Original Research Article

Molecular Psychiatry (2004) 9, 711–717. doi:10.1038/sj.mp.4001466 Published online 16 December 2003

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

V Kustanovich1, J Ishii1, L Crawford1, M Yang2, J J McGough2,3, J T McCracken2,3, S L Smalley2,3 and S F Nelson1,2,3

  1. 1Department of Human Genetics, Division of Child and Adolescent Psychiatry, UCLA School of Medicine, University of California, Los Angeles, USA
  2. 2Center for Neurobehavioral Genetics, Division of Child and Adolescent Psychiatry, UCLA School of Medicine, University of California, Los Angeles, USA
  3. 3Department of Psychiatry and Biobehavioral Sciences, Division of Child and Adolescent Psychiatry, UCLA School of Medicine, University of California, Los Angeles, USA

Correspondence: Dr SF Nelson, Department of Psychiatry and Biobehavioral Sciences, Division of Child and Adolescent Psychiatry, UCLA School of Medicine, University of California, Los Angeles 90095, USA. E-mail: snelson@ucla.edu

Received 19 April 2001; Revised 25 June 2001; Accepted 31 July 2001; Published online 16 December 2003.

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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 (chi2=7.58, P=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=0.02) and a trend toward excess transmission of the 148-bp allele (P=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.

Keywords:

attention-deficit hyperactivity disorder, transmission disequilibrium test, DRD4, DRD5, DAT1, DRD2, neuropsychiatric genetics

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Introduction

Attention-deficit hyperactivity disorder (ADHD) is the most prevalent psychiatric disorder of childhood, affecting approximately 5% of school-aged children.1 Symptoms of inattention and hyperactivity begin before the age of 7 and often continue into adolescence and adulthood.2 ADHD diagnoses are made along two primary symptom dimensions, inattention and hyperactivity/impulsivity.3 ADHD symptoms are often associated with difficulties in education as well as family and peer relationships. Furthermore, comorbid psychiatric disorders, including disruptive behavior, anxiety and mood disorders are common in ADHD individuals4, 5, 6 exacerbating difficulties. Stimulant medications, in combination with behavior therapy, have emerged as highly effective therapeutics for the management of disease symptoms.7 However, a subgroup of individuals with ADHD do not respond to stimulant medication or suffer significant side effects, and the effectiveness is variable among responders. Given the high prevalence of ADHD, these factors provide a strong motivation to further refine the diagnosis and treatment, and to understand the etiology of this disorder. Evidence from twin and adoption studies have implicated that ADHD is familial and most likely has a significant genetic component, with heritability estimated between 0.64 and 0.98.8, 9, 10

A prevailing neurochemical hypothesis of the course of ADHD underlines an involvement of alterations in dopaminergic innervation. This hypothesis of hypodopaminergic activity is based largely on the positive response to stimulant medications and their effect on increasing extracellular levels of dopamine11 as well as mouse and neuroimaging studies. Therefore, genes within dopamine metabolism and signaling pathways have been considered prime candidates and thus subjected to tests of association with ADHD. Polymorphisms in DRD4, DAT1, DRD2 and DRD5 have been widely studied.12, 13, 14, 15, 16, 17, 18 While positive and negative findings exist, viable reasons for between-study inconsistencies include insufficient power to detect the involvement of genes of small effect, genetic and etiologic heterogeneity of ADHD, and different study designs and sample characteristics.

The dopamine receptor, DRD4, is expressed at its highest density in the prefrontal cortex.19 This is an area known to be involved in executive functioning, a cognitive task adversely affected in ADHD individuals and in regions highlighted by MRI investigations of ADHD.20, 21, 22 Numerous studies have been published regarding the putative association of the DRD4 48-bp variable number tandem repeat (VNTR) and ADHD. DRD4.7 has been found by a majority of groups to be associated with ADHD, in both case–control and family-based association studies.18, 23, 24, 25, 26, 27, 28 Furthermore, a meta-analysis of these studies supported an association, albeit with a small relative risk (approx1.4) for the DRD4.7 allele.29 In addition, DRD4.7 has been suggested to be associated with novelty seeking,24, 25, 30, 31, 32 and has been associated with ADHD, as well. Other studies have examined the association of ADHD with a 120-bp insertion polymorphism in the DRD4 region (DRD4.240).33, 34 However, others have not found an association between ADHD and DRD4.7 or DRD4.24031, 35, 36, 37, 38.

