Neuropharmacology 57 (2009) 590–600

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Neuropharmacology

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Review Genetics of attention-deficit hyperactivity disorder (ADHD)

Sally I. Sharp, Andrew McQuillin, Hugh M.D. Gurling*

Molecular Psychiatry Laboratory, Research Department of Mental Health Sciences, Windeyer Institute of Medical Sciences, University College London Medical School, 46 Cleveland Street, London W1T 4JF, UK article info abstract

Article history: Attention-deficit hyperactivity disorder (ADHD) is a clinically and genetically heterogeneous syndrome Received 3 July 2009 which is comorbid with childhood conduct disorder, alcoholism, substance abuse, dis-social personality Received in revised form disorder, and affective disorders. A small but consistent overlap with autistic symptoms has also been 14 August 2009 established. Twin and family studies of ADHD show a substantial genetic heritability with little or no Accepted 18 August 2009 family environmental effect. Linkage and association studies have conclusively implicated the dopamine transporter gene (DAT1). DAT1 has also been confirmed as being associated with bipolar disorder. Keywords: Remarkably, and for the first time in psychiatry, genetic markers at the DAT1 locus appear to be able to Attention-deficit hyperactivity disorder (ADHD) predict clinical heterogeneity because the non-conduct disordered subgroup of ADHD is associated with DAT1 DAT1 whereas other subgroups do not appear to be associated. The second most well replicated DRD4 susceptibility gene encodes the DRD4 dopamine receptor and many other dopamine related genes Linkage association appear to be implicated. It is becoming increasingly clear that genes causing bipolar mania overlap with genes for a subtype of ADHD. The key to understanding the genetics of ADHD is to accept very considerable heterogeneity with different genes having effects in different families and in different individuals. It is too early to interpret the new wave of genome-wide association and copy number variant studies but preliminary data support the overlap with affective disorder genes and also with CNS connectivity genes likely to be involved in autism and affective disorders. Ó 2009 Published by Elsevier Ltd.

1. Diagnosis, Epidemiology, Twin and Family studies of ADHD and family data which shows increased risks for substance abuse (Faraone et al., 2007), unipolar affective disorder (Biederman et al., Attention-deficit hyperactivity disorder (ADHD) is the most 1991b, 2009), bipolar disorder (Biederman et al., 1997, 1991a, 2003, common, highly heritable childhood-onset psychiatric disorder. 1987; Jaideep et al., 2006; Masi et al., 2006), autism (Reiersen et al., A high degree of inattention with or without hyperactive-impulsive 2008) and dis-social personality disorder in the relatives of ADHD behaviour results in impaired social and academic functioning probands (Hofvander et al., 2009). (American-Psychiatric-Association, 1994). It is generally accepted There is a high degree of comorbidity between ADHD and other that there are three behavioural subtypes which are an inattentive disorders. Anti-social personality and affective disorders are very subtype, a hyperactive/impulsive subtype and a combined subtype strongly associated with alcoholism and substance abuse inde- (Wood et al., 2009). The estimated worldwide prevalence of ADHD pendently of ADHD (Merikangas and Gelernter, 1990; Merikangas is 5.3% in children and adolescents (Polanczyk et al., 2007). The et al., 1985; Ohlmeier et al., 2008; Pottenger et al., 1978; Preisig frequency of ADHD declines with age but persists into adulthood, et al., 2001). Both of these disorders are also associated with ADHD affecting between 2.5% and 4.4% of adults (Fayyad et al., 2007; and it is no surprise that childhood ADHD predicts adult alcoholism Kessler et al., 2006; Simon et al., 2009). Boys are more likely to and substance dependence (Clure et al., 1999; Mannuzza et al., have ADHD than girls (Pastor and Reuben, 2008), and similarly 4.1% 1991; Milin et al., 1991; Ohannessian et al., 1995; Ohlmeier et al., of men compared with 2.7% of women have adult ADHD (Fayyad 2008). There is accumulating evidence that one subgroup of et al., 2007). childhood ADHD is likely to be a variant of bipolar disorder ADHD in childhood overlaps with the diagnosis of childhood (Henin et al., 2007; Hirshfeld-Becker et al., 2006; Rubino et al., conduct disorder (CD) and there is considerable epidemiological 2009) and that another subtype may be related to CD and anti- social personality disorder (Zhou et al., 2008a). Reading disability also appears to share the same genetic cause as a proportion of * Corresponding author. Tel.: þ44 20 7679 9474; fax: þ44 20 7679 9437. ADHD cases (Loo et al., 2004). The association of ADHD with autistic E-mail address: [email protected] (H.M.D. Gurling). traits in twins (Reiersen et al., 2007) and in families seem to define

0028-3908/$ – see front matter Ó 2009 Published by Elsevier Ltd. doi:10.1016/j.neuropharm.2009.08.011 S.I. Sharp et al. / Neuropharmacology 57 (2009) 590–600 591 a genetic subgroup of ADHD associated with increased neuro- microarray genotyping to detect genetic stratification between developmental and oppositional defiant and conduct disorders cases and controls has now focussed attention on getting the very (Mulligan et al., 2009). large case control samples that are needed to overcome the Adoption, twin and family studies (Kuntsi et al., 2004; Lasky-Su problem of genetic heterogeneity. et al., 2008a; Mick et al., 2009; Ouellet-Morin et al., 2008; Rietveld The first systematic genome-wide linkage scan for loci influ- et al., 2003, 2004; Sprich et al., 2000; van ’t Ent et al., 2007) show encing ADHD employed 126 affected sib pairs and identified that there is a strong genetic aetiology for ADHD. Twenty twin chromosomal regions on 2q24, 5p12, 10q26, 12p13, 12q23, and 16p studies of ADHD have been consistent with an average heritability as possibly harbouring genes increasing susceptibility with lod rate of 76% (Faraone et al., 2005). The twin studies are able to scores greater than 1.00 (Fisher et al., 2002). A second genome- differentiate subgroups of ADHD. One of these studies (Coolidge wide linkage study using affected sib pairs from 203 families et al., 2000) examined the heritability and comorbidity of ADHD confirmed linkage to chromosome 16p13 (Smalley et al., 2002). In with CD, oppositional defiant disorder (ODD) and executive func- a follow-up study of 270 affected sib pairs significant linkage at tion (inattention) deficits. Heritabilities were high, 82% for ADHD, 5p13, 6q14, 11q25, 17p11, and 20q13 was found (Ogdie et al., 2003). 74% for CD, 61% for ODD and 77% for executive function. Multivariate In another whole-genome linkage scan of 164 white Dutch affected twin analyses showed that ADHD shared genetic liability with CD, sib pairs, chromosomes 5p13, 7p13, and 9q33 were implicated in ODD, and executive function deficits and that additional genetic ADHD (Bakker et al., 2003). A linkage study of 308 affected ADHD influences underlying CD, ODD, and executive function that are sib pairs provided further evidence that the 5p13, 6q12, and 17p11 independent of ADHD may also exist. Another twin study showed chromosomal regions harboured susceptibility genes for ADHD that oppositionality overlapped with hyperactivity-impulsivity (Ogdie et al., 2004). Linkage on chromosomes 4q13, 5q33, 8q11, (r ¼ 0.95) more than with inattentiveness (r ¼ 0.52). The study 11q22, and 17p11 were found in a Columbian study, along with found that aetiological influences on hyperactivity-impulsivity suggestive evidence for a new locus on 8q11.23 (Acosta et al., 2004). were shared with those on oppositionality, by contrast inattention Confirmation across linkage studies was found for the 11q22 and as a dimension was found to be more self contained (Wood et al., 17p11 loci (Acosta et al., 2004; Bakker et al., 2003; Fisher et al., 2009). McLoughlin and others (McLoughlin et al., 2007)studied 2002; Ogdie et al., 2003). twins and found that hyperactive-impulsivity and inattention A further genome-wide linkage scan (Loo et al., 2004) for substantially shared genetic overlap but that there were also susceptibility loci for ADHD in a sample of 233 affected sib pairs significant independent genetic effects. They predicted that many suggested linkage to four chromosomal regions, three of which genes associated with the hyperactivity-impulsivity dimension replicated previous linkages on 10q26, 16p13 and 17q22, and also would also be found to be associated with inattention but that there implicated 2p24 not far from a locus at 2p16 which has previously would be significant genetic heterogeneity. been linked with reading disorder (DYX3 (Fagerheim et al., 1999)). At least 25% of adults with a history of hyperactivity are the In addition, reading measures of individuals with ADHD showed biologic parent of a child with hyperactive symptoms (Biederman linkage to putative reading disability susceptibility regions on et al., 1990; Zametkin et al., 1990). The fact that ADHD has a high chromosomes 8p and 15q (Loo et al., 2004). Variations in genes on population frequency, that twin studies show clinical heterogeneity 2q24 (Fisher et al., 2002), 15q15 (Bakker et al., 2003), or 16p13 and that linkage analyses in families has proven heterogeneity of (Fisher et al., 2002; Smalley et al., 2002) may contribute to common linkage shows that multiple genes must have major or minor effects deficits found in genetically overlapping disorders, including both on a variety of genetic subtypes. ADHD and autism. In a whole-genome scan of 102 German families with two or 2. Genetic linkage studies more offspring who fulfilled diagnostic criteria for ADHD, linkage to chromosome 5p17 