Polymorphisms of DRD4 and DRD3 and risk of avoidant and obsessive personality traits and disorders

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Abstract

We investigated whether polymorphisms of the dopamine D4 receptor (DRD4) and polymorphisms of the dopamine D3 receptor (DRD3) were associated with personality disorder symptomatology rather than with personality traits such as novelty seeking. DNA was obtained from 145 depressed patients in a clinical trial. These patients were assessed for the presence of personality disorder symptoms and disorders. The 2-repeat allele of the DRD4 exon III polymorphism was associated with increased rates of avoidant and obsessive personality disorder symptomatology. The T,T genotype of the DRD4 −521 C>T polymorphism was also associated with increased rates of avoidant and obsessive personality disorder symptomatology. The Gly9,Gly9 genotype of the DRD3 Ser9Gly polymorphism was associated with increased rates of obsessive personality disorder symptomatology. None of these three polymorphisms were associated with novelty seeking or other temperament traits on the Temperament and Character Inventory. Our results suggest that genetic polymorphisms of DRD4 and DRD3 may well be associated with personality traits, and that conflicting findings to date may arise from the problem of phenotype definition.

Introduction

A major challenge facing psychiatric genetics is the identification of the appropriate phenotypes, that may be associated with genetic polymorphisms (Leal, 2001, Weissman, 2001). It appears possible that traditional clinical psychiatric diagnostic categories will not be directly linked to specific polymorphisms. One approach to this issue has been an attempt to identify endophenotypes that may provide a link between genes and clinical syndromes (Leal, 2001, Weissman, 2001). Another approach has been to focus on temperament or personality traits that are partially inherited, as this may represent a step between genes and clinical syndromes. In research using the latter approach, one model is the Psychobiological Model of Personality developed by Cloninger et al., 1993, Cloninger, 1994. This model proposes the existence of four independently inherited temperament dimensions (novelty seeking, harm avoidance, reward dependence and persistence) and that varying combinations of these temperament dimensions, plus the three character dimensions (self-directedness, cooperativeness and self-transcendence), predispose an individual to risk for both axis I disorders such as major depression, anxiety disorders and addictive disorders, and axis II personality disorders.

In 1996, Ebstein et al., 1996, Benjamin et al., 1996 reported an association between a dopamine D4 receptor (DRD4) exon III VNTR consisting of a 48 base pair (bp) sequence repeated 2 to 10 times, and the personality trait of novelty seeking. Since these initial reports, there have been a number of studies addressing this association, but with conflicting results (Jönsson et al., 1998, Sullivan et al., 1998, Ekelund et al., 1999, Strobel et al., 1999, Benjamin et al., 2000, Swift et al., 2000). Further studies have examined the association of the DRD4 exon III VNTR with other impulsive and addictive disorders, but again with inconsistent results (Comings et al., 1999, Faraone et al., 2001). Other polymorphisms of DRD4 have also been discovered, including the −521 C>T single nucleotide polymorphism. This has also been associated with novelty seeking (Okuyama et al., 2000, Ronai et al., 2001), but results are again inconsistent (Mitsuyasu et al., 2001). Two recent meta-analyses of the association between novelty seeking and DRD4 polymorphisms have concluded that there is no relationship between the exon III VNTR polymorphisms and novelty seeking, but there may exist a weak relationship between the −521 C>T polymorphism and novelty seeking (Kluger et al., 2002, Schinka et al., 2002). These associations of DRD4 with novelty seeking, albeit inconsistent, have prompted the development of the DRD4 knockout mouse, which shows reduced exploration of novel stimuli (Dulawa et al., 1999).

Polymorphisms of the dopamine D3 receptor (DRD3) have been examined in relationship to disorders such as schizophrenia, bipolar disorder and personality traits such as novelty seeking. Again, no consistent associations have been reported (Staner et al., 1998, Henderson et al., 2000, Wong et al., 2000).

In this article, we planned to explore associations of genetic polymorphisms of DRD4 and DRD3; with clinician-rated personality traits and disorders assessed using the American Psychiatric Association's Diagnostic and Statistical Manual (DSM-III-R). We also re-examined the associations of these genetic polymorphisms with Cloninger's temperament measures, including novelty seeking. However, 86 of the 145 depressed patients in this sample were included in an earlier report that showed no association between novelty seeking and exon III VNTR polymorphisms of DRD4 (Sullivan et al., 1998).

Section snippets

Patients

The depressed patients described in this article, were recruited for a long-term study examining predictors of outcome in patients randomised to treatment with either fluoxetine or nortriptyline (Carter et al., 2000, Joyce et al., 2002). In brief, patients were suffering from a current major depressive episode justifying treatment with an antidepressant drug. Major depression was required to be the principal current diagnosis and patients were excluded if they had a history of mania (i.e.

DRD4 exon III polymorphisms

Among 145 depressed patients, the frequencies for the various exon III alleles were: 2-repeat (7.9%), 3-repeat (6.6%), 4 repeat (60.7%), 6-repeat (1.0%), 7-repeat (22.4%), 8-repeat (1.0%) and 10-repeat (0.3%). Table 1 shows the rates of personality disorder symptoms and diagnoses by genotype, and it can also be seen that the mean number of avoidant, dependant and obsessive symptoms significantly differed across the five polymorphism groups. With all three personality symptoms, post hoc tests

Discussion

In this article, in a sample of depressed patients, in whom personality has been assessed in a number of ways, we have found no association of DRD4 or DRD3 genetic polymorphisms with temperament measures such as novelty seeking. However, with DRD4, both the presence of a 2-repeat allele of the exon III VNTR polymorphism and the C,C genotype of the −521 polymorphism are strongly associated with avoidant and obsessive personality traits and disorders. Furthermore, the Gly/Gly genotype of DRD3 is

Acknowledgements

This research was funded by grants from the Health Research Council of New Zealand. The University of Otago and Canterbury Health also provided support. We thank Isobel Stevens and Robyn Abbott for their contributions to this research. Dr Martin Kennedy is a Senior Research Fellow of the Health Research Council of New Zealand.

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