Comments on “Novelty seeking and the dopamine D4 receptor gene (DRD4) revisited in Asians: Haplotype characterization and relevance of the 2‐repeat allele” by C. Reist et al. Am J Med Genet B Neuropsychiatr Genet 2007;144(4):453–457

Reist et al. [2007] reported an investigation of the association between the novelty-seeking personality trait and the dopamine D4 receptor gene (DRD4). The authors criticized the previous association studies in Asian populations that have invariably categorized the DRD4 VNTR data based on length (comparing 2-repeat [2R], 3R, and 4R alleles with 5R, 6R, and 7R alleles) [Ono et al., 1997; Tomitaka et al., 1999; Lee et al., 2003a,b; Tsai et al., 2004], because there are research findings of evolutionary and functional (e.g., diminished potency to reduce cAMP) similarities between the 2R and 7R alleles of the DRD4 [Asghari et al., 1995; Ding et al., 2002]. They suggested that grouping the 2R and 7R alleles together will facilitate detection of biologically meaningful and reproducible association findings with behavioral traits. They reported that in their Korean sample (N1⁄4 73; 46 males, 27 females; age range: 18–30 years), subjects with a 2R and/or a 7R allele scored significantly higher on a novelty-seeking scale, whereas grouping the VNTR alleles by size (2R, 3R, and 4R alleles vs. 5R, 6R, and 7R alleles), as has been done in similar studies of Asian subjects, revealed no significant association [Reist et al., 2007]. According to their suggestion, I have reanalyzed the data used in our previous paper [Lee et al., 2003b], in which we reported that carriers of long repeat (5R, 6R, and 7R) alleles of the DRD4 showed significantly higher novelty-seeking scores. The reanalysis revealed that this relationship was not present between carriers of the 2R and/or 7R allele and the other subjects (Table I). Our sample comprised 173 alcoholand other-drug-naı̈ve Korean young female subjects (age: 13.9 0.29 years; mean SD), which represented a homogeneous group in terms of ethnicity, gender, and age. Reist et al. [2007] insisted that the 2R allele is a subsequence derivation from a 7R/4R recombination evolutionally [Ding et al., 2002], and that the 2R and 7R alleles have similar functional activity [Asghari et al., 1995]. However, Asghari et al. [1995] reported that the potency of dopamine to inhibit cAMP formation was about twofold lower for 7R (half-maximal effective concentration [EC50] of approximately 37 nM) than for 2R and 4R (EC50s of approximately 19 and 14 nM, respectively) [Asghari et al., 1995], suggesting that the 2R allele showed similarity with the 4R allele and not with the 7R allele. Furthermore, even though the 2R variant may be a derivative of a recombination event between the 4R and 7R variants [Ding et al., 2002], the functional activities of recombinant variants differ from evolutional events. Considering the subsequent protein structure changes by genetic variation, DRD4 VNTR variants bring about differences in the length of the third cytoplasmic loop region of the DRD4 [Van Tol et al., 1992]. The 7R variant associated with a long third cytoplasmic loop exhibits a blunted response to cAMP reduction, and requires a threefold increase in dopamine concentration for reductions comparable to those for the 2R and 4R variants. Therefore, the long third cytoplasmic loop region by long DRD4 variants was