Genetic polymorphisms in the dopamine-2 receptor (DRD2), dopamine-3 receptor (DRD3), and dopamine transporter (SLC6A3) genes in schizophrenia: Data from an association study

Sáiz, Pilar A.; García-Portilla, María Paz; Arango, Celso; Morales, Blanca; Arias, Bárbara; Corcoran, Paul; Fernández, Juan M.; Álvarez, Victoria; Coto, Eliécer; Bascarán, María Teresa Bobes; Bousoño, Manuel; Fañanás, Lourdes; Bobes, Julio

doi:10.1016/j.pnpbp.2009.09.008

Cited by 40 publications

(24 citation statements)

References 70 publications

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“…Consistently, SLC6A3, encoding DAT, has been a long-standing candidate gene in psychiatric diseases, such as bipolar disorder, schizophrenia, and ADHD (22,(58)(59)(60), but the reported effect sizes of associated common variants are small, as for most other genes, and this challenges deduction of potential disease relevant biological processes. Rare variants have been found to account for a significant component of the genetic architecture of several psychiatric disorders, and the association signal for both common and rare variants appears to be enriched in mutation intolerant genes (1,(61)(62)(63)(64).…”

Section: Discussionmentioning

confidence: 99%

Neuropsychiatric disease–associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes

Herborg

Andreassen

Berlin

et al. 2018

Journal of Biological Chemistry

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Genetic factors are known to significantly contribute to the etiology of psychiatric diseases such as attention deficit hyperactivity disorder (ADHD) and autism spectrum and bipolar disorders, but the underlying molecular processes remain largely elusive. The dopamine transporter (DAT) has received continuous attention as a potential risk factor for psychiatric disease, as it is critical for dopamine homeostasis and serves as principal target for ADHD medications. Constrain metrics for the DAT-encoding gene solute carrier family 6 member 3 (SLC6A3) indicate that missense mutations are under strong negative selection, pointing to pathophysiological outcomes when DAT function is compromised. Here, we systematically characterized six rare genetic variants of DAT (I312F, T356M, D421N, A559V, E602G, and R615C) identified in patients with neuropsychiatric disorders. We evaluated dopamine uptake and ligand interactions, along with ion coordination and electrophysiological properties, to elucidate functional phenotypes, and applied Zn 2+ exposure and a substituted cysteineaccessibility approach to identify shared structural changes. Three variants (I312F, T356M, and D421N) exhibited impaired dopamine uptake associated with changes in ligand binding, ion coordination, and distinct conformational disturbances. Remarkably, we found that all three variants displayed gain-offunction electrophysiological phenotypes. I312F mediated an increased uncoupled anion conductance previously suggested to modulate neuronal excitability. T356M and D421N both mediated a cocaine-sensitive leakage of cations, which for T356M, was potentiated by Zn 2+ , concurrent with partial functional rescue. Collectively, our findings support that gain of disruptive functions due to missense mutations in SLC6A3 may be key to understanding how dopaminergic dyshomeostasis arises in heterozygous carriers.A substantial proportion of the disease etiology of common psychiatric disorders, such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASD), bipolar disorder, and schizophrenia is attributed genetic components (1). The underlying neurobiological mechanisms are not clear, but dopamine disturbances are believed to constitute a central component (2-7). The allelic spectrum of these dopamine-related disorders is rapidly expanding and comprises both common variants and rare structural or exonic mutations, including de novo variants (1,(8)(9)(10)(11)(12). Moreover, an interesting overlap in the genetic architecture of psychiatric disorders has been observed, and this pleiotrophy is seen for both common and rare variants (13)(14)(15)(16)(17)(18). Despite progress, much of the genetic component remains unaccounted for, and we also have the challenge ahead of translating most of the comprehensive genetic information into an understanding of underlying biological processes, and subsequently into clinically applicable knowledge. Rare variants may provide a unique handle for obtaining new disease insights as they are expected to h...

