期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 21, 页码 5582-5587出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1717135115
关键词
gene coexpression network; DRD1; working memory; fMRI; polygenic score
资金
- Capitale Umano ad Alta Qualificazione - Fondazione Con Il Sud
- National Alliance for Research on Schizophrenia and Depression [28935]
- Ricerca Finalizzata [PE-2011-02347951]
- Hoffmann-La Roche Collaboration Grant
- European Union Seventh Framework Programme for research, technological development, and demonstration [602450]
- Takeda Pharmaceuticals Company Limited
- F. Hoffman-La Roche Ltd.
- NIH [R01MH085542, R01MH093725, P50MH066392, P50MH080405, R01MH097276, R01-MH-075916, P50M096891, P50MH084053S1, R37MH057881, R37MH057881S1, HHSN271201300031C, AG02219, AG05138, MH06692]
Dopamine D-1 receptor (D1R) signaling shapes prefrontal cortex (PFC) activity during working memory (WM). Previous reports found higher WM performance associated with alleles linked to greater expression of the gene coding for D(1)Rs (DRD1). However, there is no evidence on the relationship between genetic modulation of DRD1 expression in PFC and patterns of prefrontal activity during WM. Furthermore, previous studies have not considered that D1Rs are part of a coregulated molecular environment, which may contribute to D1R-related prefrontal WM processing. Thus, we hypothesized a reciprocal link between a coregulated (i.e., coexpressed) molecular network including DRD1 and PFC activity. To explore this relationship, we used three independent postmortem prefrontal mRNA datasets (total n = 404) to characterize a coexpression network including DRD1. Then, we indexed network coexpression using a measure (polygenic coexpression index-DRD1-PCI) combining the effect of single nucleotide polymorphisms (SNPs) on coexpression. Finally, we associated the DRD1-PCI with WM performance and related brain activity in independent samples of healthy participants (total n = 371). We identified and replicated a coexpression network including DRD1, whose coexpression was correlated with DRD1-PCI. We also found that DRD1-PCI was associated with lower PFC activity and higher WM performance. Behavioral and imaging results were replicated in independent samples. These findings suggest that genetically predicted expression of DRD1 and of its coexpression partners stratifies healthy individuals in terms of WM performance and related prefrontal activity. They also highlight genes and SNPs potentially relevant to pharmacological trials aimed to test cognitive enhancers modulating DRD1 signaling.
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