Functional Variation of the Dopamine D<sub>2</sub>Receptor Gene Is Associated with Emotional Control as well as Brain Activity and Connectivity during Emotion Processing in Humans

Blasi, Giuseppe; Bianco, Luciana Lo; Taurisano, Paolo; Franke, Barbara; Romano, Raffaella; Fazio, Leonardo; Papazacharias, Apostolos; Giorgio, Annabella Di; Caforio, Grazia; Rampino, Antonio; Masellis, Rita; Papp, Audrey C.; Ursini, Gianluca; Sinibaldi, Lorenzo; Popolizio, Teresa; Sadée, Wolfgang; Bertolino, Alessandro

doi:10.1523/jneurosci.3609-09.2009

Cited by 98 publications

(75 citation statements)

References 51 publications

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“…In addition, genotypes were double-checked with direct DNA sequencing, as previously described. 62 Subjects with MetMet genotype were excluded from further analyses, after verified that, as expected, rs6265 methylation was around 0%. Lack of methylation of the Met allele is consistent with absence of a CpG site in this position, confirming the quality of bisulfite treatment conversion of unmethylated Cytosine in Uracil/Thymine.…”

Section: Subjects Methylation Analysis and Genotypingmentioning

confidence: 96%

BDNF rs6265 methylation and genotype interact on risk for schizophrenia

et al. 2016

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Epigenetic mechanisms can mediate gene-environment interactions relevant for complex disorders. The BDNF gene is crucial for development and brain plasticity, is sensitive to environmental stressors, such as hypoxia, and harbors the functional SNP rs6265 (Val 66 Met), which creates or abolishes a CpG dinucleotide for DNA methylation. We found that methylation at the BDNF rs6265 Val allele in peripheral blood of healthy subjects is associated with hypoxia-related early life events (hOCs) and intermediate phenotypes for schizophrenia in a distinctive manner, depending on rs6265 genotype: in ValVal individuals increased methylation is associated with exposure to hOCs and impaired working memory (WM) accuracy, while the opposite is true for ValMet subjects. Also, rs6265 methylation and hOCs interact in modulating WM-related prefrontal activity, another intermediate phenotype for schizophrenia, with an analogous opposite direction in the 2 genotypes. Consistently, rs6265 methylation has a different association with schizophrenia risk in ValVals and ValMets. The relationships of methylation with BDNF levels and of genotype with BHLHB2 binding likely contribute to these opposite effects of methylation. We conclude that BDNF rs6265 methylation interacts with genotype to bridge early environmental exposures to adult phenotypes, relevant for schizophrenia. The study of epigenetic changes in regions containing genetic variation relevant for human diseases may have beneficial implications for the understanding of how genes are actually translated into phenotypes.

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Section: Subjects Methylation Analysis and Genotypingmentioning

confidence: 96%

BDNF rs6265 methylation and genotype interact on risk for schizophrenia

et al. 2016

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“…As a vital neurotransmitter in the central nervous system and an important hormone in the periphery, dopamine exerts widespread effects on the neuroendocrine secretion, behavioral and physiological functions, such as the control of movement, cognition and emotion (Blasi et al, 2009;Baskerville and Douglas, 2010;Korchounov et al, 2010). Dopamine initiates the biological actions by binding to its receptors on the cell surface.…”

Section: Introductionmentioning

confidence: 99%

Molecular cloning, expression and variation analyses of the dopamine D2 receptor gene in pig breeds in China

Hp¹,

Xm²,

Mx³

et al. 2011

Genet. Mol. Res.

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ABSTRACT. The dopamine D2 receptor (DRD2) is a crucial mediator for normal physiological processes. We cloned the pig DRD2 gene, investigated its distribution in tissues and identified polymorphisms by RT-PCR, quantitative real-time PCR and direct sequencing. Two Yorkshire pigs from Guangdong Academy of Agricultural Sciences (Guangzhou, China) were selected to clone the gene and investigate its expression; 16 individuals from four pig breeds (Yorkshire, Landrace, small-ear spotted, and Xinchang) were used to scan the variations. comprises five miRNA targeting sites, based on bioinformatics predictions. The pig DRD2 gene expresses predominantly in the pituitary gland, and then in oviducts and the hypothalamus. Both DRD2L and DRD2S mRNA were detected in cerebrum, cerebellum, hypothalamus, pituitary gland, back muscle, oviduct, uterus, and testis tissues; DRD2L was more abundant than DRD2S. The DRD2 gene is located on chromosome 9 and contains seven exons. Sixty-one different sequences were identified in this gene; among seven in the coding region, only one altered the encoded amino acid. These findings will help us understand the functions of the DRD2 gene in pigs.