Two additional dopamine receptors had been investigated for association with ADHD. The dopamine receptor, DRD2, is a G-protein coupled receptor that inhibits adenylate cyclase activity. DRD2 has been suggested as a potential candidate for ADHD and related disorders since 1991.14, 39, 40, 41 However, Rowe et al12 did not identify any association of this gene (and specifically the Taq1 polymorphism) with ADHD. Finally, Kirley et al42 did not identify an association of ADHD with DRD2.

The dopamine receptor, DRD5, is also a G-protein coupled receptor. However, this receptor stimulates adenylyl cyclase activity and is expressed in the limbic area of the mammalian brain. A dinucleotide repeat polymorphism near DRD5 was investigated by Daly et al16 and Barr et al,15 who found different alleles associated with the same polymorphic genetic marker. Subsequently, Tahir et al18 carried out a transmission disequilibrium test (TDT)43 study of DRD5 and did not find either set of alleles significantly associated with ADHD. However, the DRD5.148 allele showed a trend toward significance, thus prompting a meta-analysis by Maher et al,44 which did not identify a significant amount of excess heterogeneity in the four previously published works, indicating a lack of association. Kirley et al,42 however, found a significant association of ADHD and the DRD5.148 allele in a haplotype-based haplotype relative risk study. Most recently, Hawi et al45 identified a significant association between not only the DRD5.148 allele but also a haplotype consisting of this allele and proximal SNP and other microsatellite markers.

Dopamine Transporter 1(DAT1) interacts directly with methylphenidate and mice homozygous for a DAT1 deletion exhibit hyperlocomotion. Thus, variants in DAT1 are candidate susceptibility alleles. The 40-bp VNTR in DAT1 was found to be associated with ADHD by Cook et al,46 and subsequently replicated by others.47, 48, 49 A few groups, including our own, have failed to replicate the DAT1 association with ADHD in samples with sufficient power to detect small effect sizes.50, 51

While heritable, the available genetic data from candidate gene studies and genome scan results indicate a polygenic model of inheritance.52, 53, 54 However, genome scan data in samples of 200–300 affected sibling pairs generally lack adequate power to detect candidate genes with small effect sizes, such as that estimated for DRD4. Here, we use our large mostly multiplex families to assess the relative contributions of DRD2, DRD5, DAT1 and DRD4 polymorphisms using the TDT, which is known to be a more powerful method than linkage analysis if one has putative candidate alleles available for analysis.55

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Materials and method

Subjects

This study was approved by the UCLA Human Subject Protection Committee. Written informed consents were obtained from all families participating in the study upon the initial visit. The sample consists of 293 families, including 535 affected individuals and their parents drawn from families ascertained through at least two affected siblings (n=241) and a sample of singleton families ascertained through a single affected offspring (n=52). The mean IQ of affected children was 105 (SD=15) and the mean age at study entry was 11 (SD=4). A summary of sample descriptions for this study is provided in Table 1


Assessments

The assessment procedure is described in detail elsewhere.56ADHD diagnosis was carried out according to the DSM-IV criteria. ADHD individuals meeting the full criteria were considered ADHD according to the narrow definition of ADHD, while those who fell one symptom short of full diagnosis were considered ADHD according to the broad definition. Furthermore, all probands and parents were interviewed and assessed for lifetime psychiatric disorders using the K-SADS-PL57 for children and adolescents, and the SADS-LA-IV58 for adults. Teacher and parent rating scales (SNAP-IV, CBCL, TRF) were used to supplement the structured interview data, and a best estimate procedure was used to determine diagnoses. The inter-rater reliability exceeded 0.98 for all ADHD diagnoses, 0.95 for conduct disorder, and 0.84 for 10 other major psychiatric diagnoses, which occurred at a frequency of 5% or higher in our sample.

Full-scale IQ was determined for all probands using either the WISC-III or the WAIS-R depending on age. Children with an IQ below 70 were excluded from all analyses. All evaluated children were screened using a family history interview in order to rule out the presence of any potentially confounding comorbid medical or genetic disorders. The families were predominately Caucasian (79%) and represented a range of SES classes based on Hollingshead rankings59 as follows: I (24%), II (35%), III (30%), IV (9%), and V (2%).

