Association between the dopamine D2 receptor TaqI A2 allele and low activity COMT allele with obsessive–compulsive disorder in males
Introduction
OCD is a common and severe, but still under-recognized, psychiatric disorder. Family and twin studies have provided evidence for the involvement of a genetic factor in OCD (Nestadt et al., 2000, Pauls et al., 1995). Although very little is known about the disorder's pathogenesis, both serotonergic and dopaminergic pathways may be implicated. A role for dopamine in the pathophysiology of OCD is supported by the observation that pharmacological agents enhancing dopamine release such as methylphenidate, cocaine, and bromocriptine may induce obsessive–compulsive symptoms (Crum and Anthony, 1993, Jenike et al., 1990, Satel and McDougle, 1991). In addition, evidence has accumulated that augmentation strategies with antipsychotics are beneficial for treatment-refractory OCD patients (Denys et al., 2002, McDougle et al., 1994, McDougle et al., 2000). Recently, SPECT studies provided evidence for higher dopamine transporter densities and lower dopamine D2 binding ratios in patients with OCD relative to controls (Denys et al., 2003, Kim et al., 2003, van der Wee et al., 2001). The combined results of these receptor-binding studies provide circumstantial in vivo evidence for an increased dopaminergic activity in OCD patients.
Catechol-O-methyl transferase (COMT) is an enzyme that has a crucial role in the elimination of dopamine. Since COMT is involved in the inactivation of dopamine, and higher dopamine levels may be implicated in OCD, the COMT gene is an attractive candidate for OCD. The G→A transition in codon 158 of the COMT gene results in a valine to methionine substitution and is associated with a three- to fourfold decrease in enzyme activity (valine = high-activity, methionine = low-activity) (Lotta et al., 1995). It has already been reported by Karayiourgou et al. (1997) that the low-activity COMT (COMT L) allele occurs significantly more frequently in male OCD patients, but opposing results have also been obtained (Erdal et al., 2003, Karayiorgou et al., 1999, Ohara et al., 1998). In addition, one might theorize that lower densities of the D2 receptor in OCD patients are caused by genetic factors. The A1 allele of TaqI A polymorphism in the D2 receptor (DRD2) gene locus has been suggested to be associated with reduced DRD2 receptor densities (Hitzemann, 1998, Jonsson et al., 1999). Data on the DRD2 TaqI A polymorphism in OCD are limited, but Nicolini et al. found a higher frequency of the DRD2 TaqI A2 allele in a small subgroup of OCD patients (n = 12) with tics, when compared to controls (Nicolini et al., 1996).
In light of the putative role of the dopamine system, and in particular the dopamine D2 receptor in OCD, we tested the frequency of alleles and the distribution of genotypes of the DRD2 receptor TaqI A and of COMT genes in an OCD sample of 150 patients. As a control population, we tested 150 ethnically matched Caucasian subjects. As there is evidence for gender specificity of the D2 receptor and COMT gene and because previous findings have suggested gender differences in the clinical manifestation of OCD, males and females were analyzed separately (Castle et al., 1995, Kaasinen et al., 2001, Karayiorgou et al., 1999, Lensi et al., 1996). We firstly hypothesized that OCD patients would have higher frequencies of the COMT L allele, resulting in higher synaptic dopamine levels. Secondly, we hypothesized that OCD patients would have higher frequencies of the DRD2 receptor TaqI A1 allele, resulting in lower synaptic D2 receptor density.
Section snippets
Study sample
The patient sample comprised 159 unrelated patients with OCD from consecutive referrals to the anxiety research unit of the department of psychiatry at the University Medical Centre Utrecht, who gave written informed consent for participation in this study that had been approved by the University of Utrecht Medical Ethical Review committee (Utrecht, The Netherlands). All patients were diagnosed with OCD according to DSM-IV criteria and the M.I.N.I., a clinical and structured interview, was used
Results
The patient sample was slightly skewed towards the female population (63%) with a mean ± S.D. age at admission of 36.0 ± 11.0 years for both sexes. The mean age at onset of obsessive–compulsive symptoms in our sample was 17.7 ± 8.3 years, with a length of illness of 18.0 ± 11.0 years at entry. Males had a significantly earlier onset of illness than females (15.7 ± 8.0 years and 19.0 ± 8.3 years, respectively) (χ2 = 5.85, df = 1, p = 0.016). The mean Y-BOCS score for the whole sample was 24.9 ± 5.7, with a mean
Discussion
The findings of this study provide evidence for an association between the DRD2 TaqI A2 allele and the low-activity COMT allele on the one hand, OCD on the other, in male OCD patients.
Two previous studies have examined the association between the DRD2 TaqI A system and OCD. Nicolini et al. found no association in 67 patients with OCD, but observed a higher frequency of the A2 allele in a subgroup of OCD patients with tics (n = 12) (Nicolini et al., 1996). Billet et al. (1998) did not find an
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