Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory

Ying Zhang, Alessandro Bertolino, Leonardo Fazio, Giuseppe Blasi, Antonio Rampino, Raffaella Romano, Mei Ling T Lee, Tao Xiao, Audrey Papp, Danxin Wang, Wolfgang Sadée

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)20552-20557
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number51
DOIs
Publication statusPublished - Dec 18 2007

Keywords

  • Allelic expression imbalance
  • Brain imaging
  • Promoter polymorphism
  • Splice variant

ASJC Scopus subject areas

  • Genetics
  • General

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