Genotyping

Blood samples were collected from family members, and genomic DNA was extracted from whole blood with the Qiagen Kit using the manufacturer's protocol (Qiagen, Valencia, CA, USA).

The DRD4 120-bp insertion/deletion polymorphism was assayed according to the methods described elsewhere.33 The DRD4 48-bp repeat polymorphism was genotyped as follows. PCR amplification of 50 ng of genomic DNA was performed in 20 mul reactions containing 0.3 mM dNTPs, 0.4 muM of forward and reverse primers, 10 mM Tris (8.4 pH), 50 mM KCl, 1.5 mM MgCl2, 1 times Q solution, and 1 U of HotStar Taq DNA polymerase (Qiagen, CA, USA). The primer sequences used were: DRD4F, 5'-CTA CCC TGC CCG CTC ATG-3'; DRD4R, 5'-CCG GTG ATC TTG GCA CGC-3'. Using the MJ Research Tetrad thermal cycler, DNA was denatured at 95°C for 15 min, followed by 10 cycles of 95°C (30 s), 66°C (30 s), and 72°C (90 s), and 25 cycles of 95°C (30 s), 55°C (30 s), and 72°C (90 s), followed by a final extension at 72°C for 10 min. A measure of 10 mul of PCR products were electrophoresed in 3.5% Nusieve Agarose in 1 times TBE buffer for approximately 4 h at 70 V. The gels were stained with ethidium bromide and the alleles were determined by comparison with molecular weight standards and with control individuals with previously determined genotypes.

The DAT1 40-bp repeat polymorphism was genotyped as described elsewhere.51

The DRD2 TAQA1 polymorphism was genotyped by PCR, restriction digest and elecrophoresis. PCR amplification of 60 ng of genomic DNA was carried out in a volume of 25 mul containing 4.375 U of KlenTaq DNA polymerase (Klentaq, St Loius, MO, USA), 10 mM Tris (8.4 pH), 50 mM KCl, 3 mM MgCl2, 0.2 mM dNTPs, and 0.64 muM of forward and reverse PCR primers: DRD2-TAQ1F, 5'-CCG TCG ACG GCT GGC CAA GTT GTC TA-3'; DRD2-TAQ1R, 5'-CCG TCG ACC CTT CCT GAG TGT CAT CA-3'. DNA was denatured at 94°C for 3 min followed by 31 cycles of 94°C for 1 min, 56°C for 1 min, and 72°C for 1.5 min, completed with a 5-min extension at 72°C. An aliquot of 5 mul of PCR product was digested for approximately 15 h in a 20 mul volume consisting of 1 times TAQ A1 buffer, 2 mug BSA, and 10 U TaqA1 restriction enzyme. Electrophoresis of the sample was carried out on a 2.5% agarose gel in 1 times TBE and detected with ethidium bromide staining. The genotyping of this polymorphism is a modification of a method published by Dietz and Comings.60

The DRD5-PCR1 polymorphism was amplified with fluorescently tagged PCR primers (DRD5-PCR1F: 5'-CGT CTA TGA TCC CTG CAG-3'; DRD5-PCR1R: 5'-GCT CAT GAG AAG AAT GGA GTG-3') in a multiplex PCR reaction according to the methods described previously.53 Electrophoresis of PCR products was carried out on an ABI 3700 instrument and genotypes were gathered using the Genescan and Genotyper software (Applied Biosystems, Foster City, CA, USA).

Data analysis

The program sib_tdt, part of the ASPEX genetic analysis package, was used to calculate the asymptotic McNemar test for linkage disequilibrium of each of the candidate gene polymorphisms. Each of the previously reported risk alleles was assessed for biased transmission in comparison with all other alleles. Multiple affected siblings from the multiplex families were genotyped and included in the TDT. All affected children were used in the analyses and corrections for multiple siblings were achieved by calculating empirical P-values according to Lazzeroni and Lange,61 which uses a permutation procedure for the calculation of an association in the presence of linkage.

The genotype relative risk (GRR) ratios were calculated according to Risch and Merikangas55 from the TDT tables. Genotype inconsistencies were identified using MENDEL.62 Univariate analyses were conducted using SAS Version 6.12.63

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Results

Power calculations were carried out to determine the minimum GRR that could be detected based on the actual number of informative meioses for each polymorphism tested.55 We computed the minimum GRR that could be detected for each polymorphism using 80% power and a Type I error of 0.05. As shown in Table 2, we have sufficient power to detect a GRR of 1.5 or greater for all loci, except the relatively rare hypothesized risk allele DRD5.146 and DRD5.136 at the DRD5 gene at which power was sufficient to detect a minimum GRR of 1.68 and 2.8, respectively.