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Section: Discussionmentioning

confidence: 99%

Neuropsychiatric disease–associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes

Herborg

Andreassen

Berlin

et al. 2018

Journal of Biological Chemistry

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“…After reviewing the full text, 15 studies were excluded as six were reviews [18,19,[29][30][31][32], two were in Russian [33,34], one was in Polish [35], one was based on family members [36], two observed HWE disequilibrium in the control group [37,38] and three had overlapping data [39][40][41]. Thus, a total of 31 articles [8,[11][12][13][14][15][16]20,21, were included in this metaanalysis. The detailed retrieval process is shown in Figure 1.…”

Section: Characteristics Of Eligible Studiesmentioning

confidence: 99%

“…Several studies have shown that the Taq1A polymorphism of DRD2 increases susceptibility to schizophrenia [11,12], but other papers have shown contrary results [13,14]. The -141C Ins/Del (rs1799732) polymorphism of DRD2 has also been reported to be involved in schizophrenia risk [15,16], but again results have been inconsistent.…”

Section: Introductionmentioning

confidence: 99%

The -141C Ins/Del and Taq1A polymorphism in the dopamine D2 receptor gene may confer susceptibility to schizophrenia in Asian populations

Wang¹,

Liu

Xin

et al. 2016

Journal of Clinical Neuroscience

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“…The second DRD2 variant is rs1799732 (−141C Ins/Del). The deletion (del) allele has been associated with decreased protein expression (Arinami, Gao, Hamaguchi, & Toru, 1997) and appears to be additive in effect (see Ghosh, Pradhan, & Mittal, 2013; Sáiz et al, 2010) despite a number of studies using dominant models (e.g. Davis & Loxton, 2013).…”

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confidence: 99%

Child maltreatment, impulsivity, and antisocial behavior in African American children: Moderation effects from a cumulative dopaminergic gene index

2015

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A model examining the effects of an increasing number of maltreatment subtypes experienced on antisocial behavior, as mediated by impulsivity and moderated by a polygenic index of dopaminergic genotypes, was investigated. An African American sample of children (N = 1012, M age = 10.07) with and without maltreatment histories participated. Indicators of aggression, delinquency, and disruptive peer behavior were obtained from peer and counselor rated measures to form a latent variable of antisocial behavior; impulsivity was assessed by counselor report. Five genotypes in four dopaminergic genes (DRD4, DRD2, DAT1, and COMT) conferring heightened environmental sensitivity were combined into one polygenic index. Using SEM, a first-stage, moderated-mediation model was evaluated. Age and sex were entered as covariates, both as main effects and in interaction with maltreatment and the gene index. The model had excellent fit: χ2(32, N =1012) = 86..51, p<0.001; CFI = 0.982; TLI = 0.977; RMSEA = 0.041; SRMR = 0.022. The effect of maltreatment subtypes on antisocial behavior was partially mediated by impulsivity (β= 0.173, p<0.001), and these relations were moderated by the number of differentiating dopaminergic genotypes. Specifically, a significant GxE interaction (b = 0.016, p = 0.013) indicated that the relation between maltreatment and impulsivity was stronger as children evinced more differentiating genotypes, thereby strengthening the mediational effect of impulsivity on antisocial behavior. These findings elucidate the manner by which maltreated children develop early signs of antisocial behavior, and the genetic mechanisms involved in greater vulnerability for maladaptation in impulse-control within context of child maltreatment.

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Genetic polymorphisms in the dopamine-2 receptor (DRD2), dopamine-3 receptor (DRD3), and dopamine transporter (SLC6A3) genes in schizophrenia: Data from an association study

Cited by 40 publications

References 70 publications

Neuropsychiatric disease–associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes

Neuropsychiatric disease–associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes

The -141C Ins/Del and Taq1A polymorphism in the dopamine D2 receptor gene may confer susceptibility to schizophrenia in Asian populations

Child maltreatment, impulsivity, and antisocial behavior in African American children: Moderation effects from a cumulative dopaminergic gene index

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