title: Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory.
abstract: Subcortical dopamine D2 receptor (DRD2) signaling is implicated in cognitive processes and brain disorders, but the effect of DRD2 variants remains ambiguous. We measured allelic mRNA expression in postmortem human striatum and prefrontal cortex and then performed single nucleotide polymorphism (SNP) scans of the DRD2 locus. A previously uncharacterized promoter SNP (rs12364283) located in a conserved suppressor region was associated with enhanced DRD2 expression, whereas previously studied DRD2 variants failed to affect expression. Moreover, two frequent intronic SNPs (rs2283265 and rs1076560) decreased expression of DRD2 short splice variant (expressed mainly presynaptically) relative to DRD2 long (postsynaptic), a finding reproduced in vitro by using minigene constructs. Being in strong linkage disequilibrium with each other, both intronic SNPs (but not rs12364283) were also associated with greater activity of striatum and prefrontal cortex measured with fMRI during working memory and with reduced performance in working memory and attentional control tasks in healthy humans. Our results identify regulatory DRD2 polymorphisms that modify mRNA expression and splicing and working memory pathways.
authors: Program in Pharmacogenomics, Department of Pharmacology, Ohio State University, Columbus, OH 43210, USA.
authors: Ying
authors: Y
authors: Zhang
authors: Alessandro
authors: A
authors: Bertolino
authors: Leonardo
authors: L
authors: Fazio
authors: Giuseppe
authors: G
authors: Blasi
authors: Antonio
authors: A
authors: Rampino
authors: Raffaella
authors: R
authors: Romano
authors: Mei-Ling T
authors: ML
authors: Lee
authors: Tao
authors: T
authors: Xiao
authors: Audrey
authors: A
authors: Papp
authors: Danxin
authors: D
authors: Wang
authors: Wolfgang
authors: W
authors: Sadée
mesh_terms: D000483:Alleles; D017398:Alternative Splicing / Q000235:genetics*; D003071:Cognition; D003342:Corpus Striatum / Q000737:chemistry; D015870:Gene Expression; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D008570:Memory, Short-Term; D009474:Neurons / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000737:chemistry; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000502:physiology*
chemical_list: D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D008156:Luciferases