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“…In particular, the T allele shifts splicing from D2S to D2L, decreasing the D2S/D2L ratio relative to the G allele. This SNP has also been associated with behavior and brain activity during cognitive and emotion processing in healthy humans and in patients with schizophrenia (15,22,23). More specifically, the T allele has been associated with less efficient prefronto-striatal activity during working memory (23) and with putatively greater levels of striatal dopamine (24).…”

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confidence: 99%

DRD2/AKT1interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia

Blasi

Napolitano

Ursini

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The D2/AKT1/GSK-3β signaling pathway has been involved in the downstream intracellular effects of dopamine, in the pathophysiology of cognitive deficits and related brain activity in schizophrenia, as well as in response to treatment with antipsychotics. Polymorphisms in the D2 (DRD2 rs1076560) and AKT1 (AKT1 rs1130233) genes have been associated with their respective protein expression and with higher-order cognition and brain function, including attention. Given the strong potential for their relationship, we investigated the interaction of these polymorphisms on multiple molecular and in vivo phenotypes associated with this signaling pathway. We measured AKT1 and GSK-3β proteins and phosphorylation in human peripheral blood mononuclear cells, functional MRI cingulate response during attentional control, behavioral accuracy during sustained attention, and response to 8 wk of treatment with olanzapine in a total of 190 healthy subjects and 66 patients with schizophrenia. In healthy subjects, we found that the interaction between the T allele of DRD2 rs1076560 and the A allele of AKT1 rs1130233 was associated with reduced AKT1 protein levels and reduced phosphorylation of GSK-3β, as well as with altered cingulate response and reduced behavioral accuracy during attentional processing. On the other hand, interaction of these two alleles was associated with greater improvement of Positive and Negative Syndrome Scale scores in patients with schizophrenia after treatment with olanzapine. The present results indicate that these functional polymorphisms are epistatically associated with multiple phenotypes of relevance to schizophrenia. Our results also lend support to further investigation of this downstream molecular pathway in the etiology and treatment of this disorder.A large series of experimental data indicate that dopamine D2 receptors and schizophrenia are tightly related. First, these receptors are privileged targets of antipsychotic drugs, which antagonize their activity (1). Second, previous reports have suggested association between psychosis and relatively greater D2 density in striatum, even though change is moderate (2). Third, clinical symptoms and cognitive deficits have been associated with abnormal D2 signaling (3-12). The relationship between D2 receptors and cognitive deficits in schizophrenia is also supported by previous models postulating that relatively excessive D2 signaling may lead to lower cortical signal-to-noise ratio and reduced filtering of information, as well as blocking of distracting inputs (10-12). These brain processes contribute to different higherorder cognitive functions and are strongly involved in top-down modulation of attention (13,14). Consistent with these models, previous data have suggested that attentional behavior is affected by D2 genetic variation (15). Furthermore, deficits in attentional processing are centrally implicated in schizophrenia (16,17). In fact, patients with schizophrenia performing attentional tasks have abnormal activity in the cingulate cortex, a ...

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Functional Variation of the Dopamine D₂Receptor Gene Is Associated with Emotional Control as well as Brain Activity and Connectivity during Emotion Processing in Humans

Cited by 98 publications

References 51 publications

BDNF rs6265 methylation and genotype interact on risk for schizophrenia

BDNF rs6265 methylation and genotype interact on risk for schizophrenia

Molecular cloning, expression and variation analyses of the dopamine D2 receptor gene in pig breeds in China

DRD2/AKT1interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia

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Functional Variation of the Dopamine D2Receptor Gene Is Associated with Emotional Control as well as Brain Activity and Connectivity during Emotion Processing in Humans

Cited by 98 publications

References 51 publications

BDNF rs6265 methylation and genotype interact on risk for schizophrenia

BDNF rs6265 methylation and genotype interact on risk for schizophrenia

Molecular cloning, expression and variation analyses of the dopamine D2 receptor gene in pig breeds in China

DRD2/AKT1interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia

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Functional Variation of the Dopamine D₂Receptor Gene Is Associated with Emotional Control as well as Brain Activity and Connectivity during Emotion Processing in Humans