title: Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia.
abstract: Dopamine D2 receptor signalling is strongly implicated in the aetiology of schizophrenia. We have recently characterized the function of three DRD2 SNPs: rs12364283 in the promoter affecting total D2 mRNA expression; rs2283265 and rs1076560, respectively in introns 5 and 6, shifting mRNA splicing to two functionally distinct isoforms, the short form of D2 (D2S) and the long form (D2L). These two isoforms differentially contribute to dopamine signalling in prefrontal cortex and in striatum. We performed a case-control study to determine association of these variants and of their main haplotypes with several schizophrenia-related phenotypes. We demonstrate that the minor allele in the intronic variants is associated with reduced expression of %D2S of total mRNA in post-mortem prefrontal cortex, and with impaired working memory behavioural performance, both in patients and controls. However, the fMRI results show opposite effects in patients compared with controls: enhanced engagement of prefronto-striatal pathways in controls and reduced activity in patients. Moreover, the promoter variant is also associated with working memory activity in prefrontal cortex and striatum of patients, and less robustly with negative symptoms scores. Main haplotypes formed by the three DRD2 variants showed significant associations with these phenotypes consistent with those of the individual SNPs. Our results indicate that the three functional DRD2 variants modulate schizophrenia phenotypes possibly by modifying D2S/D2L ratios in the context of different total D2 density.
authors.affiliation: Department of Neurology and Psychiatry, University of Bari, Bari, Italy. a.bertolino@psichiat.uniba.it
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bertolino
authors.forename: Leonardo
authors.initials: L
authors.lastname: Fazio
authors.forename: Grazia
authors.initials: G
authors.lastname: Caforio
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Blasi
authors.forename: Antonio
authors.initials: A
authors.lastname: Rampino
authors.forename: Raffaella
authors.initials: R
authors.lastname: Romano
authors.forename: Annabella
authors.initials: A
authors.lastname: Di Giorgio
authors.forename: Paolo
authors.initials: P
authors.lastname: Taurisano
authors.forename: Audrey
authors.initials: A
authors.lastname: Papp
authors.forename: Julia
authors.initials: J
authors.lastname: Pinsonneault
authors.forename: Danxin
authors.initials: D
authors.lastname: Wang
authors.forename: Marcello
authors.initials: M
authors.lastname: Nardini
authors.forename: Teresa
authors.initials: T
authors.lastname: Popolizio
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sadee
mesh_terms: D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D003342:Corpus Striatum / Q000503:physiopathology*; D005260:Female; D005838:Genotype; D006801:Humans; D021621:Imaging, Three-Dimensional; D008279:Magnetic Resonance Imaging; D008297:Male; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000503:physiopathology*; D012333:RNA, Messenger / Q000032:analysis; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology*; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; D017448:Receptors, Dopamine D2