ADHD is the most common childhood-onset behavioral disorder, affecting approximately 5 to 10% of children and adolescents (Wolraich et al., 1996). In this condition, persistent inattention and/or hyperactive-impulsive behavior results in impaired social and/or academic functioning. Boys are ... ADHD is the most common childhood-onset behavioral disorder, affecting approximately 5 to 10% of children and adolescents (Wolraich et al., 1996). In this condition, persistent inattention and/or hyperactive-impulsive behavior results in impaired social and/or academic functioning. Boys are affected about 8 times more frequently than girls (Zametkin et al., 1990). By means of positron-emission tomography (PET) of the brain using (18F)-fluoro-2-deoxy-D-glucose, Zametkin et al. (1990) found that global cerebral glucose metabolism was 8.1% lower in adults with hyperactivity than in normal controls. Glucose metabolism was significantly reduced in 30 of 60 specific regions of the brain. Among the regions with greatest reduction were the premotor cortex and the superior prefrontal cortex. This study was done in adults because of ethical considerations about exposing children to a radioactive tracer; however, each of the 25 hyperactive adults was the biologic parent of a hyperactive child. Biederman et al. (1990) reported that 28.6% of the biologic parents of hyperactive children also had a history of hyperactivity. The parents in this study continued to have symptoms as adults. Smalley (1997) reviewed studies of the genetics of ADHD and autism (209850). Zametkin and Ernst (1999) reviewed the diagnostic criteria, differential diagnosis, and treatment of ADHD. Kuntsi et al. (2004) found that 86% of the association between ADHD symptom scores and IQ, and 100% of the association between ADHD diagnosis and IQ was accounted for by genetic influences that are shared by ADHD and IQ. In a large population-based sample of 5-year-old twins (both monozygotic and dizygotic), they assessed twins individually on IQ tests, and data on ADHD symptoms were obtained from mothers' and teachers' ratings. The correlation between ADHD symptoms and IQ was -0.3 (on average ADHD diagnosed children obtained an IQ score 9 points lower than comparison children).
- Association with the DRD5 Gene on Chromosome 4p16
Kustanovich et al. (2004) genotyped a large multiplex sample of ADHD-affected children and their parents for polymorphisms in genes reported to be associated with ADHD and analyzed ... - Association with the DRD5 Gene on Chromosome 4p16 Kustanovich et al. (2004) genotyped a large multiplex sample of ADHD-affected children and their parents for polymorphisms in genes reported to be associated with ADHD and analyzed the results using the transmission disequilibrium test. A dinucleotide repeat polymorphism near the DRD5 gene (126453.0002) showed an association with ADHD and with biased nontransmission of the 146-bp allele, and a trend toward excess transmission of the 148-bp allele. The DRD5 146-bp allele and the DRD4 240-bp allele of the promoter polymorphism showed estimated genotype relative risks of 1.7 and 1.37, respectively. - Association with the DAT1 (SLC6A3) Gene on Chromosome 5p15 Cook et al. (1995) used the haplotype-based haplotype relative risk (HHRR) method to test for association between a VNTR polymorphism at the DAT1 locus and ADHD in 49 individuals, as well as in 8 cases of undifferentiated attention-deficit disorder (UADD). All cases were studied in trios composed of father, mother, and affected offspring. A significant association was found between ADHD/UADD and a 480-bp DAT1 allele. When cases of UADD were dropped from the analysis, similar results were found. Waldman et al. (1998) used 4 analytic strategies to examine association and linkage of the DAT1 gene and ADHD in a sample of 122 children referred to psychiatric clinics for behavioral and learning problems that included but were not limited to ADHD. Within-family analyses of linkage disequilibrium, using the transmission disequilibrium test (TDT), confirmed the 480-bp allele as the high-risk allele. In between-family association analyses, levels of hyperactive-impulsive symptoms but not inattentive symptoms were related to the number of DAT1 high-risk alleles. Sibs discordant for the number of DAT1 high-risk alleles differed markedly in their levels of both hyperactive-impulsive and inattentive symptoms, such that the sibs with the higher number of high-risk alleles had much higher symptom levels. Within-family analyses of linkage disequilibrium, using the TDT, suggested association and linkage of ADHD with DAT1, with the relationship being especially strong with the combined but not the inattentive subtype. Using multivariate analyses of predictors of hyperactive-impulsive and inattentive behavior, including prenatal smoking and DAT polymorphism, Kahn et al. (2003) conducted a prospective cohort study of the Connors Parent Rating Scale Revised