Association of the dopamine receptor D1 gene, DRD1, with inattention symptoms in families selected for reading problems

Twin studies have provided evidence for shared genetic influences between attention-deficit/hyperactivity disorder (ADHD) and specific reading disabilities (RD), with this overlap being highest for the inattentive symptom dimension of ADHD. Previously, we found evidence for association of the dopamine receptor D1 gene (DRD1) with ADHD, and with the inattentive symptom dimension in particular. This, combined with evidence for working memory (WM) deficits in individuals with RD or ADHD, and the importance of D1 receptors in attentional processes and WM function, suggests that DRD1 may be a common genetic influence underlying both disorders. Here, in a study of 232 families ascertained through probands with reading problems, we tested for association of the DRD1 gene with RD, as a categorical trait, and with quantitative measures of key reading component skills, WM ability, and inattentive symptoms. Although no associations were found with RD, or with reading component skills or verbal WM, we found evidence for association with inattentive behaviour. Specifically, DRD1 Haplotype 3, the haplotype previously found to be associated with inattentive symptoms in ADHD, is also associated with parent- and teacher-reported symptoms of inattention in this sample selected for reading problems (P=0.023 and 0.004, respectively). Together, the replicated finding of Haplotype 3 association with inattentive symptoms in two independent study samples strongly supports a role for DRD1 in attentional ability. Furthermore, the association of DRD1 with inattention, but not with RD, or the other reading and reading-related phenotypes analysed, suggests that DRD1 contributes uniquely to inattention, without overlap for reading ability.     

A case-control association study of the polymorphism at the promoter region of the DRD4 gene in Korean boys with attention deficit-hyperactivity disorder: evidence of association with the -521 C/T SNP

Recent genetic studies at the 5' end of the dopamine D4 receptor (DRD4) gene have identified several polymorphisms having a possible relationship with attention deficit-hyperactivity disorder (ADHD). This study examined the association between the -521 and -376 promoter single nucleotide polymorphisms (SNPs) of the DRD4 gene and ADHD through a case-control association study in Korean boys, who constitute a single ethnic population. Ninety-four ADHD and ninety-five control boys were enrolled in this study. All of the ADHD subjects completed a comprehensive and standardized diagnostic and psychological evaluation battery including the ADHD Rating Scale-IV (ARS). Genotyping for the 2 promoter SNPs was performed. There were significant differences in the genotype and allele frequencies of the -521 C/T SNP between the ADHD and control groups (chi2=6.28, p=0.043 and chi2=6.22, p=0.013, respectively). However, the distribution of the -376 C/T genotypes and alleles were similar in the ADHD and control groups. The subtypes of ADHD were not related to either of these two SNPs. In the ADHD subjects, the -521 TT genotype group had a higher score in the inattentive subscale and a lower score in the hyperactive subscale of the parents version of ARS, although these differences did not attain statistical significance (p=0.146, p=0.082). In conclusion, there was a significant association between the -521 C/T SNP and ADHD in Korean boys. These results suggest a role of the -521 C/T SNP in the susceptibility for ADHD.     

Do SNPs of DRD4 gene predict adult persistence of ADHD in a Chinese sample?

The dopamine D4 receptor (DRD4) gene has been frequently studied in relation to attention deficit hyperactivity disorder (ADHD) but little is known about the contribution of single nucleotide polymorphisms (SNPs) of the DRD4 gene to the development and persistence of ADHD. In the present study, we examined the association between two SNPs in DRD4 (rs1800955, rs916455) and adult ADHD persistence in a Chinese sample. Subjects (n=193) were diagnosed with ADHD in childhood and reassessed in young adulthood at an affiliated clinic of Peking University Sixth Hospital. Kaplan-Meier survival analyses and Cox proportional hazard models were used to test the association between ADHD remission and alleles of the two SNPs. DRD4 rs916455 C allele carriers were more likely to have persistent ADHD symptoms in adulthood. No significant association was found between rs1800955 allele and the course of ADHD. These newly detected associations between DRD4 polymorphisms and ADHD prognosis in adulthood may help to predict the persistence of childhood ADHD into adulthood.     

