Genetic Studies of ADHD in Chinese Children

Professor Patrick W. L. Leung
Ph.D., University of Sheffield
Professor, Department of Psychology
The Chinese University of Hong Kong

Seminar

Two pilot studies on the genetics of ADHD in Chinese children will be presented. First, a twin study, involving a community sample, was conducted in Mainland China. However, the heritability estimates varied according to the characteristics of the participants included. A subset of the sample with severer inattentive, hyperactive, and impulsive problems gave higher heritability estimates comparable to those found in the Western studies. Second, a molecular genetic study was conducted with a clinic sample of Chinese ADHD children in Hong Kong. We used a candidate gene approach and examined the 48-base-pair (bp) variable number of tandem repeats (VNTR) in the exon III of the dopamine receptor D4 (DRD4) gene located on chromosome 11p15.5. Using a case-control design, we found a significantly increased prevalence of the 2-repeat (2R) allele in our ADHD probands. This association between the 2R allele and ADHD was reconfirmed using a family-based design. Analysis by haplotype relative risk test (HRRT) and transmission disequilibrium test (TDT) indicated a preferential, biased transmission of the 2R allele from the parents to the probands. Contrarily, no such biased transmission was found with the 10R allele in the 3’ untranslated region of dopamine transporter (DAT1) gene. This finding regarding the 2R allele had not been reported before in the literature. In the European-ancestry children, the association was instead found between the 7R allele and ADHD, but the frequency of the former was very low in Asian children. The Chinese ADHD probands in our study simply did not have any 7R allele at all, in line with its very low frequency in the general population. However, analysis by gene sequencing suggested that the 2R allele in Asians was likely to be derived from the 7R allele, judging from the adjacent single-nucleotide polymorphisms (SNPs). Furthermore, available biochemical data indicated that both the 2R and 7R protein had blunted responses to dopamine compared to the 4R protein. Based on these results, we proposed that the observed association between the 2R allele and ADHD in our Chinese probands was still consistent with the 7R allele hypothesis of ADHD in European-ancestry children. Perhaps, any variant from the conserved ancestral 4R allele might potentially alter biochemistry/phenotype. We hypothesized that an increased frequency of any non-4R allele might define the association of the DRD4 gene with ADHD that held across ethnicity. This presentation ends with a discussion of the challenges ahead in our line of research in ADHD.