DRD4 exon 3 variants associated with delusional symptomatology in major psychoses: A study on 2,011 affected subjects

Abstract

We previously reported an association of DRD4 exon3 long allele variants with delusional symptomatology independently from diagnoses. The aim of this investigation was to study DRD4 in major psychoses and to test the association in a larger sample. We studied 2,011 inpatients affected by bipolar disorder (n = 811), major depressive disorder (n = 635), schizophrenia (n = 419), delusional disorder (n = 104), psychotic disorder not otherwise specified (n = 42), and 601 healthy controls. A subsample of 1,264 patients were evaluated using the OPCRIT checklist and differences of symptomatology factor scores among genetic variants were assessed using one-way analysis of variance (ANOVA). DRD4 allele and genotype frequencies in bipolars, schizophrenics, delusionals, and psychotic NOS were not significantly different from controls; major depressives showed a trend toward an excess of DRD4*Short and DRD4*Short/Short variants versus controls. The ANOVA on factor scores in the whole subsample of 1,264 subjects showed a significant difference on delusion factor in allele analysis (P = 0.007), and in genotype one (P = 0.018), with DRD4*Long containing variants associated with severe symptomatology. The analysis in the replication subjects only (n = 803) showed a trend in the same direction, though not reaching the significance level. This analysis in an enlarged sample suggests that DRD4*Long alleles exert a small but significant influence on the delusional symptomatology in subjects affected by major psychoses.

Variable number of tandem repeat polymorphisms of DRD4: re-evaluation of selection hypothesis and analysis of association with schizophrenia

“…11,12 Also, there has been growing literature reporting genetic association of the allele 7R with psychiatric traits/illnesses including novelty seeking, 13,14 attention-deficit hyperactivity disorder (ADHD) 15,16 as well as schizophrenia. 13,17 -31 Some studies declared association of the VNTR size polymorphisms with schizophrenia, 13,17,21,22,24,27 although not all studies agree. 18,23,25,26,28,30 -33 Also, supporting the functional role of the VNTR is evidence of selection favoring the allele 7R of the VNTR.…”

Dopamine D4 receptor and tyrosine hydroxylase genes in bipolar disorder: evidence for a role of DRD4

“…15 The short arm of chromosome 11 on p15.5 harbors two dopamine system genes, ie the dopamine D4 receptor (DRD4) and the tyrosine hydroxylase (TH) genes, and these genes have been extensively investigated in bipolar disorder. [16][17][18][19][20][21][22][23][24][25] The gene for the dopamine D4 receptor is highly polymorphic containing a functional variable number of tandem repeats (VNTR) in the third exon that encodes for the longest intracellular loop of the receptor. 26,27 The polymorphism consists of 2-10 imperfect tandem repeats of 48 bp, each repeat encoding for 16 amino acids.…”

“…33 The majority of the association studies that have investigated the role of DRD4 in bipolar disorder did not show evidence for association. [18][19][20][21][22]25 However, a large sample of bipolar disorder patients has shown association with delusional symptoms in bipolar patients, 23 although the grouping of the DRD4 exon III alleles obscured the effect of the single alleles. In a similar fashion, the association studies of HUMTH01 in bipolar disorder produced both positive and negative association.…”

Bipolar Disorder: Diagnosis, Neuroanatomical and Biochemical Background

“…Excess dopamine activity facilitates mania and delusional symptoms (Manji H. and Potter W., 1997;Serretti et al, 2001;Wightman and Robinson, 2002). Dopamine has also been proposed to play a role in the etiology of bipolar disorder.…”

“…This particular region incorporates the tyrosine hydroxylase (TH) and the dopamine D4 receptor gene (DRD4) (Todd et al, 1996;Oruc et al, 1997;Furlong et al, 1999;Li et al, 1999;Serretti et al, 2001). Tyrosine hydroxylase plays a significant role in the formation of dopamine since it is the key and rate-limiting enzyme of the catecholamine synthesis converting tyrosine to DOPA, a precursor of dopamine (Muglia et al, 2002).…”