Decreasing ADHD phenotypic heterogeneity: searching for neurobiological underpinnings of the restrictive inattentive phenotype

During the process of developing the DSM-5, a new phenotype of ADHD was proposed—the ADHD restrictive inattentive presentation (ADHD-RI), describing subjects with high endorsement of inattentive symptoms and a low level of hyperactivity. However, this phenotype was not included in the DSM-5 because of the lack of robust neurobiological data. We aimed to assess the specific neurobiological underpinnings of individuals presenting ADHD-RI. We compared a sample of 301 subjects (101 ADHD-Combined; 50 ADHD-RI; 50 ADHD predominantly inattentive type and 100 typically developing subjects) aged 8–15 years, using a complete neuropsychological battery, molecular genetic data (DRD4 and DAT1 most studied polymorphisms) and functional MRI during a Go-No/Go task. Subjects with ADHD-RI had a significantly different neuropsychological profile compared with the other groups, including lower psychomotor speeds, longer reaction times and the worst overall performance in the global neurocognitive index. The proportion of subjects with the presence of DRD4–7 repeat allele was significantly higher in ADHD-RI. The fMRI data suggested that more attention-related posterior brain regions (especially temporo-occipital areas) are activated in ADHD-RI during both Go and No-Go cues compared to TD controls and ADHD predominantly inattentive type. ADHD-RI may represent a different phenotype than other types of ADHD. In addition, our results suggest that reducing the phenotypic heterogeneity may aid in the search for the neurobiological underpinnings of ADHD.     

Candidate system analysis in ADHD: Evaluation of nine genes involved in dopaminergic neurotransmission identifies association with DRD1

Abstract

Objectives. Several pharmacological and genetic studies support the involvement of the dopamine neurotransmitter system in the aetiology of attention-deficit hyperactivity disorder (ADHD). Based on this information we evaluated the contribution to ADHD of nine genes involved in dopaminergic neurotransmission (DRD1, DRD2, DRD3, DRD4, DRD5, DAT1, TH, DBH and COMT). Methods. We genotyped a total of 61 tagging single nucleotide polymorphisms (SNPs) in a sample of 533 ADHD patients (322 children and 211 adults), 533 sex-matched unrelated controls and additional 196 nuclear ADHD families from Spain. Results. The single- and multiple-marker analysis in both population and family-based approaches provided preliminary evidence for the contribution of DRD1 to combined-type ADHD in children (P = 8.8e-04; OR = 1.50 (1.18–1.90) and P = 0.0061; OR = 1.73 (1.23–2.45)) but not in adults. Subsequently, we tested positive results for replication in an independent sample of 353 German families with combined-type ADHD children and replicated the initial association between DRD1 and childhood ADHD (P = 8.4e-05; OR = 3.67 (2.04–6.63)). Conclusions: The replication of the association between DRD1 and ADHD in two European cohorts highlights the validity of our finding and supports the involvement of DRD1 in childhood ADHD.     

Genetic contributions to the development of ADHD subtypes from childhood to adolescence

OBJECTIVES: Little is known about how genes influence the development of symptoms included in the DSM-IV subtypes of attention-deficit/hyperactivity disorder (ADHD) from childhood to adolescence. The aim of this study was to examine genetic influences contributing to the development of hyperactive-impulsive symptoms and inattentive symptoms of ADHD from childhood to adolescence. METHOD: The sample included all 1,480 twin pairs born in Sweden between May 1985 and December 1986. Parents responded to mailed questionnaires on three occasions, when the twins were 8 to 9, 13 to 14, and 16 to 17 years old. The authors used dimensional scales of hyperactivity-impulsivity and inattention derived from a checklist of items based on the DSM symptoms of ADHD. RESULTS: Symptoms of hyperactivity-impulsivity declined with increasing age, whereas there was no decline in symptoms of inattention. Persistent genetic influences explain between 45% and 90% of the total genetic variance in hyperactivity-impulsivity and inattention across age. Persistent genetic variance was primarily operating across subtypes, even though persistent subtype-specific influences were also significant. CONCLUSIONS: The finding of persistent cross-subtype (i.e., combined) and persistent subtype-specific genetic influences (i.e., primarily hyperactive-impulsive and primarily inattentive) are in line with a genetic basis for the DSM-IV classification of ADHD subtypes.     

