Scientific Correspondence | Published:

An association between fibromyalgia and the dopamine D4 receptor exon III repeat polymorphism and relationship to novelty seeking personality traits

Molecular Psychiatryvolume 9pages730731 (2004) | Download Citation


  • An Erratum to this article was published on 27 September 2004
  • A Corrigendum to this article was published on 25 October 2004

SIR – Fibromyalgia (FM) is a common syndrome consisting of diffuse aching, pain, or stiffness in the muscles or joints, accompanied by multiple tender points on examination and the clinical profile includes many comorbid psychiatric symptoms as well as an atypical personality profile characterized by high harm avoidance (HA) and low novelty seeking (NS).1, 2 We have reported a higher frequency of the short promoter region of the serotonin transporter (HTTLPR), associated in some studies with both anxiety-related personality traits and stress-related depression, in FMS patients confirming a previous study.2, 3 A second gene widely studied in personality genetics is the dopamine D4 receptor (DRD4), characterized by a highly polymorphic repeat (2–9 repeats of 48 bp) region in its third exon; the 7 repeat was initially associated with NS in some4, 5 but not all studies.6 Reduced NS scores in FM patients,2 prompted us to characterize the DRD4 exon III repeat region in a group we had previously investigated regarding HTTLPR.2 Altogether, we genotyped 81 female patients and 458 female control subjects.

As we predicted, a significant decrease in the frequency of the 7 repeat genotype was observed in the FM patients (χ2=29.91, P=0.008, 14 df) (Table 1, Part a). Note that the two most common genotypes are the 4/4 repeat followed by the 4/7 repeat as has been observed in most Caucasian populations. No difference in the frequency of the 7 repeat was observed in the control group when grouped by ethnicity (data not shown: likelihood ratio=2.39, P=0.302 comparing Ashkenazi Jews, non-Ashkenazi Jews and Bedouin). When the genotype was collapsed into subjects with at least one 7 repeat vs ‘all others’ (no 7 repeat) the frequency of the 7 repeat was significantly reduced (39.5 vs 27.2%) in the FM subjects (data not shown: χ2=4.478, P=0.034; OR=1.62 95% CI {1.025–2.56}). Finally, we cross tabulated both polymorphisms by diagnosis (Table 1, Part b) and observed a significant association of the DRD4 exon III repeat region and FM solely in subjects with the HTTLPR short deletion (χ2=16.56, P=0.01, 2 df) but not with the promoter long insertion (χ2=3.86, P=0.70, 2 df).

Table 1 Cross tabulation of DRD4 and HTTLPR genotypes by diagnosis

We also had information regarding tridimensional personality questionnaire (TPQ) temperament scores and as previously reported marked differences are observed between patients and controls; see Cohen et al2 for reference values. Patients score higher on HA,2 lower on NS and higher on persistence. In the current control population, no association was observed between NS and the 7 repeat. However, in the phenotypically extreme, albeit smaller, FM group a significant association was observed (one-way ANOVA: F=4.47, P=0.038). Patients with at least one 7-repeat had higher NS scores (7 repeat NS=14.57±3.26 SD vs ‘all others’ NS=12.72±3.49 SD). Multivariate tests of significance showed a significant three-way interaction between personality trait, diagnosis and HTTLPR & DRD4 (Hotelling's Trace=2.517, P=0.04). We have previously observed an interaction between the DRD4 and HTTLPR genes on NS in a large nonclinical sample.7

Women suffering from FM show an unusual personality profile compared to control subjects. It makes sense, therefore, that provisional associations between genes associated with personality traits in nonselected populations will show stronger associations in an extreme phenotypic group such as FM. The current study strengthens this notion. We observed a decreased representation of the DRD4 7 repeat in a small group of FM patients characterized by unusually low scores on NS as measured by a self-report personality inventory, the TPQ. Moreover, an association was also observed between TPQ NS scores and the 7 repeat only in the FM group: subjects with the 7 repeat had significantly higher scores than subjects without this repeat, but nevertheless significantly lower than the control group. Altogether, recent evidence including the current investigation suggests an involvement of both serotonergic2, 3 as well as dopaminergic8 neurotransmitter pathways in FM likely mediated by personality traits.


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  1. Department of Medicine, Rheumatic Disease Unit, Soroka Medical Center, Beer Shera, Israel

    • B Dan
  2. Ministry of Health Mental Health Center, Anxiety and Stress Research Unit, Beer Shera, Israel

    • C Hagit
  3. Epidemiology Department, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel

    • N Lily
  4. Psychology Department, Scheinfeld Center for Human Genetics in the Social Sciences, Hebrew University & Herzog Hospital, Jerusalem, Israel

    • R P Ebstein


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Correspondence to R P Ebstein.

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