Dopamine receptor D2 Ser/Cys 311 variant is associated with delusion and disorganization symptomatology in major psychoses

Abstract

The D2 receptor (DRD2) is a binding site of many psychoactive drugs and it has been proposed as a genetic risk factor for psychiatric disorders. The aim of this investigation was to study the DRD2 S311C variant in major psychoses. We studied 1182 inpatients with diagnoses of bipolar disorder (n = 480), major depressive disorder (n = 269), schizophrenia (n = 366), delusional disorder (n = 44), psychotic disorder not otherwise specified (n = 23) and 267 healthy controls. Eight hundred and eighty-seven subjects were also scored for their lifetime symptomatology using the the Operational Criteria checklist for psychotic illness (OPCRIT). DRD2 variants were not associated with affected subjects even when possible confounders like gender and onset were considered. When we considered the 887 subjects with the symptomatologic analysis, we observed a significant association of the DRD2 S311C variant with both delusion and disorganization features. The association was present independently from diagnoses. Our results do not show that coding variants of the DRD2 S311C play a major role in conferring susceptibility to major psychoses, but they may be connected with disorganized and delusional symptomatology independently from diagnoses. Molecular Psychiatry (2000) The D2 receptor is the major binding site of many typical and atypical neuroleptic drugs and its gene has been cloned and mapped to 11q22-23.2 Itokawa et al 3 reported a polymorphism causing a structural change from Serine to Cysteine at codon 311 of DRD2 (S311C); this substitution occurs in the third intracellular loop of the receptor. Preliminary results showed that DRD2 rarer TaqI variants were associated with higher levels of the monoamine metabolites homovanillic acid and 3-methoxy-4-hydroxyphenylglycol in lumbar cerebrospinal fluid in controls. 4 S311C has been proposed as Correspondence: A Serretti MD,

The Cys allele of the DRD2 Ser311Cys polymorphism has a dominant effect on risk for schizophrenia: Evidence from fixed‐ and random‐effects meta‐analyses

“…The magnitude of this effect was quite sizable (odds ratio [OR] ¼ 3.1; 95% confidence interval [CI] ¼ 1.4-6.7; P ¼ 0.004), and the polymorphism also was shown to alter the physiology and function of the receptor [Itokawa et al, 1993]; thus, this promising association quickly became the object of widespread replication efforts, most of which failed. In fact, only two of the 23 subsequent association studies of schizophrenia and the DRD2 Ser311Cys polymorphism found a significant relationship [Serretti et al, 2000;Jonsson et al, 2003]. As a consequence, the initial finding of association became widely regarded as a type-I inferential error [Verga et al, 1997]; however, it remained unclear if these failed replication attempts were due to the low power of individual studies, etiologic heterogeneity across samples, or random error in the absence of a true effect.…”

Genetic heterogeneity, modifier genes, and quantitative phenotypes in psychiatric illness: searching for a framework

“…These have reported associations between polymorphisms in DRD4 and catatonia 18 and delusions, 19 DRD2 and disorganization and delusions 20 CCK and positive symptoms, 21 5-HT promoter and auditory hallucinations 22 and affective symptoms, 23 HkCa3 and negative symptoms 24 and BDNF and DAT1 and negative symptoms. 23 Moreover, these polymorphisms were not associated with illness in these samples.…”

Genetics and delusional disorder

“…In the dopamine D2 receptor (DRD2) gene, there is a polymorphism that results in an amino acid change in the receptor protein (from serine to cysteine at position 311; hence referred to as Ser311Cys). Several studies have not found a significant association between this polymorphism and delusional disorder (Morimoto et al, 2002;Sasaki et al, 1996;Serretti, Lattuada, Lorenzi, Lilli, & Smeraldi, 2000). A polymorphism in the dopamine D3 receptor (DRD3) gene, which results in a serine to glycine substitution (Ser9Gly), has shown association with delusional disorder in one study (Di Bella et al, 1994), but not in another (Morimoto et al, 2002).…”