title: Variation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics.
abstract: Dopamine D2 and serotonin 5-HT2A receptors contribute to modulate prefrontal cortical physiology and response to treatment with antipsychotics in schizophrenia. Similarly, functional variation in the genes encoding these receptors is also associated with these phenotypes. In particular, the DRD2 rs1076560 T allele predicts a lower ratio of expression of D2 short/long isoforms, suboptimal working memory processing, and better response to antipsychotic treatment compared with the G allele. Furthermore, the HTR2A T allele is associated with lower 5-HT2A expression, impaired working memory processing, and poorer response to antipsychotics compared with the C allele. Here, we investigated in healthy subjects whether these functional polymorphisms have a combined effect on prefrontal cortical physiology and related cognitive behavior linked to schizophrenia as well as on response to treatment with second-generation antipsychotics in patients with schizophrenia. In a total sample of 620 healthy subjects, we found that subjects with the rs1076560 T and rs6314 T alleles have greater fMRI prefrontal activity during working memory. Similar results were obtained within the attentional domain. Also, the concomitant presence of the rs1076560 T/rs6314 T alleles also predicted lower behavioral accuracy during working memory. Moreover, we found that rs1076560 T carrier/rs6314 CC individuals had better responses to antipsychotic treatment in two independent samples of patients with schizophrenia (n=63 and n=54, respectively), consistent with the previously reported separate effects of these genotypes. These results indicate that DRD2 and HTR2A genetic variants together modulate physiological prefrontal efficiency during working memory and also modulate the response to antipsychotics. Therefore, these results suggest that further exploration is needed to better understand the clinical consequences of these genotype-phenotype relationships.
authors.affiliation: 1] Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy [2] IRCCS 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Blasi
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Selvaggi
authors.affiliation: IRCCS 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Fazio
authors.affiliation: 1] Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy [2] Department of Education Science, Psychology, Communication Science, Aldo Moro University, Bari, Italy.
authors.forename: Linda Antonella
authors.initials: LA
authors.lastname: Antonucci
authors.affiliation: 1] Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy [2] IRCCS 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Taurisano
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Masellis
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Romano
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Mancini
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors.forename: Fengyu
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Caforio
authors.affiliation: IRCCS 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Popolizio
authors.affiliation: National Institutes of Health, National Institute of Mental Health, Clinical Brain Disorders Branch, Bethesda, MD, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Apud
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.affiliation: 1] Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy [2] pRED, NORD DTA, F. Hoffman-La Roche Ltd., Basel, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bertolino
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001921:Brain / Q000098:blood supply / Q000187:drug effects*; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects* / Q000502:physiology; D009483:Neuropsychological Tests; D010100:Oxygen / Q000097:blood; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics*; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D010100:Oxygen