Two polymorphisms were genotyped in the DRD4 gene in order to test the transmission disequilibrium in ADHD and extend our earlier findings.33, 23 Our previous evaluations of the DRD4 gene polymorphisms were conducted in a sample of 197 families, in which 210 informative meioses were available for DRD4.7 and 241 informative meioses for DRD4.240. The current sample consists of 138 additional independent families, including 78 additional informative meioses at DRD4.7 and 53 additional informative meioses at DRD4.240. As shown in Table 3, DRD4.240 continues to show a significant association with ADHD (chi2=7.58, P=0.006); however, the finding is largely driven by the earlier set of families with a marginal trend toward biased transmission in the 53 new meioses (chi2=1.88, P=0.17).


The estimated GRR from the total sample is 1.37 for this polymorphism, with the common 240 variant providing risk toward ADHD. The previously reported association of the DRD4.7 allele falls short of significance in the larger data set, although a trend continues to be evident (chi2=2.21, P=0.137). The estimated GRR for this polymorphism is 1.4. As reported previously,33 there is a significant linkage disequilibrium between the DRD4 promoter polymorphism and the DRD4 48-bp repeat (P=0.05), but the haplotype analysis does not reveal any significant biased transmission of the DRD4.240/DRD4.7 haplotype variant (chi2=2.61, P=0.106).

As shown in Table 3, biased nontransmission of the 146-bp allele is seen at the DRD5 dinucleotide repeat polymorphism. The previously reported 'protective' 146-bp allele15 was under-represented among transmitted alleles (P=0.02), while a trend emerged for increased transmission of the DRD5.148 allele (P=0.053), also consistent with prior reports.16 Another putative risk allele reported by Barr et al,15 the DRD5.136, showed no significant biased transmission (P=0.178), but the small number of informative meioses (N=27) makes extrapolation from either our study or that of Barr et al,15 difficult. Previous findings of association prompted the analysis of the association of these particular alleles with ADHD susceptibility. However, a locus-wise TDT has been carried out in order to examine the association of the DRD5 locus with ADHD. In such an analysis, the sum of chi2 of 16 alleles is chi2=19.27 (P=0.231) and the maximum of chi2 is chi2=4.77 (P=0.270).

No evidence of bias in the transmission of the previously reported risk allele 480-bp allele of the 40-bp VNTR in DAT1 is evident in the extended sample as shown in Table 3. The current sample contains 131 additional families over our previous report,51 and there is no evidence of an association in the subset of new families (chi2=0.29, P=0.591) or the extended sample. Lastly, we see no transmission bias of alleles at the DRD2-TaqI polymorphism (chi2=0.30, P=0.583).

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Discussion

In the present study, we sought to test for an association of ADHD and four previously suggested risk genes in the dopamine regulatory system. The size of our sample allowed for adequate power to detect associations of small effect and should be relatively robust to stochastic fluctuations, which may force other studies, with smaller samples to conclude that associations exist where they do not.

The results of our study continue to support the fact that the DRD4 gene plays a minor role in ADHD susceptibility, although this conclusion is somewhat complicated by the contradictory evidence from the two polymorphisms examined in this study. The DRD4.240 allele is associated with ADHD susceptibility in this sample, with an estimated GRR of 1.37. The DRD4.7 allele in the exon III 48-bpVNTR does not meet statistical significance in the extended sample, although a trend toward excess transmission of this allele is present and the estimated GRR is 1.4, similar to that reported by Faraone et al,29 in their meta-analysis, which included a subset of our ADHD families. A recent extensive analysis of the haplotype structure of DRD4, with a special focus on the exon III repeat polymorphism,64 found that DRD4.7 was a relatively new allele. While alleles with two through six repeats could be explained by one-step recombination of the most common four repeat allele, the seven repeat allele required multiple recombination and mutation events, indicating that it is significantly 'younger' than the other alleles. The authors speculate that the reason for the dramatic increase in the allele frequency of the DRD4.7 allele may be positive selection due to a hypothesized effect of this allele on human behavior. Ding et al64 further found that there was a great deal of linkage disequilibrium between the DRD4.240 allele and the DRD4.7 allele, such that some 90.8% of DRD4.7 alleles are associated with the DRD4.240 form of the 120 bp insertion/deletion. This indicates that while the haplotype analysis does not help to resolve the risk variant at DRD4 in ADHD, DRD4.7, DRD4.240, and/or another polymorphism in linkage disequilibrium may account for the observed association. In the light of these findings, additional effort directed at identifying DNA variants at DRD4 that alter expression or function are needed.

