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

被引：334

作者：

Zhang, Ying ^{[2
]}

Bertolino, Alessandro ^{[5
]}

Fazio, Leonardo ^{[5
]}

Blasi, Giuseppe ^{[5
]}

Rampino, Antonio ^{[5
]}

Romano, Raffaella ^{[5
]}

Lee, Mei-Ling T. ^{[4
]}

Xiao, Tao ^{[4
]}

Papp, Audrey ^{[2
]}

Wang, Danxin ^{[2
]}

Sadee, Wolfgang ^{[1
,2
,3
]}

机构：

[1] Ohio State Univ, Coll Med & Publ Hlth, Dept Pharmacol, Columbus, OH 43210 USA

[2] Ohio State Univ, Coll Publ Hlth, Dept Pharmacol, Program Pharmacogenom, Columbus, OH 43210 USA

[3] Ohio State Univ, Coll Pharm, Coll Med, Div Human Genet, Columbus, OH 43210 USA

[4] Ohio State Univ, Coll Publ Hlth, Div Biostat, Columbus, OH 43210 USA

[5] Univ Bari, Dept Neurol & Psychiat, Grp Psychiat Neurosci, I-70124 Bari, Italy

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2007年 / 104卷 / 51期

关键词：

allelic expression imbalance; splice variant; promoter polymorphism; brain imaging;

D O I：

10.1073/pnas.0707106104

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 SNIPS (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.

引用

页码：20552 / 20557

页数：6

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