Long Version (CPRS-R:L) scales in 161 children. They found that hyperactivity-impulsivity and oppositional behaviors, but not inattention, were associated with homozygosity for the 480-bp DAT allele only in the presence of maternal prenatal smoking. Langley et al. (2005) tested the DAT1 3-prime VNTR and 3 putative DAT1 promoter SNPs for association with ADHD in 263 parent-proband trios using family-based association methods. No evidence of association with any of the promoter region SNPs or the VNTR was seen. Haplotype analysis was also nonsignificant, and no association was found between the VNTR and response to stimulant medications. By case-control analysis of the VNTR in 263 cases and 287 controls, the 10-repeat allele showed no significant association compared to all other alleles combined. Feng et al. (2005) investigated whether the DAT1 3-prime UTR contributed to ADHD by genotyping DNA variants around the VNTR region in a sample of 178 ADHD families. Variants included an MspI polymorphism (dbSNP rs27072), a DraI T-C transition reported to influence DAT1 expression levels, and a BstUI polymorphism (dbSNP rs3863145), in addition to the VNTR. They found an association between the G allele of the MspI SNP and ADHD (P = 0.009) but not with alleles of the VNTR polymorphism or the BstUI polymorphism. Feng et al. (2005) screened the VNTR region by direct sequencing to determine if there were additional variants within the repeats that could account for association with ADHD and found no variation in the VNTR region for either the 10- or 9-repeat alleles in the probands screened. In both a Taiwanese ADHD sample and an English ADHD sample, Brookes et al. (2006) identified association with the DAT1 3-prime UTR VNTR and a novel DAT1 intron 8 repeat polymorphism. A risk haplotype comprised of the 2 repeat polymorphisms was also associated with ADHD in both populations, and the authors found that the risk haplotype showed significant interactions with maternal use of alcohol during pregnancy in the English sample. Bakker et al. (2005) conducted a family-based study of 236 Dutch children with ADHD to investigate previously described associations between VNTR polymorphisms and 2 additional microsatellites at the DAT1 and DRD4 loci. DRD5 was also investigated using a microsatellite previously found to be associated with ADHD. Transmission disequilibrium tests did not show preferential transmission for alleles or 2-marker haplotypes to affected offspring, suggesting that these genes do not contribute to ADHD in the Dutch population. - Association with the HTR1B Gene on Chromosome 6q13 Smoller et al. (2006) examined the haplotype structure of the 5HTR1B (HTR1B; 182131) gene in reference to ADHD by genotyping 21 SNPs in and around the gene in 12 multigenerational CEPH pedigrees. A haplotype block encompassing the gene was identified and single-marker association analyses for 8 SNPs within this block was performed in 229 families of ADHD probands to include association with inattentive and combined ADHD subtypes. Although Hawi et al. (2002) and Quist et al. (2003) had reported association of the G861 variant (861G-C) with ADHD, Smoller et al. (2006) observed only nonsignificant overtransmission of the G861 allele to ADHD offspring (one-tailed p = 0.07). Single-marker and haplotype tests of a haplotype block encompassing 5HTR1B revealed no other associations with ADHD. However, the haplotype block was associated with the inattentive subtype (global p less than 0.01). Additionally, 3 polymorphisms in this block were nominally associated with the inattentive subtype, but the associations did not remain significant after correction for multiple testing (p less than 0.05). Paternal overtransmission of G861 alleles to offspring with ADHD was observed and was largely attributable to inattentive cases. - Association with the ADRA2A Gene on Chromosome 10q24 In a Brazilian sample of 92 ADHD patients and their biologic parents, Roman et al. (2003) studied the -1291C-G SNP (dbSNP rs1800544) of the ADRA2A gene (104210). No association was observed through the Haplotype Relative Risk method, although an influence of the GG genotype on inattention and combined ADHD scores was detected. To further investigate the -1291C-G SNP, Roman et al. (2006) studied a new sample of 128 Brazilian ADHD probands. Patients were genotyped and symptoms for each ADHD cluster (inattention, hyperactivity/impulsivity, and combined) were obtained. An association with inattention symptoms was again detected in individuals with the GG genotype (p = 0.017). - Association with the DRD4 gene on Chromosome 11p15 Manor et al. (2002) noted that polymorphisms (specifically the short allele in exon 3) of the dopamine D4 receptor gene (DRD4; 126452) have been associated with ADHD in some studies but not in others. They studied 178 Israeli triads using the transmission disequilibrium test (TDT). Preferential transmission of the short allele was