Previous investigations identified associations between ADHD and variants of a polymorphism located near the DRD5 gene.15, 16, 18, 42, 45 While Daly et al found that a 148-bp allele was preferentially transmitted to affected offspring, Barr did not identify this excess of transmission, but rather found that two minor alleles of this same polymorphism displayed a preferential lack of transmission to affected offspring. We examined the same polymorphism and found a trend consistent with Daly et al's finding of increased transmission of the 148-bp allele and a significant lack of transmission of the 146-bp to affected offspring. The distortion was of approximately the same magnitude as that reported by Barr et al.15 In contrast, we found no evidence of a lack of transmission of the minor 136-bp allele reported by Barr et al,15 but the number of informative meioses for this analysis (n=27) suggests that low power may play a role. These data suggest that the DRD5 gene likely plays a minor role in susceptibility to ADHD, but that additional work looking at functional variants is needed.

We found no evidence in our sample for an association of ADHD with a DAT1 VNTR polymorphism, despite an 80% power to detect a GRR of 1.4 or greater. Multiple groups46, 47, 48, 49 have reported associations of ADHD with polymorphisms within the DAT1 gene. Notably, DAT1 was one of the first genes suggested for involvement in the etiology of ADHD because of its interaction with the highly effective pharmacological agent, methylphenidate.46 However, we have consistently found no evidence of a role of the DAT1 gene in our ADHD families. At least in largely multiplex families, DAT1 does not appear to contribute to the susceptibility to ADHD. However, future experiments should examine other polymorphisms in this gene in order to form discrete haplotypes and examine the transmission of that haplotype. For example, an examination by Barr et al found an association with a haplotype of this gene where analysis of the VNTR had found none.65

There was no evidence that the DRD2 Taq1 polymorphism plays a role in ADHD in the current investigation. Prior investigations have shown a role for this polymorphism with a variety of psychiatric and behavioral phenotypes, including Tourette syndrome,40, 60 impulsive behaviors,66, 67 pathological gambling,68 and ADHD.12, 42, 69 Despite the existence of multiple reports regarding the involvement of this gene in impulsive behaviors, including ADHD,14, 40, 41, 70 we see no evidence of transmission distortion in our sample, despite adequate power to detect a relatively small GRR of 1.43. As many of the previous reports identified an association of this DRD2 polymorphism with impulsive phenotypes, we tested the subgroup of ADHD children with the Combined or Hyperactive-Impulsive subtypes in which at least five symptoms of hyperactivity or impulsivity were evident. The restriction to subtypes with hyperactive-impulsive behaviors did not reveal any evidence of involvement in ADHD (chi2=0.01, transmitted/nontransmitted=45/46).

It should be noted that this sample was predominantly composed of multiplex families, which differ somewhat from other studies compared herein. These studies were often carried out using simplex families and this may account for some of the differences identified.

The genes evaluated in this study were compared with regions highlighted by genome-wide scans in ADHD. As discussed by Ogdie et al,54 no regions containing the putative candidates evaluated in the present study were excluded for effect sizes estimated for such candidates (eg GRR of 1.5). Conversely, no region containing the candidates under investigation in the present study show evidence of linkage in the genome-wide scan studies, supporting the idea that that their role in ADHD, if confirmed through functional analysis, is likely to be of very minor effect.

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Acknowledgements

This work was supported by National Institute of Mental Health Grants MH58277 (to SLS), MH01969 (to JJM), MH01805 (to JTM), and USPHS National Research Service Award GM07104 (to VK). Thanks to all the families who participated in this research and to Elva Rios, Tae Kim, Laura Combs, Leah Pressman, PhD, and Deborah Lynn, MD, for their help in data collection and to Dr Dennis Cantwell, who inspired our work on ADHD.

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