was shown (lod score 2.59). The previous Linkage analysis is a robust and elegant method for identifying linkage studies were for an ADHD locus at 5p13 near the solute the presence of susceptibility genes for a genetic disorder within carrier 6A3 (SLC6A3; dopamine transporter 1; DAT1) at 5p15.33. regions of chromosome of up to forty million bases of DNA possibly There was also suggestive evidence for linkage to chromosomes 6q, containing thousands of genes. The presence of linkage is usually 7p, 9q, 11q, 12q, and 17p (Hebebrand et al., 2006). expressed as log10 of the odds (lod) score for the probability of A recent meta-analysis of seven ADHD linkage studies (Arcos- observing marker alleles cosegregating with the disorder in Burgos et al., 2004; Asherson et al., 2008; Bakker et al., 2003; multiple affected families compared to the null hypothesis of no Faraone et al., 2008; Hebebrand et al., 2006; Ogdie et al., 2003; cosegregation or 50% recombination between marker alleles and Romanos et al., 2008) confirms genome-wide significance for the disease. In another approach called the sib pair linkage method, a region on chromosome 16, between 16q21–16q24, and ADHD marker alleles are observed in affected siblings to test the (Zhou et al., 2008b). Furthermore, 10 chromosomal regions on 5, 6, hypothesis that they are shared in affected cases more than by 7, 8, 9, 15, 16, and 17 with nominal evidence for linkage with ADHD chance. In disorders which are heterogeneous, such as ADHD, small were identified (Zhou et al., 2008b). or medium sized families have the power to detect different genetic subtypes, as defined by positive lods at linkage hotspots, whereas 3. Allelic association studies and susceptibility genes the affected sib pair linkage method has little or no power to detect heterogeneity. In order to identify which gene is involved in ADHD Allelic association studies are able to pin down aetiological once a linked region has been confirmed using the lod or sib pair genes for ADHD from a large group of genes in a region showing method, it is necessary to make use of evolutionarily determined linkage with ADHD derived from family data. This employs the patterns of allelic association (linkage disequilibrium) between phenomenon of linkage disequilibrium in unrelated cases of disease mutations and closely linked genetic markers in order to ADHD and compares frequencies of neutral SNP base pair changes narrow down the actual susceptibility gene. Methods which in cases of ADHD to those in comparison subjects. Genetic asso- combine tests of linkage and allelic association to do both linkage ciation detects SNP markers that have an evolutionarily created and fine mapping in the same family sample have been popular linkage disequilibrium relationship with an unknown disease because they are immune to population stratification effects. mutation that is very close to the genetic marker. In practice this However, restrictions on the size of samples, and the ability of means less than one million base pairs away and usually within 592 S.I. Sharp et al. / Neuropharmacology 57 (2009) 590–600 a few hundred thousand bases of the associated SNP markers. 3.3. The dopamine D4 receptor (DRD4) Genome-wide association studies with microarrays able to geno- type up to 1 million SNP markers in a single person in large Ebstein et al. (1996) first reported an association between an samples in a short time have now begun in ADHD (Franke et al., exon 3 VNTR in the DRD4 gene and novelty seeking in a comparison 2009). Pharmacologic, neuroimaging studies and animal-models population sample. Novelty seeking has been hypothesised to be on suggest an imbalance of dopaminergic, serotonergic, and norad- a continuum with anti-social personality disorder and impulsivity renergic neurotransmission in ADHD. The aetiology of ADHD is which are traits that are comorbid with ADHD. The VNTR is made strongly genetic therefore monoamine genes were strong a priori up of two to eleven 48 bp repeats. The most commonly observed candidates. alleles comprise 2, 4 and 7 repeats. Alleles with six or fewer repeats have been defined as short and those with seven or more repeats as long. The seven repeat (7R) allele has been reported to be func- 3.1. The dopamine transporter (DAT1) tionally different from the common shorter alleles (Asghari et al., 1995). This VNTR has been studied in a number of systematic meta- In retrospect it was no surprise that the dopamine transporter analyses of ADHD (Faraone et al., 2001, 2005; Gizer et al., 2009; Li DAT1 has been conclusively implicated in the genetics of ADHD by et al., 2006a). The results from all of these have shown evidence for both linkage and association studies. DAT1 is localised to a recur- association of allele 7R with ADHD. The most recent meta-analysis rent linkage hotspot on chromosome 5p. One further linkage study showed a fixed effects significance of P < 0.00001 (random effects of DAT1 haplotypes segregating in affected ADHD families also P ¼ 0.00007) with evidence of substantial heterogeneity (Gizer suggested the involvement of DAT1 (Barr et al., 2001b). The positive et al., 2009). There is also a very low prevalence of the 7R allele in genetic association studies are numerous and five of the most Asian populations (Leung et al., 2005). TDT (transmission disequi- commonly studied polymorphisms have been subjected to meta- librium test) analysis shows preferential transmission of short analyses (Asherson et al., 2007; Barkley et al., 2006; Brookes et al., alleles of the VNTR in 178 Israeli triads in association with ADHD 2006b; Carrasco et al., 2006; Cook et al., 1995; Curran et al., 2001; (P ¼ 0.006). Probands with short alleles of the repeat performed Daly et al., 1999; Das and Mukhopadhyay, 2007; Feng et al., 2005b; significantly worse on a test of attention and a ‘dose effect’ was Genro et al., 2008, 2007; Hawi et al., 2003; Kim et al., 2006; observed with increasing repeat size. Presence of between two and Kopeckova et al., 2008; Lim et al., 2006; Waldman et al., 1998). seven repeats was accompanied by a reduced performance on the VNTRs in the 30 untranslated region (UTR) and intron 8 are the most attention test (Manor et al., 2002). Lynn et al. (2005) found that widely studied DAT1 polymorphisms. Meta-analysis of the VNTRs a novelty-seeking temperament in adults with either a lifetime and two 30UTR SNPs were significantly associated with ADHD (30 history of ADHD, but not a current diagnosis of adult ADHD, was UTR VNTR fixed effects P ¼ 0.002, random effects P ¼ 0.028; intron associated with the 7R allele in 171 parents from 96 families with VNTR fixed effects P ¼ 0.002, random effect P ¼ 0.034; rs27072 ADHD-affected sib pairs. Neuropsychological testing of children fixed effects P ¼ 0.003, random effects P ¼ 0.006; rs40184 fixed revealed that possession of the 7R allele is associated with an effects P ¼ 0.036, random effects P ¼ 0.249) (Gizer et al., 2009). inaccurate, impulsive response style in neuropsychological tasks A second wave of studies has found correlations between endo- that was not explained by ADHD symptom severity. Children with phenotypes such as cognitive function (Bellgrove and Mattingley, the 7R allele had significantly more incorrect responses, shorter 2008; Boonstra et al., 2008), EEG variation in ADHD (Loo et al., mean reaction times for incorrect responses, and displayed higher 2009, 2003), MRI volumetric changes (Durston et al., 2005) and activity levels compared to children without the allele. The children drug treatment response (Cheon et al., 2005; Gruber et al., 2009; with and without allele 7R did not differ significantly in the number Lott et al., 2005) which are all correlated with DAT1 marker poly- of ADHD symptoms when the symptoms were split into the areas of morphisms. Not all studies of ADHD are positive for DAT1 (Bakker inattention and hyperactivity/impulsivity (Langley et al., 2004). et al., 2005; Banoei et al., 2008; Bobb et al., 2005; Cheuk et al., 2006; A family-based association analysis of the DRD4 120-bp inser- Friedel et al., 2007; Galili-Weisstub and Segman, 2003; Guan et al., tion/deletion promoter 1.2 kb upstream of the transcriptional start 2009; Hebebrand et al., 2006; Kim et al., 2005; Kustanovich et al., site showed a significant association with ADHD in 372 ADHD cases 2004; Langley et al., 2005; Lunetta et al., 2000; Maher et al., 2002; and their parents (McCracken et al., 2000). This finding was sup- Qian et al., 2004; Simsek et al., 2006; Smith et al., 2003; Swanson ported in an expanded ADHD sample (Kustanovich et al., 2004). et al., 2000; Todd et al., 2001; Wang et al., 2008). This can be However, there have been a number of studies that have failed to explained by hidden population stratification between cases and replicate these findings and a meta-analysis of the data from this controls, by lack of power due to small sample sizes and also by polymorphism found no evidence for association (Gizer et al., extensive genetic heterogeneity even within European populations 2009). SNP rs1800955 located 521 bp upstream of the DRD4 tran- (Gizer et al., 2009). The DAT1 findings are supported by brain scriptional start site has recently been found to show association imaging changes in ADHD which find abnormalities in the fronto- with ADHD in a Korean sample (P ¼ 0.013, Yang et al., 2008). striatal circuits (Durston, 2003). The finding of behavioural changes Previous case control and TDT studies had not found evidence for in DAT1 mice heterozygous and homozygous for DAT1 hypofunction, association with this polymorphism however, meta-analysis of the such as neophobia, behavioural inflexibility, anxiety-reduction, data (Barr et al., 2001a; Kereszturi et al., 2007; Lowe et al., 2004b; increased novelty seeking and increased stereotypical-perseveration Payton et al., 2001) suggests that this polymorphism