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Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during
Ying Zhang1, Alessandro Bertolino, Leonardo Fazio
1Program in Pharmacogenomics, Department of Pharmacology, Ohio State University, Columbus, OH 43210, USA.
Summary
New dopamine D2 receptor (DRD2) gene variants were found to affect gene expression and splicing. These genetic variations impact working memory and attention in healthy individuals.
Area of Science:
- Neuroscience
- Genetics
- Cognitive Science
Background:
- Subcortical dopamine D2 receptor (DRD2) signaling plays a role in cognition and brain disorders.
- The precise impact of DRD2 genetic variants on its function and associated cognitive processes remains unclear.
Purpose of the Study:
- To investigate the functional effects of DRD2 genetic variants on gene expression, splicing, and cognitive performance.
- To identify specific DRD2 polymorphisms influencing mRNA levels and working memory pathways.
Main Methods:
- Measured allelic mRNA expression in human postmortem brain tissue (striatum and prefrontal cortex).
- Performed single nucleotide polymorphism (SNP) scans of the DRD2 locus.
- Utilized in vitro minigene assays to validate splicing effects.
- Assessed brain activity using fMRI during working memory tasks and evaluated cognitive performance in healthy humans.
Main Results:
- A novel promoter SNP (rs12364283) was associated with enhanced DRD2 expression.
- Two intronic SNPs (rs2283265 and rs1076560), in linkage disequilibrium, decreased the expression of the short DRD2 splice variant relative to the long variant.
- These intronic SNPs correlated with increased striatal and prefrontal cortex activity during working memory tasks.
- The intronic SNPs were also associated with reduced performance in working memory and attentional control tasks.
Conclusions:
- Identified specific DRD2 polymorphisms that regulate gene expression and alternative splicing.
- Demonstrated that these regulatory variants impact neural activity in working memory circuits and cognitive functions.
- Provides insights into the genetic underpinnings of individual differences in working memory and attention.
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