Transmission disequilibrium testing of dopamine-related candidate gene polymorphisms in ADHD: confirmation of association of ADHD with DRD4 and DRD5

Abstract

Attention-deficit hyperactivity disorder (ADHD) is one of the most common childhood behavioral disorders. Genetic factors contribute to the underlying liability to develop ADHD. Reports implicate variants of genes important for the synthesis, uptake, transport and receptor binding of dopamine in the etiology of ADHD, including DRD4, DAT1, DRD2, and DRD5. In the present study, we genotyped a large multiplex sample of ADHD affected children and their parents for polymorphisms in genes previously reported to be associated with ADHD. Associations were tested by the transmission disequilibrium test (TDT). The sample is sufficient to detect genotype relative risks (GRRs) for putative risk alleles. The DRD4 gene 120-bp insertion/deletion promoter polymorphism displayed a significant bias in transmission of the insertion (v 2 ¼ 7.58, P ¼ 0.006) as suggested by an analysis of a subset of these families. The seven repeat allele of the DRD4 48-bp repeat polymorphism (DRD4.7) was not significantly associated with ADHD in the large sample in contrast to our earlier findings in a smaller subset. We replicate an association of a dinucleotide repeat polymorphism near the DRD5 gene with ADHD by showing biased nontransmission of the 146-bp allele (P ¼ 0.02) and a trend toward excess transmission of the 148-bp allele (P ¼ 0.053). No evidence for an association was found for polymorphisms in DRD2 or DAT1 in this sample. The DRD5 146-bp (DRD5.146) allele and the DRD4 240-bp (DRD4.240) allele of the promoter polymorphism emerge as the two DNA variants showing a significant association in this large sample of predominantly multiplex families with ADHD, with estimated GRRs of 1.7 and 1.37, respectively.

Animal models of attention deficit/hyperactivity disorder (ADHD): a critical review

“…Another polymorphism that has been associated with the D 4 receptor, and ADHD is located in the promoter region of this gene. Some studies have found an association between ADHD and the 240-bp-allele in the promoter region of the D 4 receptor gene (Kustanovich et al 2004;McCracken et al 2000) while other studies were not able to confirm this association (Barr et al 2001;Todd et al 2001). Other authors have suggested a role of the D 5 receptor (Daly et al 1999;Fisher et al 2002) or the D 1 receptor (Cook et al 1995;Daly et al 1999;Gill et al 1997;Waldman et al 1998).…”

Association of Adult Attention Deficit Hyperactivity Disorder With Dopamine Transporter Gene, Dopamine D3 Receptor, and Dopamine D4 Receptor Gene Polymorphisms

“…We found that 4R allele and 4/4 genotypes are the most common in study and control groups. The results in the literature were also conflicting on this topic (33,34). Ethnicity is also an important factor in association of ADHD and DRD4 gene polymorphism.…”

The DRD4 receptor Exon 3 VNTR and 5′ SNP variants and mRNA expression in human post‐mortem brain tissue

“…Additionally, a 5 0 120-bp tandem duplication approximately 1.2 kb upstream of the initiation codon [Seaman et al, 1999] has been associated with ADHD as a single marker [McCracken et al, 2000;Kustanovich et al, 2004;Kereszturi et al, 2007] or as part of a haplotype [Barr et al, 2001;Mill et al, 2003;Lowe et al, 2004], although which allele is associated has shown conflicting findings. Evidence for involvement of the 120 bp repeat has also been presented for schizophrenia [Xing et al, 2003] and metamphetamine abuse [Li et al, 2004].…”