may have are all compatible with human ADHD. a role in ADHD (fixed effects P ¼ 0.007, Gizer et al., 2009). Alleles of both of these upstream polymorphisms have been reported to alter 3.2. Other monoamine related genes associated with ADHD promoter activity (D’Souza et al., 2004; Okuyama et al., 1999). Over- transmission of paternal risk alleles with the DRD4 SNP rs12720373 Several other monoamine related genes dopamine beta was also observed in an Irish ADHD sample (Hawi et al., 2005). hydroxylase (DBH), D4 dopamine receptor (DRD4), D5 dopamine receptor (DRD5), serotonin 1B receptor (HTR1B) and synaptosomal- 3.4. The dopamine D5 receptor (DRD5) associated protein 25 isoform (SNAP25) have been associated with ADHD (Brophy et al., 2002; Daly et al., 1999; Hawi et al., 2002; Lowe A 146-bp dinucleotide repeat allele 18.5 kb from the DRD5 gene et al., 2004a; Sheehan et al., 2005). has been associated with ADHD (P ¼ 0.02). The estimated genotype S.I. Sharp et al. / Neuropharmacology 57 (2009) 590–600 593 relative risk of 1.7 was modest (Kustanovich et al., 2004). However, were both shown not to be associated with ADHD in a meta-anal- the 148 bp allele of the DRD5 microsatellite was not found to be ysis (Gizer et al., 2009). associated with ADHD in 236 Dutch families (Bakker et al., 2005). A meta-analysis of nine DRD5 studies shows that the 148 bp allele 3.8. The alpha2A and 1A adrenergic receptors of the dinucleotide repeat is significantly associated with ADHD (ADRA2A and ADRA1A) (fixed effects P ¼ 0.000095; random effects P ¼ 0.0027) with moderately significant heterogeneity in effect sizes across studies Methylphenidate, prescribed to treat ADHD, increases cate- (Gizer et al., 2009). cholaminergic activity through increased activation of alpha2A adrenergic receptors (Andrews and Lavin, 2006). In a Brazilian 3.5. The tachykinin receptor 1 (TACR1) sample of 92 ADHD patients and their biologic parents, the GG genotype of the 1291C-G SNP (rs1800544) of the ADRA2A gene Another gene strongly related to dopaminergic function in the was associated with inattention and combined ADHD scores prefrontal cortex is the neurokinin (substance P) receptor (NK1R) (P ¼ 0.02, Roman et al., 2003). In a new sample of 128 Brazilian also called the tachykinin receptor 1 (TACR1). In a knockout mouse ADHD probands, the ADRA2A GG genotype was also associated lacking the TACR1 gene (NK1R/) mice were found to be hyper- with symptoms of inattention (Roman et al., 2006). However active (Yan et al., 2009). This was prevented by psychostimulants a meta-analysis of 11 studies could not confirm the ADRA2A (D-amphetamine and methylphenidate). The mice had reduced association with ADHD (Gizer et al., 2009). A recent study has (>50%) spontaneous dopamine efflux in the prefrontal cortex and found allelic association between the ADRA1A gene and ADHD displayed lack of the striatal dopamine response to D-amphet- (Elia et al., 2009a) amine. These behavioural and neurochemical abnormalities in NK1R/ mice, together with their atypical response to psychos- 3.9. The dopamine D2 receptor (DRD2) timulants, are very similar to clinical characteristics of ADHD in humans (see: Stanford et al. (ibid)). An allelic association study of Early studies focused on a Taq1 polymorphism (rs1800497) 450 ADHD cases and 600 controls found that four TACR1 SNPs 10 kb downstream of DRD2. This SNP causes a non-synonymous previously associated with bipolar disorder and alcoholism were Glu to Lys change in an exon of neighbouring ANKK1 gene. SNP also associated with ADHD (Yan et al., 2009). If confirmed TACR1 rs1800497 has been shown to affect DRD2 expression (Hirvonen may turn out to be another dopamine related gene which is more et al., 2004), the levels of the dopamine metabolite homovanillic strongly associated with an affective disorder subgroup of ADHD acid (Ponce et al., 2004) and has been implicated in alcohol rather than the CD subtype. dependence (Blum et al., 1991). The first study to report an asso- ciation between with the rs1800497 A2A2 genotype and the 3.6. The serotonin 1B receptor (HTR1B) highest mean level of symptoms in children with ADHD did not find significant effect sizes of the SNP (Rowe et al., 1999). Results of six Evidence of significant genetic association of the 861G allele of studies were reviewed in a meta-analysis, which showed a signifi- the HTR1B gene using parent offspring transmission tests has been cant association between the A1 allele and childhood ADHD (fixed shown in 273 European families (P ¼ 0.0065, Hawi et al., 2002), as effects P < 0.001). There was only a trend towards an association well as in 115 Canadian families (P ¼ 0.03, Quist et al., 2003). with random effects analysis (P ¼ 0.110), although this may be Similarly, paternal over-transmission of the HTR1B G861 allele to explained by the significant heterogeneity of effect sizes across offspring with the inattentive ADHD subtype was observed in 12 studies (Gizer et al., 2009). This gene has been convincingly asso- multi-generational Centre d’Etude du Polymorphisme Humain ciated with alcoholism in many genetic association studies as well (CEPH) pedigrees, comprising 229 families of ADHD probands as in a linkage study (Cook et al., 1996). A recent genetic association (Smoller et al., 2006). A haplotype block encompassing the gene report showed that DRD2 may be associated with dis-social was associated with the inattentive ADHD subtype. In addition, psychopathic personality traits rather than alcoholism per se three polymorphisms in this block were nominally associated with (Ponce et al., 2008). this subtype but did not remain significant after correction for multiple testing (Smoller et al., 2006). Meta-analysis from nine 3.10. Tryptophan hydroxylase 1 (TPH1) studies indicates a modest, yet significant, risk associated with the HTR1B 861 G allele on susceptibility to ADHD (fixed Tryptophan hydroxylase (TPH) catalyzes tryptophan in a rate- effects P ¼ 0.01) with no heterogeneity in study-effect sizes (Gizer limiting step to synthesise 5-hydroxy-tryptophan (5-HT), the et al., 2009). precursor for serotonin. A silent polymorphism in intron 7 (rs1800532) of tryptophan hydroxylase gene, TPH1, was identified 3.7. Dopamine beta hydroxylase (DBH) and the rare 218A/6526G haplotype was significantly under- transmitted to probands with ADHD (P ¼ 0.034) in the Chinese Han Dopamine beta hydroxylase gene (DBH) polymorphisms have population (Li et al., 2006b). This association was confirmed in been shown to influence plasma dopamine beta hydroxylase (DbH) a meta-analysis of four studies (Gizer et al., 2009). activity. Low plasma DbH levels are said to be associated with CD (Bowden et al., 1988). A significant association between an SNP in 3.11. Tryptophan hydroxylase 2 (TPH2) DBH (rs2519152) has been shown in 118 children with ADHD (Daly et al., 1999). Meta-analysis of six studies (Gizer et al., 2009) found A second isoform of TPH (Walther and Bader, 2003), coded for a trend towards an association between the DBH A2 allele and by the TPH2 gene, was found to be responsible for TPH expression ADHD (P ¼ 0.074). However, there was significant heterogeneity in the brain, not TPH1. Excess transmission of two SNPs in the TPH2 between the study-effect sizes (P ¼ 0.004). After correcting for this gene in 225 children with ADHD in 103 families was found using by removing one study from the analysis, heterogeneity was the pedigree disequilibrium test (Walitza et al., 2005). A second reduced (P ¼ 0.057), increasing evidence for an association study reported association with SNPs in intron 5 (Sheehan et al., between the A2 allele and ADHD. Two functional mutations, 2005). Neither marker was significantly associated with ADHD in rs1108580 and rs1611115 associated with plasma levels of DbH a meta-analysis (Gizer et al., 2009; Sheehan et al., 2005). 594 S.I. Sharp et al. / Neuropharmacology 57 (2009) 590–600

3.12. Serotonin 2A receptor (HTR2A) 3.16. Central nicotinic cholinergic A4 receptor (CHRNA4)

Serotonin-2A receptor antagonists block increases in dopamine Nicotine agonists reduce ADHD symptom severity (Levin et al., activity and hyperlocomotion following amphetamine treatment 2001). Association between CHRNA4 markers and ADHD has been (O’Neill et al., 1999). However, meta-analysis of three SNPs (rs6311, described, although an SNP found in exon 5 was not associated with rs6313 and rs6314), previously implicated in ADHD, showed the ADHD in 70 children (Kent et al., 2001). A non-significant trend association was non-significant (Gizer et al., 2009). towards an association with two additional SNPs in exon 5 (rs2273506 and rs6090384) and ADHD has been reported (Gizer et al., 2009). 3.13. Solute carrier 6A2 noradrenaline transporter (SLC6A2) 3.17. Catechol-O-methyl transferase (COMT) The noradrenaline transporter gene (SLC6A2) is highly expressed in the frontal cortex and regulates noradrenaline and Early-onset anti-social behaviour accompanied by ADHD is dopamine reuptake. It is an initial site of action for therapeutic a clinically severe variant of anti-social behaviour with a poor drugs such as amphetamines (Pacholczyk et al., 1991) that are used outcome (Thapar et al., 2005). In 240 British children with ADHD in the treatment of ADHD (Solanto, 1998). Neither a synonymous or hyperkinetic disorder, the COMT val158met variation (rs4680) SNP (rs5569) in exon 9 of SLC6A2 nor a T to C SNP in intron 13 was associated with increased symptoms of CD and a significant (rs2242447) were significantly associated with ADHD following gene–environment interaction between the COMT polymorphism meta-analysis of five studies (Gizer et al., 2009). and birth weight was confirmed (Thapar et al., 2005). A meta- analysis of 16 studies found no significant association between 3.14. Solute carrier 5A4 serotonin transporter (SLC5A4) the COMT val158met polymorphism (Gizer et al., 2009).