Gender differences among children with DSM-IV ADHD in Australia

OBJECTIVE: To examine gender differences among children meeting symptom criteria for DSM-IV attention-deficit/hyperactivity disorder (ADHD) identified in a nationally representative sample of Australian children. METHOD: From 2,404 children aged 6 to 13 years, 225 boys and 99 girls with ADHD symptoms were identified using the parent version of the Diagnostic Interview Schedule for Children and compared on parent reports of children's behavioral problems and impairment. RESULTS: When ADHD types were collapsed into a single group, boys and girls did not differ on core symptoms, comorbidity, and impairment with the exception that girls rated higher on somatic complaints and boys had poorer school functioning. However, gender patterns were found to vary across ADHD type on impairment measures of social problems, schoolwork difficulties, and self-esteem, with boys being generally rated as more impaired in the combined and hyperactive-impulsive groups but equally or less impaired in the inattentive group. CONCLUSIONS: The findings suggest the possibility of gender-specific risks associated with high levels of inattentive and hyperactive-impulsive symptoms indicating that ADHD subtype membership should be considered when conducting ADHD gender comparisons.     

The association between children's ADHD subtype and parenting stress and parental symptoms

Objective. To investigate the association between two attention deficit/hyperactivity disorder (ADHD) subtypes—combined and inattentive subtypes—and parental stress in a Taiwanese population. Method. One hundred and nine children with ADHD were interviewed using the MINI Kid questionnaire. The children were divided into combined and inattentive subtypes. The level of parenting stress was measured with the self-report Parenting Stress Index and Parental Symptom Scale (Symptom Check List, SCL-90). The data were used to identify child and parental risk factors. Results. Combined subtype was highly associated with parental stress. Parents of children in this group were significantly younger, had a poorer understanding of ADHD, and had significantly higher levels of marital discord, parenting stress, parental symptoms, and life stress (all P<0.05). Multivariate analysis revealed that age of mother, child with comorbidity diagnosis, and parents with poor understanding of ADHD were significantly associated with the combined subtype relative to inattentive subtype (all P<0.05). Conclusion. The combined subtype of ADHD is associated with more parental psychopathology and stress than the inattentive subtype and the presence of combined subtype may indicate that such a child is at greater risk than the inattentive subtype for comorbid conditions such as oppositional defiant disorder and conduct disorder.     

Association between the 5HT1B receptor gene (HTR1B) and the inattentive subtype of ADHD.

BACKGROUND: Preclinical and genetic studies have implicated the 5HT1B receptor gene (HTR1B) in attention-deficit/hyperactivity disorder (ADHD). Association with a single nucleotide polymorphism (SNP; G861C) has been observed, but more extensive linkage disequilibrium analyses have not been reported. METHODS: To examine haplotype structure, we genotyped 21 SNPs in and around the gene in 12 multigenerational CEPH pedigrees. We identified a haplotype block encompassing HTR1B and performed haplotype and single-marker association analyses for the eight SNPs within or flanking this block in 229 families of ADHD probands. In light of previous studies suggesting distinct genetic influences on ADHD subtypes, we also examined association with the inattentive and combined subtypes. RESULTS: We observed nonsignificant overtransmission of the G861 allele to ADHD offspring (one-tailed p = .07). Single-marker and haplotype tests of a haplotype block encompassing HTR1B revealed no other associations with ADHD. However, this haplotype block was associated with the inattentive subtype (global p < .01). Additionally, three SNPs in this block were nominally (p < .05) associated with the inattentive subtype, although these did not remain significant after correction for multiple testing. As reported in previous studies, we found paternal overtransmission of the G861 allele to offspring with ADHD; this appeared to be largely attributable to inattentive cases. CONCLUSIONS: These analyses suggest that variation in the HTR1B gene may primarily affect the inattentive subtype of ADHD.     

