Family-based association study of DRD4 gene in methylphenidate-responded Attention Deficit/Hyperactivity Disorder

Abstract

The 48-basepair (48-bp) variable number tandem repeat (VNTR) polymorphism in exon 3 of the dopamine receptor D4 gene (DRD4) is implicated in the etiology of attention-deficit/ hyperactivity disorder (ADHD). In particular, ADHD in European-ancestry population is associated with an increased prevalence of the 7-repeat (7R) allele of the exon 3 VNTR. However, it is intriguing to note that the 7R allele has been found to be of very low prevalence in the Chinese general population. In a previous case-control study, our research team had found that the 7R allele was similarly absent in Chinese ADHD children in Hong Kong. Instead, there was an increased prevalence of the 2R allele in Chinese ADHD children. Interestingly, in Asian samples, the 2R allele had been found to be an evolutionary derivative of the 7R allele with equivalent biochemical functionality. So, the finding of an association between ADHD and 2R allele in Chinese population does not exactly contradict the original 7R allele finding in European-ancestry population. However, given the potential pitfall of population stratification in the previous case-control design, this current study tested the 2R allele and ADHD association using a methodologically more rigorous family-based approach on 33 Chinese ADHD probands who had favorable clinical responses to stimulant medication (methylphenidate). Haplotype Relative Risk (HRR) analysis and Transmission Disequilibrium Test (TDT) both showed a significant preferential transmission of the 2R allele from the biological parents to ADHD probands (pone-tailed = 0.038, OR = 2.04; pone-tailed = 0.048, OR = 2.29, respectively). A second hypothesis speculates that it is the deviation, including 7R and 2R alleles, from the conserved ancestral 4R allele which confers risk to ADHD. Thus, a preferential transmission of non-4R alleles, against the 4R allele, from biological parents to their ADHD probands is predicted. Both HRR analysis and TDT confirmed such prediction (pone-tailed = 0.029, OR = 2.07; pone-tailed = 0.032, OR = 2.43, respectively). This study re-confirmed the original finding of a previous study that in Chinese population, the 2R allele of the DRD4 exon 3 VNTR was related to ADHD. This endorses the general thesis that DRD4 exon 3 VNTR polymorphism is related to ADHD, despite that the exact length or number of repeats of the associated alleles varies across ethnicity. This in turn supports the dopamine dysregulation theory of ADHD.

Genetic Variation Underpinning ADHD Risk in a Caribbean Community

“…Family-based designs are robust against population admixture and stratification, and allow conducting complex segregation analysis and linkage and association studies that would be next to impossible in case/control-based designs [32,61,62,63]. With few exceptions [64,65,66,67], recent genetic studies on ADHD have primarily focused on case/control-based designs to study genetic contributions to ADHD susceptibility [15,16,18,68,69,70].…”

Drug Regimen Individualization for Attention‐Deficit/Hyperactivity Disorder: Guidance for Methylphenidate and Dexmethylphenidate Formulations

“…Several candidate genotypic variants have been identified as associated with positive MPH response. For instance, (i) specific polymorphisms in the gene expressing synaptosomal associated protein of 25 kDa (SNAP‐25), a common gene candidate underlying ADHD, have been shown to correlate with the likelihood of MPH efficacy; (ii) also an allelic variant of SLC6A2 , which expresses the norepinephrine transporter, correlates with positive response to MPH; (iii) the Val 66 Met phenotypic variant of brain‐derived neurotrophic factor, a neuronal gene product that facilitates fiber connections and memory, has been predictive of MPH efficacy; (iv) specific indel allelic variants of the gene expressing the D4 dopamine receptor subtype, considered risk alleles for ADHD, have also been associated with an increased probability of MPH efficacy; (v) as have specific indel variants expressing the dopamine transporter (DAT) …”

No relationship between dopamine D3 receptor gene Ser9Gly polymorphism (rs6280) and schizophrenia: a meta-analysis of family-based association studies

“…Methodologically, it uses a more rigorous approach than the population-based study. 53 There are two limitations in our current meta-analysis. Initially, we detected a slight but significant publication bias in the HHRR studies.…”