A functional 44 bp deletion/insertion polymorphism in the 3.18. Monoamine oxidase A (MAOA) promoter region 5-hydoxytryptamine (5-HT, serotonin) trans- porter (5-HTT) gene, SLC6A4, has been associated with depression Monoamine oxidase A and B catalyze the oxidative deamination and anxiety (Acosta et al., 2004; Lotrich and Pollock, 2004; of naturally occurring monoamines, dopamine, noradrenaline, and Munafo et al., 2006; Schinka et al., 2004). The long promoter serotonin. Furthermore, MAO inhibitors have been shown to variant is associated with more rapid reuptake of serotonin than improve the symptoms of ADHD (Zametkin et al., 1985). Impulsive the short allele (Lesch et al., 1996). Meta-analysis of ten TDT and aggressive behaviour have shown to be caused by a stop codon studies and nine case control and haplotype relative risk studies mutation in MAOA in a large Dutch family (Brunner et al., 1993). shows a significant association with the long allele and ADHD Several polymorphisms near or in MAOA have been reported to be (fixed effects P ¼ 0.004, random effects P ¼ 0.010), with significant associated with ADHD (Jiang et al., 2006; Payton et al., 2001), while heterogeneity across studies (P ¼ 0.00003, Gizer et al., 2009). a functional 30 bp VNTR comprising 2, 3, 3.5, 4, or 5 copies, 1.2 kb Furthermore, a 17 bp VNTR in intron 2 and an SNP in the 30 UTR upstream of MAOA, is associated with impulsivity and aggressive (rs3813034) have been associated with ADHD. The 12-repeat allele behaviour (Manuck et al., 2000). Meta-analysis of six studies of the VNTR has been shown to enhance transcription more than indicates a non-significant association between ADHD and the the 10 repeat allele (Fiskerstrand et al., 1999; MacKenzie and high-activity MAOA alleles (Gizer et al., 2009). Quinn, 1999). SNP rs3813034 is a putative polyadenylation site that may affect mRNA stability (Battersby et al., 1999). Neither 4. Genome-wide association studies (GWAS) polymorphism was found to be significantly associated with ADHD when results from nine studies were tested in a meta-analysis A recent review of the first few attempts at genome-wide (Gizer et al., 2009). association studies (GWAS) of ADHD (Franke et al., 2009) reported that few studies had been completed and that sample sizes were still too small to unravel heterogeneity. Unlike previous genetic 3.15. Synaptosomal-associated protein 25 isoform association studies of ADHD highlighting genes involved in (SNARE protein SNAP25) monoaminergic neurotransmission the studies completed with genome-wide methods provide some evidence for the involvement The synaptosomal-associated protein of 25 kDa gene (SNAP25) of genes in cell division, cell adhesion especially via the cadherin has been suggested as a genetic susceptibility factor in ADHD gene, CDH13, and also the integrin system. Genes implicated in based on the mouse strain coloboma. Four polymorphisms in neuronal migration and plasticity; along with gene transcription, SNAP25 were significantly associated with ADHD in 186 Canadian cell polarity and extracellular matrix regulation as well as cyto- families with 234 ADHD children (P ¼ 0.039–0.005) (Feng et al., skeletal remodelling processes have shown some degree of allelic 2005a). However, these results were not replicated in an inde- association with ADHD (Franke et al., 2009). pendent sample of 99 families with 102 ADHD children from The first GWAS in ADHD was set up by the Genetic Association southern California, possibly due to differences in selection Information Network (GAIN) (Manolio et al., 2007), which collected criteria, ethnicity, medication response and other clinical charac- 958 Caucasian case-parent trios as part of the International teristics of the samples (Feng et al., 2005a). Analysis of the DSM- Multicentre ADHD genetics (IMAGE) study in children (Brookes IV subtypes in the Toronto sample indicated that the differential et al., 2006a; Kuntsi et al., 2006). A TDT analysis of a categorically results were not attributable to ADHD subtype. Quantitative trait defined ADHD phenotype identified a highly significant imbalance analyses of the dimensions of hyperactivity/impulsivity and in the number of major and minor allele over-transmissions. After inattention in the Toronto sample found that both behavioral applying a correction factor the research identified 25 SNPs in or traits were associated with SNAP25. Meta-analysis revealed that near genes with a putative role in ADHD, including nucleobindin 1, only one of the four SNPs (rs3746544) in SNAP25 to be signifi- cannabinoid receptor 1 (CNR1), potassium channel interacting cantly associated with ADHD across seven studies (Gizer et al., protein 1 isoform 2 and protein 4 isoform 3 (KCNIP1 and KCNIP4), 2009). cytoskeletal-organizer doublecortin and CaM kinase-like 1 S.I. Sharp et al. / Neuropharmacology 57 (2009) 590–600 595

(DCLK1), cadherin 13 (CDH13), inositol 1,4,5-triphophate 2 (ITPR2), 5. Copy number variants and extracellular matrix component SPOCK3 (Lasky-Su et al., 2008b; Neale et al., 2008). The CNR1 gene falls within a linkage Copy number variants (CNVs) arising through non-allelic region for ADHD (Ogdie et al., 2004; Zhou et al., 2008b) and was homologous recombination play an important role in the aetiology previously associated with ADHD in candidate gene-based associ- of psychiatric disorders such autism, bipolar disorder, schizo- ation studies (Lu et al., 2008; Ponce et al., 2003). phrenia (Cichon et al., 2009) and ADHD. A girl with ADHD was Cadherin 13 or T-cadherin is a cell adhesion protein (Patel et al., shown to have a de novo 600 kb deletion on a maternal copy of 2003) and also acts as a negative regulator of neural cell growth chromosome 16p11.2, encompassing CORO1A (coronin-1A, essen- (Takeuchi et al., 2000). The CDH13 protein is expressed on neuronal tial for T cell release from the thymus), flanked by 146 kb segmental cell surface membranes and on neurites in the adult cerebral cortex, duplications (Shiow et al., 2009). Deletion as well as duplication at medulla oblongata, and nucleus olivaris (Takeuchi et al., 2000) the 16q11.2 locus has also been associated with autism spectrum which are brain regions that are relevant to ADHD. The cerebellum, disorder and neurodevelopmental disorders (Ghebranious et al., prefrontal and frontal cortical regions show significant volumetric 2007). One recent study has identified 222 structural variants in reduction in ADHD (Makris et al., 2007). One study focusing on the 335 ADHD patients and their parents, that were not detected in quantitative ADHD phenotypes of the GAIN/IMAGE GWAS identi- 2026 unrelated healthy controls (Elia et al., 2009b). No excess fied one SNP in an intron of CDH13, located on chromosome 16q24, deletions or insertions were found in ADHD patients, although which was strongly associated with the family-based association inherited rare CNVs encompassed genes that have been identified test-principal components (FBAT-PC) analyses of total ADHD in structural variation studies carried out on neuropsychiatric and symptom scores (Lasky-Su et al., 2008b). Furthermore, CDH13 was neurological disorders. These genes include A2BP1, APOL4, CHL1, highlighted in a second GWAS with pooled DNA from 343 German CHN2, CNTNAP2, CPLX2, CTNND2, DPP6, GRM5, GRM7, NKAIN2, patients with persistent ADHD and 304 controls (Lesch et al., 2008). PARK2, RTN4, SEPP1, SERPINI1 and TACR3. Some of these such as Of additional interest, one genome-wide scan found that CDH13 is GRM7, DPP6 and TACR3 have been nominally associated with associated with methamphetamine abuse and dependence (Uhl bipolar disorder in a recent GWAS (Ferreira et al., 2008). The et al., 2008). The GAIN/IMAGE GWAS identified a second association deletion in the glutamate receptor gene (GRM5) was identified in with the FBAT-PC phenotype for inattentive symptoms and an SNP an affected parent and three affected offspring, who displayed in glucose-fructose oxidoreductase-domain containing 1 gene, problems with spatial orientation (Elia et al., 2009b), a behavioural GFOD1, which may be involved in electron transport (Lasky-Su trait in the GRM5 knockout mouse (Lu et al., 1997). The CNV in et al., 2008b). GRM7 was present in an ADHD proband who presented with an A third positive SNP in the GAIN/IMAGE study was in the anxiety disorder. Additional genes disrupted by CNVs in ADHD that neuronal nitric oxide