ADHD and epilepsy in childhood

Attention-deficit-hyperactivity disorder (ADHD) has been associated with childhood epilepsy; prevalence figures have ranged from 8 to 77%, depending on the sample studied and the criteria used for diagnosis. In the general population the prevalence of ADHD is approximately 5%, with the majority of affected children having ADHD combined type. As part of a larger study of behavioral problems in children with epilepsy, we assessed 175 children (90 males, 85 females; age range 9 to 14 years, mean age was 11 years 10 months, SD 1 year 8 months) for evidence of ADHD. The children had at least a 6-month history of epilepsy. The primary caregiver completed both the Child Behavior Checklist (CBCL) and the Child Symptom Inventory-4 (CSI) or Adolescent Symptom Inventory-4 (ASI). On the CBCL, the mean attention problem T score was 64.6 (SD 10.5) for adolescents and 67.9 (SD 11.6) for children. On the CSI or ASI, 20 of 175 children met DSM-IV criteria for ADHD combined type; 42 of 175 had ADHD predominantly inattentive type; and 4 of 175 met criteria for ADHD predominantly hyperactive-impulsive type. There were significant correlations between the CBCL attention score and inattention (r = 0.68) and hyperactivity-impulsivity (r = 0.59). Sex, seizure type, and focus of seizure discharge were not predictors of symptoms of ADHD. Children with epilepsy are at risk for symptoms of ADHD. They differ from other samples of children with ADHD by the higher proportion of children with ADHD predominantly inattentive type and by an equal male: female ratio.     

Genetic findings in Attention-Deficit and Hyperactivity Disorder (ADHD)

Attention-Deficit and Hyperactivity Disorder (ADHD) is a common child and adolescent psychiatric disorder with a prevalence rate of 3-7%. Formal genetic studies provided an estimated heritability of 0.6-0.8 and an approximately five-fold elevated risk for ADHD in first-degree relatives. Currently, four genome scans have led to the identification of chromosomal regions potentially relevant in ADHD; especially the evidence for linkage to chromosome 5p13 is convincing. Meta-analyses of a large number of candidate gene studies suggest association with gene variants of the dopaminergic receptors DRD4 and DRD5, the serotonergic receptor HTR1B, and the synaptosomal receptor protein (SNAP-25). Hyperactivity has been investigated particularly in animal models, focusing on knockout- and quantitative trait loci (QTL) designs, with promising results for the dopaminergic system. It is likely that several gene polymorphisms with moderate to small effect sizes contribute to the phenotype ADHD; different combinations of such predisposing variants presumably underlie ADHD in different individuals. Therefore, large samples for molecular genetic studies are mandatory to detect these polymorphisms. Accordingly, several of today's findings have to be regarded as preliminary. The understanding of ADHD's neurobiology may be advanced by new technologies, such as SNP-based genome scans performed with gene chips comprising 10,000-1,000,000 SNPs, as well as using more sophisticated animal model designs.     

Association and linkage of alpha-2A adrenergic receptor gene polymorphisms with childhood ADHD

Attention-deficit hyperactivity disorder (ADHD) is a heritable disorder, prevalent from childhood through adulthood. Although the noradrenergic (NA) system is thought to mediate a portion of the pathophysiology of ADHD, genes in this pathway have not been investigated as frequently as those in the dopaminergic system. Previous association studies of one candidate gene in the NA system, ADRA2A, showed inconsistent results with regard to an MspI polymorphism. In the current study, two nearby single-nucleotide polymorphisms, which define HhaI and DraI restriction fragment length polymorphisms, were also genotyped and were in significant linkage disequilibrium with the MspI RFLP. Transmission disequilibrium tests (TDTs) in a sample of 177 nuclear families showed significant association and linkage of the DraI polymorphism with the ADHD combined subtype (P=0.03), and the quantitative TDT showed association of this polymorphism with the inattentive (P=0.003) and hyperactive-impulsive (P=0.015) symptom dimensions. The haplotype that contained the less common allele of the DraI polymorphism likewise showed a strong relationship with the inattentive (P=0.001) and hyperactive-impulsive (P=0.004) symptom dimensions. This study supports the hypothesis that an allele of the ADRA2A gene is associated and linked with the ADHD combined subtype and suggests that the DraI polymorphism of ADRA2A is linked to a causative polymorphism.     

