Converging evidence implicates the dopamine D3 receptor gene in vulnerability to schizophrenia

Abstract

The dopamine D3 receptor has been implicated in the pathophysiology of schizophrenia (SZ). A glycine-to-serine polymorphism at codon 9 of the dopamine D3 receptor gene (DRD3), rs6280, has been widely studied for its association with SZ, but with conflicting results. Altered levels of DRD3 mRNA have also been reported in SZ compared with normal controls. Moreover, it has been suggested that DRD3 is subject to recent positive selection in European populations. To explore the potential role of DRD3 in SZ from these various aspects, we conducted a threefold study. First, we tested the genetic association of rs6280 with SZ in 685 SZ patients and 768 normal controls. Second, we examined DRD3 mRNA levels in peripheral leukocytes in a subset of 37 patients and 37 controls. Finally, we investigated the possible recent positive selection on DRD3 in an East Asian population. Consequently, we observed that the genotypic distribution of rs6280 was nominally associated with SZ (P = 0.045), with the ancestral CC genotype being significantly over-represented in SZ patients. DRD3 mRNA levels were significantly lower in patients than in controls (P = 5.91E-5). The derived C-allele of rs6280 might have been subject to recent positive selection (P < 0.001) in the East Asian population. Taken together, our results suggest that DRD3, a gene possibly under natural selection, might be involved in vulnerability to SZ in the Han Chinese population. These findings may further add to the body of data implicating DRD3 as a schizophrenia risk gene.

Epistasis between COMT Val158Met and DRD3 Ser9Gly polymorphisms and cognitive function in schizophrenia: genetic influence on dopamine transmission

“…[26][27][28] The Gly allele frequency reported herein is similar to that described in these studies, which provides further evidence supporting the hypothesis that this allele is under the influence of natural selection, being more frequent in Asian and Latin American regions. 28 Regarding the relationship between the COMT Val 158 Met polymorphism and schizophrenia, although we found a higher frequency of heterozygosity among patients, there is no consensus in the literature about this issue. A meta-analysis conducted by Glatt et al 29 indicated that the Val 158 allele might be a weak risk factor for the development of schizophrenia.…”

The Functional DRD3 Ser9Gly Polymorphism (rs6280) Is Pleiotropic, Affecting Reward as Well as Movement

“…It has not only been implicated in mood disorders and addiction, but personality traits [69], schizophrenia [70], [71], cognition [72], autism [73], obsessive compulsive disorder [74], and response to clozapine [75], [76] in the context of psychosis. Conceivably, the ser9gly polymorphism is capable of modulating a variety of functions and circuits in which the D3 receptor plays an integral role, perhaps explaining evidence for a recent positive selection sweep in favor of the ser9 allele in European [70] and east Asian populations [71].…”

Aberrant Dopamine D2-Like Receptor Function in a Rodent Model of Schizophrenia

“…Furthermore, increased D2-like binding is observed in patients with schizophrenia after dopamine depletion, demonstrating enhanced baseline occupancy of the D2-like receptors (Abi-Dargham et al, 2000). A further association between the D3 receptor and schizophrenia is observed in genetic studies where polymorphisms of the D3 receptor have been associated with the disease (Urraca et al, 2011;Zhang et al, 2011) as well as antipsychotic efficacy (Hwang et al, 2010;Vehof et al, 2012). For this reason, there have been a number of preclinical studies suggesting that the D3-specific antagonist may represent a more specific antipsychotic profile (Gyertyán et al, 2008;Millan et al, 2008;Kiss et al, 2010).…”