synthase (NOS1) gene which was significantly are also thought to be involved in autism include AUTS2, and associated with ADHD (Lasky-Su et al., 2008b). The NOS1 gene has IMMP2L. Furthermore, other ADHD CNV-associated genes are been associated with impulsive and aggressive behaviour and implicated in learning, behaviour, synaptic transmission and ADHD (Reif, 2009; Reif et al., 2009) as well as schizophrenia (Reif neuronal development. These include the ADHD CNV disrupted et al., 2006). Other SNPs found to have some degree of association gene ATM, which has been associated with ataxia-telangiectasia in the GAIN/IMAGE GWAS include the familiar monoamine related and neurodegeneration, while BLMH and PDCD10 are associated genes SLC9A9, DDC, SNAP25, SLC6A1, ADRB2, HTR1E, ADRA1A, with Alzheimer’s disease and cerebral cavernous malformations, DBH, BDNF, DRD2, TPH2, HTR2A, SLC6A2, PER1, CHRNA4, COMPT respectively. Four separate deletions were found in the protein and SYT1 (Lasky-Su et al., 2008b). In a GWAS using pooled DNA, tyrosine phosphatase gene (PTPRD), a gene thought to play a role in none of the findings achieved genome-wide significance, however, restless leg syndrome, which is a common symptom in ADHD (Elia several genes were of interest to ADHD including CTNNA2, MOBP, et al., 2009b). It is of note that a CNV in the tachykinin receptor 3 MAP1B, REEP5, ASTN2, ATP2C2, CDH13 (as mentioned above), and (TACR3) gene was found to be associated with ADHD. ITGAE, along with KALRN, ZNF354C, WRNIP1, GRB10, DPP6, ARH- GAP22, RAB38, FAT2, DA259379, NDT5DC3 genes. Several of these 6. Discussion genes are involved in neuronal plasticity, cell–cell communication and/or adhesion (Lesch et al., 2008). Clinical genetic studies of ADHD demonstrate a rich variety of In addition to replication of association between CDH13 and comorbidities and patterns of familial recurrence. The earlier ADHD in two genome-wide studies there has also been replication linkage studies which showed heterogeneity of linkage showed of the genetic association between the brain expressed metal- a quite pleasing concordance with the later genetic association loprotease genes TLL1 and TLL2 genes with ADHD (Lasky-Su et al., studies implicating single genes such as those on 5p and 17q. The 2008b; Lesch et al., 2008). The genes HAS3, SPOCK3, MAN2A2, evidence for association between DAT1 on 5p and ADHD is very GPC6, MMP24, KCNIP1, KCNIP4, and DPP10 have all been found to strong and it has become a test bed for the molecular genetic be associated with ADHD in three studies (Lasky-Su et al., 2008b; approach to psychiatric disorders. Sequencing and gene expression Lesch et al., 2008; Neale et al., 2008). studies should soon find aetiological base pair changes actually One GWAS has taken a novel analytical approach to evaluate responsible for the underlying molecular pathology. gene–environment interaction using maternal warmth and criti- Once it is accepted that there are no common high frequency cism as a variable but no interactions with ADHD reached genome- genetic markers associated with ADHD and that there is extensive wide significance. Nineteen SNPs were associated with ADHD in the heterogeneity it is possible to interpret the more recent genome- presence of genetic effects, while two SNPs were related to wide association literature. The earlier candidate gene association maternal criticism. KIF6 and PIWIL4 as well as unique SNPs in studies required much less stringent statistical correction for a region on chromosome 13 were associated with maternal warmth multiple testing and one can argue that they were successful. The (Sonuga-Barke et al., 2008). Several genetic associations were multiple testing problem with microarray data means that it is replicated including the MTA3 gene association on chromosome premature to draw any strong statistical conclusions from the 2(Lasky-Su et al., 2008b; Sonuga-Barke et al., 2008) as well as DDC, current GWAS data. In any case the extant GWAS are underpow- HTR2A and SLC9A9 (Brookes et al., 2006a; Sonuga-Barke et al., ered and none of the results would have been expected to show 2008). genome-wide significance levels of association with ADHD 596 S.I. Sharp et al. / Neuropharmacology 57 (2009) 590–600

(Franke et al., 2009). Genes with dominant effects associated with deficit disorder and in their relatives: a controlled family study. Am. J. Psychi- ADHD subtype phenotypes have been proposed (Acosta et al., atry 144, 330–333. Biederman, J., Faraone, S.V., Keenan, K., Knee, D., Tsuang, M.T., 1990. Family-genetic 2004). A plausible outcome is likely to be a mixture of dominant and psychosocial risk factors in DSM-III attention deficit disorder. J. Am. Acad. and recessive major genes with other more complex, perhaps Child. Adolesc. Psychiatry 29, 526–533. polygenic, transmission patterns. Genome-wide association Biederman, J., Faraone, S.V., Keenan, K., Tsuang, M.T., 1991a. Evidence of familial association between attention deficit disorder and major affective disorders. studies based on clinical subtypes and endophenotypes of ADHD Arch. Gen. Psychiatry 48, 633–642. are needed in much larger samples. Inherited CNVs could plau- Biederman, J., Newcorn, J., Sprich, S., 1991b. Comorbidity of attention deficit sibly play an increasingly important role in the diagnosis and hyperactivity disorder with conduct, depressive, anxiety, and other disorders. Am. J. Psychiatry 148, 564–577. treatment of ADHD after they have been further investigated. The Biederman, J., Faraone, S.V., Hatch, M., Mennin, D., Taylor, A., George, P., 1997. field of ADHD genetics has moved into a highly productive phase Conduct disorder with and without mania in a referred sample of ADHD and new treatment and preventive strategies are already being children. J. Affect Disord. 44, 177–188. Biederman, J., Mick, E., Wozniak, J., Monuteaux, M.C., Galdo, M., Faraone, S.V., 2003. sought with the genetic information obtained. Can a subtype of conduct disorder linked to bipolar disorder be identified? Integration of findings from the Massachusetts General Hospital Pediatric Psychopharmacology Research Program. Biol. Psychiatry 53, 952–960. References Biederman, J., Petty, C.R., Byrne, D., Wong, P., Wozniak, J., Faraone, S.V., 2009. Risk for switch from unipolar to bipolar disorder in youth with ADHD: a long term Acosta, M.T., Arcos-Burgos, M., Muenke, M., 2004. Attention deficit/hyperactivity prospective controlled study. J. Affect Disord. disorder (ADHD): complex phenotype, simple genotype? Genet. Med. 6, 1–15. Blum, K., Noble, E.P., Sheridan, P.J., Finley, O., Montgomery, A., Ritchie, T., American-Psychiatric-Association, 1994. Diagnostic and Statistical Manual of Ozkaragoz, T., Fitch, R.J., Sadlack, F., Sheffield, D., et al., 1991. Association of the Mental Disorders. American Psychiatric Association, Washington, DC. A1 allele of the D2 dopamine receptor gene with severe alcoholism. Alcohol 8, Andrews, G.D., Lavin, A., 2006. Methylphenidate increases cortical excitability via 409–416. activation of alpha-2 noradrenergic receptors. Neuropsychopharmacology 31, Bobb, A.J., Addington, A.M., Sidransky, E., Gornick, M.C., Lerch, J.P., Greenstein, D.K., 594–601. Clasen, L.S., Sharp, W.S., Inoff-Germain, G., Wavrant-De Vrieze, F., Arcos- Arcos-Burgos, M., Castellanos, F.X., Pineda, D., Lopera, F., Palacio, J.D., Palacio, L.G., Burgos, M., Straub, R.E., Hardy, J.A., Castellanos, F.X., Rapoport, J.L., 2005. Rapoport, J.L., Berg, K., Bailey-Wilson, J.E., Muenke, M., 2004. Attention-deficit/ Support for association between ADHD and two candidate genes: NET1 and hyperactivity disorder in a population isolate: linkage to loci at 4q13.2, 5q33.3, DRD1. Am. J. Med. Genet. B Neuropsychiatr. Genet. 134B, 67–72. 11q22, and 17p11. Am. J. Hum. Genet. 75, 998–1014. Boonstra, A.M., Kooij, J.J., Buitelaar, J.K., Oosterlaan, J., Sergeant, J.A., Heister, J.G., Asghari, V., Sanyal, S., Buchwaldt, S., Paterson, A., Jovanovic, V., Van Tol, H.H., 1995. Franke, B., 2008. An exploratory study of the relationship between four Modulation of intracellular cyclic AMP levels by different human dopamine D4 candidate genes and neurocognitive performance in adult ADHD. Am. J. Med. receptor variants. J. Neurochem. 65, 1157–1165. Genet. B Neuropsychiatr. Genet. 