ADHD and learning disabilities: Research findings and clinical implications

Children with attention-deficit/hyperactivity disorder (ADHD) are at higher than average risk for academic achievement difficulties and learning disabilities (LDs). Several decades of research indicate that about 27% to 31% of students with ADHD also have LDs, although estimates vary widely depending on the criteria used to define LDs. Recent studies have demonstrated that 1) the association between ADHD and achievement difficulties is driven more by inattentive than hyperactive-impulsive symptoms, 2) deficits in working memory and processing speed are shared across ADHD and LDs, 3) multiple genes seem involved in the etiology of both ADHD and reading disabilities, and 4) neither cognitive nor behavioral constructs fully account for the relationship between ADHD and LDs. Comprehensive longitudinal studies assessing children with ADHD, LDs, and combined disorders are necessary to further explicate the relationship between these two disorders.     

The DRD2 TaqI polymorphism and symptoms of attention deficit hyperactivity disorder

The relationship of the DRD2 TaqI-A1 allele to hyperactive/impulsive and inattentive symptoms of attention deficit hyperactivity disorder (ADHD) in children and adolescents was examined in a sample of clinic-referred children and their siblings, and control children and their siblings (n = 236). The contribution of genetic dominance and additivity to mean differences among the A2A2, A1A2, and A1A1 genotypes was estimated using structural equation modeling. The effect of genetic additivity was statistically significant for both traits in an analysis of all children. The heritability from the DRD2 locus was estimated at 4.27% for hyperactive-impulsive symptoms and 2.12% for inattentive symptoms. Children with the A2A2 genotype had the highest mean level of symptoms. To control for any possible effects of population stratification, this analysis was repeated with parental genotypes as controls. In this smaller sample, although the direction of the effect was the same as that in the whole sample, the genotypic differences failed to reach conventional significance levels and the effect sizes were smaller (h2 = 1.62% and 0.79%, respectively). Furthermore, a genotype relative risk test of children who had questionnaire-based diagnoses of ADHD also failed to yield evidence of either association or linkage. Given that the A1 allele was expected to be the high risk allele, and that results were non-significant in tests that controlled for population heterogeneity, we doubt that this DRD2 polymorphism influences symptoms of ADHD in childhood.     

Executive function in adolescents with ADHD

OBJECTIVE: The aim of this study was to clarify executive function weakness in attention-deficit/hyperactivity disorder (ADHD) during adolescence and determine the specificity of executive function weakness to ADHD symptom domains. METHOD: A total of 182 adolescents (105 boys), ages 13 to 17 years, completed a multistage diagnostic assessment; 85 were diagnosed with ADHD: 43 primarily Inattentive type (ADHD-PI) and 42 Combined type (ADHD-C). Participants completed the Stop, Trail Making, Wisconsin Card Sort, and Stroop tasks. RESULTS: The ADHD group exhibited impaired performance compared with the non-ADHD group on executive function measures (multivariate p < .05); there were no ADHD subtype differences. A composite executive function factor was significantly related to inattentive but not hyperactive-impulsive symptoms. CONCLUSIONS: Executive function weakness in adolescent ADHD is specifically related to symptoms of inattention-disorganization. Results are congruent with a dual-pathway model of ADHD cognitive mechanisms.     

Epigenetic regulation of the DRD4 gene and dimensions of attention-deficit/hyperactivity disorder in children

Recent evidence suggests that epigenetic regulation of the DRD4 gene may characterise specific aspects of ADHD symptomology. We tested associations between ADHD symptoms and epigenetic changes to the DRD4 gene in DNA extracted from blood and saliva in N = 330 children referred for a variety of behavioural and emotional problems. ADHD was indexed using DSM diagnoses as well as mother, father, and teacher reports. Methylation levels were assayed for the island of 18 CpG sites in the DRD4 receptor gene. A nearby SNP, rs3758653, was also genotyped as it has previously been shown to influence methylation levels. There was high consistency of methylation levels across CpG sites and tissue sources, and higher methylation levels were associated with the major allele of SNP rs3758653. Higher methylation levels were associated with more severe ADHD independent of SNP status, tissue source, ethnicity, environmental adversity, and comorbid conduct problems. The association applied specifically to the cognitive/attentional, rather than hyperactivity problems that characterise ADHD. The results indicate that epigenetic regulation of the DRD4 gene in the form of increased methylation is associated with the cognitive/attentional deficits in ADHD.     

