero e Cura a Carattere Scientifico “Casa Sollievo della Sofferenza,” San Giovanni Rotondo, Italy
4Psychiatric Unit, Department of Mental Health, United Hospitals of Ancona, Polytechnic University of Marche, Italy
5Department of Biochemistry, Biology and Genetics, Polytechnic University of Marche, Ancona, Italy
6Department of Neuroscience and Sense Organs, Aldo Moro University, Bari, Italy
7Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland
8Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, Maryland
JAMA Psychiatry. 2013;70(9):921-930. doi:10.1001/jamapsychiatry.2013.1378.
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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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Figure 1.
Serotonin (5-Hydroxytryptamine) Receptor 2a (5-HT2AR) Messenger RNA (mRNA) Prefrontal Expression

Normalized log2 (sample/reference) shown in postmortem prefrontal cortex of healthy individuals as a function of HTR2A rs6314 genotype. A trend (P = .06) for the association between the presence of the T allele and lower 5-HT2AR expression relative to individuals with the CC genotype was found. Error bars indicate confidence intervals.

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Figure 2.
Serotonin (5-Hydroxytryptamine) Receptor 2a Expression in HeLa Cells

Graphs showing serotonin (5-hydroxytryptamine) receptor 2a (5-HT2AR) messenger RNA (mRNA) expression (2–ΔΔC(T)) (A) and 5-HT2AR protein expression (percentage of expression relative to presence of the C allele) (B) in HeLa cells as a function of the rs6314 genotype, with lower expression in T carriers relative to individuals with the CC genotype for both of these variables (aP = .004; bP < .001). Error bars indicate confidence intervals.

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Figure 3.
rs6314 and Prefrontal Activity During Cognition

Individuals carrying the T allele had greater activity relative to CC-genotype individuals during the N-back (x = –51, y = 38, z = 12) (A) and the variable attentional control (x = 45, y = 26, z = 26) (B) tasks, with the relative parameter estimates. Colors indicate the t values within brain regions associated with significant effects of interest (yellow indicates the greater t value); bullets, mean values; and error bars, confidence intervals.

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Figure 4.
rs6314 and Accuracy During Working Memory

Reduced accuracy in T carriers compared with CC-genotype individuals at the 2-back working memory task (P = .007). Error bars indicate confidence intervals.

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Figure 5.
rs6314 and Performance on Trail Making Test

Statistically significantly reduced speed of processing (longer time in seconds to perform the task) in healthy individuals with the CT genotype relative to those with the CC genotype in Trail Making Test Part B (A) and Trail Making Test Parts B − A (B) (P = .04). Data are given as mean (bullets) and 95% CI (error bars).

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Figure 6.
rs6314 and Difference in Positive and Negative Syndrome Scale Scores

Difference in negative symptoms scores at 8 weeks of treatment with olanzapine relative to baseline of each patient with schizophrenia (CC-genotype patients had greater frequency of response compared with CT-genotype patients (χ2 = 6.2; P = .01; analysis of covariance, F = 4.6; P = .03).

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