147, 397–402. Asherson, P., Brookes, K., Franke, B., Chen, W., Gill, M., Ebstein, R.P., Buitelaar, J., Bowden, C.L., Deutsch, C.K., Swanson, J.M., 1988. Plasma dopamine-beta-hydroxy- Banaschewski, T., Sonuga-Barke, E., Eisenberg, J., Manor, I., Miranda, A., lase and platelet monoamine oxidase in attention deficit disorder and conduct Oades, R.D., Roeyers, H., Rothenberger, A., Sergeant, J., Steinhausen, H.C., disorder. J. Am. Acad. Child. Adolesc. Psychiatry 27, 171–174. Faraone, S.V., 2007. Confirmation that a specific haplotype of the dopamine Brookes, K., Xu, X., Chen, W., Zhou, K., Neale, B., Lowe, N., Anney, R., Franke, B., transporter gene is associated with combined-type ADHD. Am. J. Psychiatry Gill, M., Ebstein, R., Buitelaar, J., Sham, P., Campbell, D., Knight, J., Andreou, P., 164, 674–677. Altink, M., Arnold, R., Boer, F., Buschgens, C., Butler, L., Christiansen, H., Asherson, P., Zhou, K., Anney, R.J., Franke, B., Buitelaar, J., Ebstein, R., Gill, M., Feldman, L., Fleischman, K., Fliers, E., Howe-Forbes, R., Goldfarb, A., Heise, A., Altink, M., Arnold, R., Boer, F., Brookes, K., Buschgens, C., Butler, L., Cambell, D., Gabriels, I., Korn-Lubetzki, I., Johansson, L., Marco, R., Medad, S., Minderaa, R., Chen, W., Christiansen, H., Feldman, L., Fleischman, K., Fliers, E., Howe- Mulas, F., Muller, U., Mulligan, A., Rabin, K., Rommelse, N., Sethna, V., Sorohan, J., Forbes, R., Goldfarb, A., Heise, A., Gabriels, I., Johansson, L., Lubetzki, I., Marco, R., Uebel, H., Psychogiou, L., Weeks, A., Barrett, R., Craig, I., Banaschewski, T., Medad, S., Minderaa, R., Mulas, F., Muller, U., Mulligan, A., Neale, B., Rijsdijk, F., Sonuga-Barke, E., Eisenberg, J., Kuntsi, J., Manor, I., McGuffin, P., Miranda, A., Rabin, K., Rommelse, N., Sethna, V., Sorohan, J., Uebel, H., Psychogiou, L., Oades, R.D., Plomin, R., Roeyers, H., Rothenberger, A., Sergeant, J., Weeks, A., Barrett, R., Xu, X., Banaschewski, T., Sonuga-Barke, E., Eisenberg, J., Steinhausen, H.C., Taylor, E., Thompson, M., Faraone, S.V., Asherson, P., 2006a. Manor, I., Miranda, A., Oades, R.D., Roeyers, H., Rothenberger, A., Sergeant, J., The analysis of 51 genes in DSM-IV combined type attention deficit hyperac- Steinhausen, H.C., Taylor, E., Thompson, M., Faraone, S.V., 2008. A high-density tivity disorder: association signals in DRD4, DAT1 and 16 other genes. Mol. SNP linkage scan with 142 combined subtype ADHD sib pairs identifies linkage Psychiatry 11, 934–953. regions on chromosomes 9 and 16. Mol. Psychiatry 13, 514–521. Brookes, K.J., Mill, J., Guindalini, C., Curran, S., Xu, X., Knight, J., Chen, C.K., Bakker, S.C., van der Meulen, E.M., Buitelaar, J.K., Sandkuijl, L.A., Pauls, D.L., Huang, Y.S., Sethna, V., Taylor, E., Chen, W., Breen, G., Asherson, P., 2006b. A Monsuur, A.J., van ’t Slot, R., Minderaa, R.B., Gunning, W.B., Pearson, P.L., common haplotype of the dopamine transporter gene associated with atten- Sinke, R.J., 2003. A whole-genome scan in 164 Dutch sib pairs with attention- tion-deficit/hyperactivity disorder and interacting with maternal use of alcohol deficit/hyperactivity disorder: suggestive evidence for linkage on chromosomes during pregnancy. Arch. Gen. Psychiatry 63, 74–81. 7p and 15q. Am. J. Hum. Genet. 72, 1251–1260. Brophy, K., Hawi, Z., Kirley, A., Fitzgerald, M., Gill, M., 2002. Synaptosomal-associ- Bakker, S.C., van der Meulen, E.M., Oteman, N., Schelleman, H., Pearson, P.L., ated protein 25 (SNAP-25) and attention deficit hyperactivity disorder (ADHD): Buitelaar, J.K., Sinke, R.J., 2005. DAT1, DRD4, and DRD5 polymorphisms are not evidence of linkage and association in the Irish population. Mol. Psychiatry 7, associated with ADHD in Dutch families. Am. J. Med. Genet. B Neuropsychiatr. 913–917. Genet. 132B, 50–52. Brunner, H.G., Nelen, M., Breakefield, X.O., Ropers, H.H., van Oost, B.A., 1993. Banoei, M.M., Majidizadeh, T., Shirazi, E., Moghimi, N., Ghadiri, M., Najmabadi, H., Abnormal behavior associated with a point mutation in the structural gene for Ohadi, M., 2008. No association between the DAT1 10-repeat allele and ADHD in monoamine oxidase A. Science 262, 578–580. the Iranian population. Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B, 110–111. Carrasco, X., Rothhammer, P., Moraga, M., Henriquez, H., Chakraborty, R., Aboitiz, F., Barkley, R.A., Smith, K.M., Fischer, M., Navia, B., 2006. An examination of the Rothhammer, F., 2006. Genotypic interaction between DRD4 and DAT1 loci is behavioral and neuropsychological correlates of three ADHD candidate gene a high risk factor for attention-deficit/hyperactivity disorder in Chilean families. polymorphisms (DRD4 7þ, DBH TaqI A2, and DAT1 40 bp VNTR) in hyperactive Am. J. Med. Genet. B Neuropsychiatr. Genet. 141B, 51–54. and normal children followed to adulthood. Am. J. Med. Genet. B Neuro- Cheon, K.A., Ryu, Y.H., Kim, J.W., Cho, D.Y., 2005. The homozygosity for 10-repeat psychiatr. Genet. 141B, 487–498. allele at dopamine transporter gene and dopamine transporter density in Barr, C.L., Feng, Y., Wigg, K.G., Schachar, R., Tannock, R., Roberts, W., Malone, M., Korean children with attention deficit hyperactivity disorder: relating to Kennedy, J.L., 2001a. 50-Untranslated region of the dopamine D4 receptor gene treatment response to methylphenidate. Eur. Neuropsychopharmacol. 15, and attention-deficit hyperactivity disorder. Am. J. Med. Genet. 105, 84–90. 95–101. Barr, C.L., Xu, C., Kroft, J., Feng, Y., Wigg, K., Zai, G., Tannock, R., Schachar, R., Cheuk, D.K., Li, S.Y., Wong, V., 2006. No association between VNTR poly- Malone, M., Roberts, W., Nothen, M.M., Grunhage, F., Vandenbergh, D.J., Uhl, G., morphisms of dopamine transporter gene and attention deficit hyperactivity Sunohara, G., King, N., Kennedy, J.L., 2001b. Haplotype study of three poly- disorder in Chinese children. Am. J. Med. Genet. B Neuropsychiatr. Genet. morphisms at the dopamine transporter locus confirm linkage to attention- 141B, 123–125. deficit/hyperactivity disorder. Biol. Psychiatry 49, 333–339. Cichon, S., Craddock, N., Daly, M., Faraone, S.V., Gejman, P.V., Kelsoe, J., Lehner, T., Battersby, S., Ogilvie, A.D., Blackwood, D.H., Shen, S., Muqit, M.M., Muir, W.J., Levinson, D.F., Moran, A., Sklar, P., Sullivan, P.F., 2009. Genomewide association Teague, P., Goodwin, G.M., Harmar, A.J., 1999. Presence of multiple functional studies: history, rationale, and prospects for psychiatric disorders. Am. J. polyadenylation signals and a single nucleotide polymorphism in the 30 Psychiatry 166, 540–556. untranslated region of the human serotonin transporter gene. J. Neurochem. 72, Clure, C., Brady, K.T., Saladin, M.E., Johnson, D., Waid, R., Rittenbury, M., 1999. 1384–1388. Attention-deficit/hyperactivity disorder and substance use: symptom pattern Bellgrove, M.A., Mattingley, J.B., 2008. Molecular genetics of attention. Ann. NY and drug choice. Am. J. Drug Alcohol Abuse 25, 441–448. Acad. Sci. 1129, 200–212. Cook Jr., E.H., Stein, M.A., Krasowski, M.D., Cox, N.J., Olkon, D.M., Kieffer, J.E., Biederman, J., Munir, K., Knee, D., Armentano, M., Autor, S., Waternaux, C., Leventhal, B.L., 1995. Association of attention-deficit disorder and the dopamine Tsuang, M., 1987. High rate of affective disorders in probands with attention transporter gene. Am. J. Hum. Genet. 56, 993–998. S.I. Sharp et al. / Neuropharmacology 57 (2009) 590–600 597

