Dopamine receptor D4 (DRD4) gene in Han Chinese children with attention‐deficit/hyperactivity disorder (ADHD): Increased prevalence of the 2‐repeat allele

Abstract

There is an increased prevalence of the 7-repeat (7R) allele of the dopamine receptor D4 (DRD4) gene in attention-deficit/hyperactivity disorder (ADHD). However, the population prevalence of the 7R allele varies considerably across ethnicity and is very low in Asians. To test whether this 7R allele/ADHD association still held in a Chinese clinical sample, 32 Han Chinese children with a confirmed ADHD diagnosis and normal IQ who were methylphenidate-responders were genotyped. None of them had a DRD4 7R allele. Instead, we observed a significantly increased prevalence of the 2-repeat (2R) allele in this clinical sample (33%) compared to ethnically-matched controls (20%) (chi(2)(1d.f.) = 5.90, P = 0.015). This approximately 1.65-fold increase of the 2R allele in our probands is close to the observed increase of the 7R allele in European-ancestry ADHD children. Recent genetic studies have indicated that the 2R allele in Asians is likely derived from the 7R allele. Further, available biochemical data indicate that both the 2R and 7R protein have blunted responses to dopamine compared to the 4R protein. Based on these results, we propose that the observed increased prevalence of the 2R allele in our Han Chinese ADHD probands is still consistent with the 7R allele hypothesis of ADHD in European-ancestry children. Recent studies have suggested that any variant from the conserved ancestral 4R allele might potentially alter biochemistry/phenotype. We hypothesize that an increased frequency of any non-4R allele may define the association of the DRD4 gene with ADHD that holds across ethnicity. The present findings, however, obtained with a small ADHD sample size, should be replicated.

Association of 4-Repeat Allele of the Dopamine D4 Receptor Gene Exon III Polymorphism and Response to Methylphenidate Treatment in Korean ADHD Children

“…Recently, Leung et al (2005) reported a significantly increased prevalence of the 2-repeat allele at DRD4 in Han Chinese ADHD children, whereas none of them had the DRD4 7-repeat allele. In this context, it should be noted that a biochemical analysis conducted in a previous study demonstrated that the 7-repeat protein has a threefold reduced ability to reduce cAMP levels, as compared to the 4-repeat protein.…”

Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls

“…[44][45][46] Furthermore, it appears that it may not be just the 7R allele, but rather rare haplotypes that are associated with ADHD, as Wang et al 43 have shown that the 2R is derived from a recombination of a 4R and a 7R allele. In addition, Leung et al 47 have recently shown that in the Asian population it is not the 7R but rather the 2R that is associated with ADHD. Both alleles have been suggested to be less responsive to dopamine stimulation than the 4R 43 and may therefore have similar effects on neurobiological measures.…”

Dopaminergic D4 receptor polymorphism among 24 populations of India: an anthropological insight

“…Moreover, available biochemical data indicate that both the 2R and 7R proteins have blunted responses to dopamine as compared to that of the 4R protein (Leung et al, 2005). Despite such similarity in their biochemical manifestation, the 2R and 7R alleles show remarkable differences in their distribution patterns among various world populations: the 2R allele is more abundant among south and east Asian populations, including Indian populations, while the 7R allele is more widely distributed among the New World populations.…”