Family-based association testing strongly implicates DRD2 as a risk gene for schizophrenia in Han Chinese from Taiwan

The gene that codes for dopamine receptor D2 (DRD2 on chromosome 11q23) has long been a prime functional and positional candidate risk gene for schizophrenia. Collectively, prior case-control studies found a reliable effect of the Ser311Cys DRD2 polymorphism (rs1801028) on risk for schizophrenia, but few other polymorphisms in the gene had ever been evaluated and no adequately powered family-based association study has been performed to date. Our objective was to test 21 haplotype-tagging and all three known nonsynonymous single-nucleotide polymorphisms (SNPs) in DRD2 for association with schizophrenia in a family-based study of 2408 Han Chinese, including 1214 affected individuals from 616 families. We did not find a significant effect of rs1801028, but we did find significant evidence for association of schizophrenia with two multi-marker haplotypes spanning blocks of strong linkage disequilibrium (LD) and nine individual SNPs (Ps<0.05). Importantly, two SNPs (rs1079727 and rs2283265) and both multi-marker haplotypes spanning entire LD blocks (including one that contained rs1801028) remained significant after correcting for multiple testing. These results further add to the body of data implicating DRD2 as a schizophrenia risk gene; however, a causal variant(s) in DRD2 remains to be elucidated by further fine mapping of the gene, with particular attention given to the area surrounding the third through fifth exons.     

Differential association between the norepinephrine transporter gene and ADHD: role of sex and subtype

Background

Pharmacologic and animal studies have strongly implicated the norepinephrine transporter (NET) in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD). We conducted a family-based study, with stratification based on sex and subtype, to test the association between 30 tag single-nucleotide polymorphisms (SNPs) within the gene encoding NET (SLC6A2) and ADHD.

Methods

Family-based association tests were conducted with the categorical diagnosis of ADHD, as well as quantitative phenotypes of clinical relevance (Conners Global Index for Teachers and Parents, and Child Behavior Checklist measures). Sliding window haplotype analysis was conducted with screening based on conditional power using PBAT.

Results

A previously reported association with rs3785143 was confirmed in this study. Further, extensive association was observed with haplotype blocks, with a differential pattern observed based on sex and subtype. The 5′ region of the gene (encompassing haplotype block 1 and including a functional promoter SNP, rs28386840) showed an association with ADHD in girls (irrespective of subtype). A different region of the gene (distributed around haplotype block 2) was associated with distinct behavioural phenotypes in boys. These findings are correlated with previously reported functional studies of gene variants in SLC6A2.

Limitations

The most important limitation of the study is the small size of the groups resulting from the stratification based on sex followed by subtype.

Conclusion

The results obtained in this family-based study suggest that haplotype blocks within different regions of SLC6A2 show differential association with the disorder based on sex and subtype. These associations may have been masked in previous studies when tests were conducted with pooled samples.     

How common are symptoms of ADHD in typically developing preschoolers? A study on prevalence rates and prenatal/demographic risk factors

According to the Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV - American Psychiatric Association, 1994), one of the diagnostic criteria for attention deficit hyperactivity disorder (ADHD) is the presence of symptoms of inattention and/or hyperactivity-impulsivity before the age of 7 years. In contrast to studies with older children, relatively little is known about ADHD symptoms in preschoolers. In order to address this issue, the present study was designed to investigate to what extent ADHD behaviors exist in a large community based group of preschoolers in the Netherlands. A second aim of this study was to shed light on the etiology of ADHD, by examining if and how a range of prenatal and demographic factors contribute to the prediction of ADHD behaviors in young children. Participants included 652 parents of children between the ages of 3 and 6 years. Parents were asked to complete two questionnaires: the Preschool Behavior Questionnaire (Smidts and Oosterlaan, 2005) and a background information questionnaire, specifically designed for this study. Findings from the present study show that ADHD symptoms are quite common in preschoolers, with approximately one-third of all ADHD behaviors listed in the Preschool Behavior Questionnaire being highly frequent in early childhood. It appears that hyperactive-impulsive symptoms are more common in preschoolers than inattentive behavior. For the purpose of an early identification of ADHD, this finding is particularly important, as it may be argued that inattentive behavior in preschoolers may be indicative of psychopathology. Significant predictors of ADHD behaviors included maternal smoking and alcohol, and illness of the mother during pregnancy; however, together these factors explained less than 10% of the variance.     

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

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 (chi(2)=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.