associated with ADHD. Study of the same triad using the Test of Variables of Attention (TOVA) revealed that individuals with the short allele of the exon 3 repeat performed significantly worse on the TOVA measured both by errors of commission and response time variable. A dosage effect was observed in that increasing repeat size was accompanied by a reduced number of errors of commission and a significant difference was observed between the 2 versus 7 repeats. Langley et al. (2004) found that in children with ADHD, possession of the DRD4 7-repeat (7R) allele appeared to be associated with an inaccurate, impulsive response style on neuropsychologic tasks that was not explained by ADHD symptom severity. Children with the 7R allele had significantly more incorrect responses, shorter mean reaction times for incorrect responses, and displayed higher activity levels as measured by actigraphy compared to children without the allele. Kustanovich et al. (2004) genotyped a large multiplex sample of ADHD-affected children and their parents for polymorphisms in genes reported to be associated with ADHD and analyzed the results using the transmission disequilibrium test. The DRD4 120-bp insertion/deletion promoter polymorphism (126452.0003) displayed a significant bias for transmission of the insertion (240-bp allele). A dinucleotide repeat polymorphism near the DRD5 gene (126453.0002) showed an association with ADHD and with biased nontransmission of the 146-bp allele, and a trend toward excess transmission of the 148-bp allele. The DRD5 146-bp allele and the DRD4 240-bp allele of the promoter polymorphism showed estimated genotype relative risks of 1.7 and 1.37, respectively. The 7R allele of the DRD4 48-bp repeat polymorphism was not significantly associated with ADHD, nor was there evidence for associations with polymorphisms in the DRD2 (126450) or DAT1 (SLC6A3; 126455) genes in this sample. Lynn et al. (2005) investigated the link between ADHD in adults, novelty-seeking temperament, and the DRD4 7R allele in 171 parents from 96 families with ADHD-affected sib pairs. Of the parents, 56 (33%) had a lifetime history of ADHD with 28 (50%) continuing to meet DSM-IV criteria. Novelty seeking and 7R variant were associated with a lifetime history of ADHD; however, novelty seeking and ADHD did not appear to be due to the DRD4 7R variant. Leung et al. (2005) noted that the DRD4 7-repeat allele associated with ADHD varies in prevalence across ethnic groups and is very low in Asian populations. Leung et al. (2005) studied 32 Han Chinese children with a confirmed ADHD diagnosis and normal IQ who were methylphenidate responders and observed no evidence of 7R alleles. Instead, they found a 2-repeat (2R) allele in this clinical sample (33%) compared to ethnically matched controls (20%) (p = 0.015). This 1.65-fold increase in the 2R allele was close to the increase of the 7R allele observed in ADHD children of European ancestry. Leung et al. (2005) postulated that an increased frequency of any non-4R allele may define the association of the DRD4 gene with ADHD. - Association with the SCN8A Gene on Chromosome 12q13 Trudeau et al. (2006) identified heterozygosity for a 2-bp deletion in the SCN8A gene (600702.0001), which maps to chromosome 12q, in 4 members of a family. In 3 of the individuals cognitive and behavioral deficits including ADHD were found, while 1 patient had cerebellar atrophy, ataxia, and mental retardation. - Association with the SNAP25 Gene on Chromosome 20p11.2 Feng et al. (2005) screened polymorphisms of the SNAP25 gene (600322) in 186 Canadian families with 234 ADHD children, some of whom were previously reported by Barr et al. (2000), and in an independent sample of 99 families with 102 ADHD children from southern California. Significant results were observed for 4 markers in the Canadian sample but not in the independent sample. Quantitative analysis of hyperactivity/impulsivity and inattention dimensions in the Canadian sample found that both behavioral traits were associated with SNAP25. Feng et al. (2005) noted that the different results may have been due to differences in selection criteria, ethnicity, medication response, and other clinical characteristics of the samples. - Association with the COMT Gene on Chromosome 22q11 Thapar et al. (2005) noted that early-onset antisocial behavior accompanied by ADHD is a clinically severe variant of antisocial behavior with a poor outcome. In 240 British children with ADHD or hyperkinetic disorder, they studied the COMT val158-to-met variation (116790.0001) and the effects of birth weight, which is an environmentally influenced index. A comprehensive standardized assessment including measures of antisocial behavior and IQ was conducted. The val/val genotype (P = 0.002) and lower birth weight (P = 0.002) were associated with increased symptoms of conduct disorder and a significant gene-environment interaction (P = 0.006) was also confirmed.