Cook, C.C., Palsson, G., Turner, A., Holmes, D., Brett, P., Curtis, D., Petursson, H., Cantwell, D.P., Nelson, S.F., Monaco, A.P., Smalley, S.L., 2002. A genomewide scan Gurling, H.M., 1996. A genetic linkage study of the D2 dopamine receptor locus for loci involved in attention-deficit/hyperactivity disorder. Am. J. Hum. Genet. in heavy drinking and alcoholism. Br. J. Psychiatry 169, 243–248. 70, 1183–1196. Coolidge, F.L., Thede, L.L., Young, S.E., 2000. Heritability and the comorbidity of Fiskerstrand, C.E., Lovejoy, E.A., Quinn, J.P., 1999. An intronic polymorphic domain attention deficit hyperactivity disorder with behavioral disorders and executive often associated with susceptibility to affective disorders has allele dependent function deficits: a preliminary investigation. Dev. Neuropsychol. 17, 273–287. differential enhancer activity in embryonic stem cells. FEBS Lett. 458, 171–174. Curran, S., Mill, J., Tahir, E., Kent, L., Richards, S., Gould, A., Huckett, L., Sharp, J., Franke, B., Neale, B.M., Faraone, S.V., 2009. Genome-wide association studies in Batten, C., Fernando, S., Ozbay, F., Yazgan, Y., Simonoff, E., Thompson, M., ADHD. Hum. Genet. Taylor, E., Asherson, P., 2001. Association study of a dopamine transporter Friedel, S., Saar, K., Sauer, S., Dempfle, A., Walitza, S., Renner, T., Romanos, M., polymorphism and attention deficit hyperactivity disorder in UK and Turkish Freitag, C., Seitz, C., Palmason, H., Scherag, A., Windemuth-Kieselbach, C., samples. Mol. Psychiatry 6, 425–428. Schimmelmann, B.G., Wewetzer, C., Meyer, J., Warnke, A., Lesch, K.P., D’Souza, U.M., Russ, C., Tahir, E., Mill, J., McGuffin, P., Asherson, P.J., Craig, I.W., 2004. Reinhardt, R., Herpertz-Dahlmann, B., Linder, M., Hinney, A., Remschmidt, H., Functional effects of a tandem duplication polymorphism in the 50flanking Schafer, H., Konrad, K., Hubner, N., Hebebrand, J., 2007. Association and linkage region of the DRD4 gene. Biol. Psychiatry 56, 691–697. of allelic variants of the dopamine transporter gene in ADHD. Mol. Psychiatry Daly, G., Hawi, Z., Fitzgerald, M., Gill, M., 1999. Mapping susceptibility loci in 12, 923–933. attention deficit hyperactivity disorder: preferential transmission of parental Galili-Weisstub, E., Segman, R.H., 2003. Attention deficit and hyperactivity disorder: alleles at DAT1, DBH and DRD5 to affected children. Mol. Psychiatry 4, 192–196. review of genetic association studies. Isr. J. Psychiatry Relat. Sci. 40, 57–66. Das, M., Mukhopadhyay, K., 2007. DAT1 30-UTR 9R allele: preferential transmission Genro, J.P., Zeni, C., Polanczyk, G.V., Roman, T., Rohde, L.A., Hutz, M.H., 2007. A in Indian children with attention deficit hyperactivity disorder. Am. J. Med. promoter polymorphism (839 C > T) at the dopamine transporter gene is Genet. B Neuropsychiatr. Genet. 144B, 826–829. associated with attention deficit/hyperactivity disorder in Brazilian children. Durston, S., 2003. A review of the biological bases of ADHD: what have we learned Am. J. Med. Genet. B Neuropsychiatr. Genet. 144B, 215–219. from imaging studies? Ment. Retard. Dev. Disabil. Res. Rev. 9, 184–195. Genro, J.P., Polanczyk, G.V., Zeni, C., Oliveira, A.S., Roman, T., Rohde, L.A., Hutz, M.H., Durston, S., Fossella, J.A., Casey, B.J., Hulshoff Pol, H.E., Galvan, A., Schnack, H.G., 2008. A common haplotype at the dopamine transporter gene 50 region is Steenhuis, M.P., Minderaa, R.B., Buitelaar, J.K., Kahn, R.S., van Engeland, H., 2005. associated with attention-deficit/hyperactivity disorder. Am. J. Med. Genet. B Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter Neuropsychiatr. Genet. 147B, 1568–1575. volumes in a sample of subjects with attention deficit hyperactivity disorder, Ghebranious, N., Giampietro, P.F., Wesbrook, F.P., Rezkalla, S.H., 2007. A novel their unaffected siblings, and controls. Mol. Psychiatry 10, 678–685. microdeletion at 16p11.2 harbors candidate genes for aortic valve development, Ebstein, R.P., Novick, O., Umansky, R., Priel, B., Osher, Y., Blaine, D., Bennett, E.R., seizure disorder, and mild mental retardation. Am. J. Med. Genet. A 143A, Nemanov, L., Katz, M., Belmaker, R.H., 1996. Dopamine D4 receptor (D4DR) exon 1462–1471. III polymorphism associated with the human personality trait of Novelty Gizer, I.R., Ficks, C., Waldman, I.D., 2009. Candidate gene studies of ADHD: a meta- Seeking. Nat. Genet. 12, 78–80. analytic review. Hum. Genet. Elia, J., Capasso, M., Zaheer, Z., Lantieri, F., Ambrosini, P., Berrettini, W., Devoto, M., Gruber, R., Joober, R., Grizenko, N., Leventhal, B.L., Cook Jr., E.H., Stein, M.A., 2009. Hakonarson, H., 2009a. Candidate gene analysis in an on-going genome-wide Dopamine transporter genotype and stimulant side effect factors in youth association study of attention-deficit hyperactivity disorder: suggestive asso- diagnosed with attention-deficit/hyperactivity disorder. J. Child. Adolesc. ciation signals in ADRA1A. Psychiatr. Genet. 19, 134–141. Psychopharmacol. 19, 233–239. Elia, J., Gai, X., Xie, H.M., Perin, J.C., Geiger, E., Glessner, J.T., D’Arcy, M., Guan, L., Wang, B., Chen, Y., Yang, L., Li, J., Qian, Q., Wang, Z., Faraone, S.V., Wang, Y., Deberardinis, R., Frackelton, E., Kim, C., Lantieri, F., Muganga, B.M., Wang, L., 2009. A high-density single-nucleotide polymorphism screen of 23 candidate Takeda, T., Rappaport, E.F., Grant, S.F., Berrettini, W., Devoto, M., Shaikh, T.H., genes in attention deficit hyperactivity disorder: suggesting multiple suscep- Hakonarson, H., White, P.S., 2009b. Rare structural variants found in attention- tibility genes among Chinese Han population. Mol. Psychiatry 14, 546–554. deficit hyperactivity disorder are preferentially associated with neuro- Hawi, Z., Dring, M., Kirley, A., Foley, D., Kent, L., Craddock, N., Asherson, P., Curran, S., developmental genes. Mol. Psychiatry. Gould, A., Richards, S., Lawson, D., Pay, H., Turic, D., Langley, K., Owen, M., Fagerheim, T., Raeymaekers, P., Tonnessen, F.E., Pedersen, M., Tranebjaerg, L., O’Donovan, M., Thapar, A., Fitzgerald, M., Gill, M., 2002. Serotonergic system Lubs, H.A., 1999. A new gene (DYX3) for dyslexia is located on chromosome 2. and attention deficit hyperactivity disorder (ADHD): a potential susceptibility J. Med. Genet. 36, 664–669. locus at the 5-HT(1B) receptor gene in 273 nuclear families from a multi-centre Faraone, S.V., Doyle, A.E., Mick, E., Biederman, J., 2001. Meta-analysis of the asso- sample. Mol. Psychiatry 7, 718–725. ciation between the 7-repeat allele of the dopamine D(4) receptor gene and Hawi, Z., Lowe, N., Kirley, A., Gruenhage, F., Nothen, M., Greenwood, T., Kelsoe, J., attention deficit hyperactivity disorder. Am. J. Psychiatry 158, 1052–1057. Fitzgerald, M., Gill, M., 2003. Linkage disequilibrium mapping at DAT1, DRD5 Faraone, S.V., Perlis, R.H., Doyle, A.E., Smoller, J.W., Goralnick, J.J., Holmgren, M.A., and DBH narrows the search for ADHD susceptibility alleles at these loci. Mol. Sklar, P., 2005. Molecular genetics of attention-deficit/hyperactivity disorder. Psychiatry 8, 299–308. Biol. Psychiatry 57, 1313–1323. Hawi, Z., Segurado, R., Conroy, J., Sheehan, K., Lowe, N., Kirley, A., Shields, D., Faraone, S.V., Wilens, T.E., Petty, C., Antshel, K., Spencer, T., Biederman, J., 2007. Fitzgerald, M., Gallagher, L., Gill, M., 2005. Preferential transmission of paternal Substance use among ADHD adults: implications of late onset and subthreshold alleles at risk genes in attention-deficit/hyperactivity disorder. Am. J. Hum. diagnoses. Am. J. Addict. 16 (Suppl 1), 24–32. quiz 33–24. Genet. 77, 958–965. Faraone, S.V., Doyle, A.E., Lasky-Su, J., Sklar, P.B., D’Angelo, E., Gonzalez-Heydrich, J., Hebebrand, J., Dempfle, A., Saar, K., Thiele, H., Herpertz-Dahlmann, B., Linder, M., Kratochvil, C., Mick, E., Klein, K., Rezac, A.J., Biederman, J., 2008. Linkage analysis Kiefl, H., Remschmidt, H., Hemminger, U., Warnke, A., Knolker, U., Heiser, P., of attention deficit hyperactivity disorder. Am. J. Med. Genet. B Neuropsychiatr. Friedel, S., Hinney, A., Schafer, H., Nurnberg, P., Konrad, K., 2006. A genome- Genet. 147B, 1387–1391. wide scan for attention-deficit/hyperactivity disorder in 155 German sib-pairs. Fayyad, J., De Graaf, R., Kessler, R., Alonso, J., Angermeyer, M., Demyttenaere, K., De Mol. Psychiatry 11, 196–205. Girolamo, G., Haro, J.M., Karam, E.G., Lara, C., Lepine, J.P., Ormel, J., Posada- Henin, A., Mick, E., Biederman, J., Fried, R., Wozniak, J., Faraone, S.V., Harrington, K., Villa, J., Zaslavsky, A.M., Jin, R., 2007. Cross-national prevalence and correlates of Davis, S., Doyle, A.E., 2007. Can bipolar disorder-specific neuropsychological adult attention-deficit hyperactivity disorder. Br. J. Psychiatry 190, 402–409. impairments in children be identified? J. Consult. Clin. Psychol. 75, 210–220. Feng, Y., Crosbie, J., Wigg, K., Pathare, T., Ickowicz, A., Schachar, R., Tannock, R., Hirshfeld-Becker, D.R., Biederman, J., Henin, A., Faraone, S.V., Dowd, S.T., De Roberts, W., Malone, M., Swanson, J., Kennedy, J.L., Barr, C.L., 2005a. The SNAP25 Petrillo, L.A., Markowitz, S.M., Rosenbaum, J.F., 2006. Psychopathology in the gene as a susceptibility gene contributing to attention-deficit hyperactivity young offspring of parents with bipolar disorder: a controlled pilot study. disorder. Mol. Psychiatry 10, 998–1005. 1973. Psychiatry Res. 145, 155–167. Feng, Y., Wigg, K.G., Makkar, R., Ickowicz, A., Pathare, T., Tannock, R., Roberts, W., Hirvonen, M., Laakso, A., Nagren, K., Rinne, J.O., Pohjalainen, T., Hietala, J., 2004. Malone, M., Kennedy, J.L., Schachar, R., Barr, C.L., 2005b. Sequence variation in C957T polymorphism of the dopamine D2 receptor (DRD2) gene affects striatal the 30-untranslated region of the dopamine transporter gene and attention- DRD2 availability in vivo. Mol. Psychiatry 9, 1060–1061. deficit hyperactivity disorder (ADHD). Am. J. Med. Genet. B Neuropsychiatr. Hofvander, B., Ossowski, D., Lundstrom, S., Anckarsater, H., 2009. Continuity of Genet. 139B, 1–6. aggressive antisocial behavior from childhood to adulthood: the question of Ferreira, M.A., O’Donovan, M.C., Meng, Y.A., Jones, I.R., Ruderfer, D.M., Jones, L., phenotype definition. Int. J. Law Psychiatry 32, 224–234. Fan, J., Kirov, G., Perlis, R.H., Green, E.K., Smoller, J.W., Grozeva, D., Stone, J., Jaideep, T., Reddy, Y.C., Srinath, S., 2006. Comorbidity of attention deficit hyperac- Nikolov, I., Chambert, K., Hamshere, M.L., Nimgaonkar, V.L., Moskvina, V., tivity disorder in juvenile bipolar disorder. Bipolar Disord. 8, 182–187. Thase, M.E., Caesar, S., Sachs, G.S., Franklin, J., Gordon-Smith, K., Ardlie, K.G., Jiang, S.D., He, M., Qian, Y.P., Wang, D.X., Zhang, Y., Li, F., Tian, H.J., Xin, R.E., Gabriel, S.B., Fraser, C., Blumenstiel, B., Defelice, M., Breen, G., Gill, M., Tang, G.M., Wu, X.D., 2006. [Genome-wide search for linkage to attention deficit Morris, D.W., Elkin, A., Muir, W.J., McGhee, K.A., Williamson, R., MacIntyre, D.J., hyperactivity disorder (ADHD) on the X chromosome]. Yi Chuan 28, 26–30. MacLean, A.W., St, C.D., Robinson, M., Van Beck, M., Pereira, A.C., Kent, L., Middle, F., Hawi, Z., Fitzgerald, M., Gill, M., Feehan, C., Craddock, N., 2001. Kandaswamy, R., McQuillin, A., Collier, D.A., Bass, N.J., Young, A.H., Lawrence, J., Nicotinic acetylcholine receptor alpha4 subunit gene polymorphism and Ferrier, I.N., Anjorin, A., Farmer, A., Curtis, D., Scolnick, E.M., McGuffin, P., attention deficit hyperactivity disorder. Psychiatr. Genet. 11, 37–40. Daly, M.J., Corvin, A.P., Holmans, P.A., Blackwood, D.H., Gurling, H.M., Owen, M.J., Kereszturi, E., Kiraly, O., Csapo, Z., Tarnok, Z., Gadoros, J., Sasvari-Szekely, M., Purcell, S.M., Sklar, P., Craddock, N., 2008. Collaborative genome-wide associa- Nemoda, Z., 2007. Association between the 120-bp duplication of the dopamine tion analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat. D4 receptor gene and attention deficit hyperactivity disorder: genetic and Genet. 40, 1056–1058. molecular analyses. Am. J. Med. Genet. B Neuropsychiatr. Genet. 144B, 231–236. Fisher, S.E., Francks, C., McCracken, J.T., McGough, J.J., Marlow, A.J., MacPhie, I.L., Kessler, R.C., Adler, L., Barkley, R., Biederman, J., Conners, C.K., Demler, O., Newbury, D.F., Crawford, L.R., Palmer, C.G., Woodward, J.A., Del’Homme, M., Faraone, S.V., Greenhill, L.L., Howes, M.J., Secnik, K., Spencer, T., Ustun, T.B., 598 S.I. Sharp et al. / Neuropharmacology 57 (2009) 590–600

Walters, E.E., Zaslavsky, A.M., 2006. The prevalence and correlates of adult Lott, D.C., Kim, S.J., Cook Jr., E.H., de Wit, H., 2005. Dopamine transporter gene ADHD in the United States: results from the national comorbidity Survey associated with diminished subjective response to amphetamine. Neuro- replication. Am. J. Psychiatry 163, 716–723. psychopharmacology 30, 602–609. Kim, Y.S., Leventhal, B.L., Kim, S.J., Kim, B.N., Cheon, K.A., Yoo, H.J., Kim, S.J., Lowe, N., Kirley, A., Hawi, Z., Sham, P., Wickham, H., Kratochvil, C.J., Smith, S.D., Badner, J., Cook, E.H., 2005. Family-based association study of DAT1 and DRD4 Lee, S.Y., Levy, F., Kent, L., Middle, F., Rohde, L.A., Roman, T., Tahir, E., Yazgan, Y., polymorphism in Korean children with ADHD. Neurosci. Lett. 390, 176–181. Asherson, P., Mill, J., Thapar, A., Payton, A., Todd, R.D., Stephens, T., Ebstein, R.P., Kim, J.W., Kim, B.N., Cho, S.C., 2006. The dopamine transporter gene and the Manor, I., Barr, C.L., Wigg, K.G., Sinke, R.J., Buitelaar, J.K., Smalley, S.L., impulsivity phenotype in attention deficit hyperactivity disorder: a case-control Nelson, S.F., Biederman, J., Faraone, S.V., Gill, M., 2004a. Joint analysis of the association study in a Korean sample. J. Psychiatr. Res. 40, 730–737. DRD5 marker concludes association with attention-deficit/hyperactivity Kopeckova, M., Paclt, I., Petrasek, J., Pacltova, D., Malikova, M., Zagatova, V., 2008. disorder confined to the predominantly inattentive and combined subtypes. Some ADHD polymorphisms (in genes DAT1, DRD2, DRD3, DBH, 5-HTT) in Am. J. Hum. Genet. 74, 348–356. case-control study of 100 subjects 6–10 age. Neuro Endocrinol. Lett. 29, Lowe, N., Kirley, A., Mullins, C., Fitzgerald, M., Gill, M., Hawi, Z., 2004b. Multiple 246–251. marker analysis at the promoter region of the DRD4 gene and ADHD: evidence Kuntsi, J., Eley, T.C., Taylor, A., Hughes, C., Asherson, P., Caspi, A., Moffitt, T.E., 2004. of linkage and association with the SNP -616. Am. J. Med. Genet. B Neuro- Co-occurrence of ADHD and low IQ has genetic origins. Am. J. Med. Genet. B psychiatr. Genet. 131B, 33–37. Neuropsychiatr. Genet. 124B, 41–47. Lu, Y.M., Jia, Z., Janus, C., Henderson, J.T., Gerlai, R., Wojtowicz, J.M., Roder, J.C., 1997. Kuntsi, J., Neale, B.M., Chen, W., Faraone, S.V., Asherson, P., 2006. The IMAGE Mice lacking metabotropic glutamate receptor 5 show impaired learning and project: methodological issues for the molecular genetic analysis of ADHD. reduced CA1 long-term potentiation (LTP) but normal CA3 LTP. J. Neurosci. 17, Behav. Brain Funct. 2, 27. 5196–5205. Kustanovich, V., Ishii, J., Crawford, L., Yang, M., McGough, J.J., McCracken, J.T., Lu, A.T., Ogdie, M.N., Jarvelin, M.R., Moilanen, I.K., Loo, S.K., McCracken, J.T., Smalley, S.L., Nelson, S.F., 2004. Transmission disequilibrium testing of McGough, J.J., Yang, M.H., Peltonen, L., Nelson, S.F., Cantor, R.M., Smalley, S.L., dopamine-related candidate gene polymorphisms in ADHD: confirmation of 2008. Association of the cannabinoid receptor gene (CNR1) with ADHD and association of ADHD with DRD4 and DRD5. Mol. Psychiatry 9, 711–717. post-traumatic stress disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. Langley, K., Marshall, L., van den Bree, M., Thomas, H., Owen, M., O’Donovan, M., 147B, 1488–1494. Thapar, A., 2004. Association of the dopamine D4 receptor gene 7-repeat allele Lunetta, K.L., Faraone, S.V., Biederman, J., Laird, N.M., 2000. Family-based tests of with neuropsychological test performance of children with ADHD. Am. association and linkage that use unaffected sibs, covariates, and interactions. J. Psychiatry 161, 133–138. Am. J. Hum. Genet. 66, 605–614. Langley, K., Turic, D., Peirce, T.R., Mills, S., Van Den Bree, M.B., Owen, M.J., Lynn, D.E., Lubke, G., Yang, M., McCracken, J.T., McGough, J.J., Ishii, J., Loo, S.K., O’Donovan, M.C., Thapar, A., 2005. No support for association between the Nelson, S.F., Smalley, S.L., 2005. Temperament and character profiles and the dopamine transporter (DAT1) gene and ADHD. Am. J. Med. Genet. B Neuro- dopamine D4 receptor gene in ADHD. Am. J. Psychiatry 162, 906–913. psychiatr. Genet. 139B, 7–10. MacKenzie, A., Quinn, J., 1999. A serotonin transporter gene intron 2 polymorphic Lasky-Su, J., Lange, C., Biederman, J., Tsuang, M., Doyle, A.E., Smoller, J.W., Laird, N., region, correlated with affective disorders, has allele-dependent differential Faraone, S., 2008a. Family-based association analysis of a statistically derived enhancer-like properties in the mouse embryo. Proc. Natl. Acad. Sci. USA 96, quantitative traits for ADHD reveal an association in DRD4 with inattentive 15251–15255. symptoms in ADHD individuals. Am. J. Med. Genet. B Neuropsychiatr. Genet. Maher, B.S., Marazita, M.L., Ferrell, R.E., Vanyukov, M.M., 2002. Dopamine system 147B, 100–106. genes and attention deficit hyperactivity disorder: a meta-analysis. Psychiatr. Lasky-Su, J., Neale, B.M., Franke, B., Anney, R.J., Zhou, K., Maller, J.B., Vasquez, A.A., Genet. 12, 207–215. Chen, W., Asherson, P., Buitelaar, J., Banaschewski, T., Ebstein, R., Gill, M., Makris, N., Biederman, J., Valera, E.M., Bush, G., Kaiser, J., Kennedy, D.N., Miranda, A., Mulas, F., Oades, R.D., Roeyers, H., Rothenberger, A., Sergeant, J., Caviness, V.S., Faraone, S.V., Seidman, L.J., 2007. Cortical thinning of the atten- Sonuga-Barke, E., Steinhausen, H.C., Taylor, E., Daly, M., Laird, N., Lange, C., tion and executive function networks in adults with attention-deficit/hyper- Faraone, S.V., 2008b. Genome-wide association scan of quantitative traits for activity disorder. Cereb. Cortex 17, 1364–1375. attention deficit hyperactivity disorder identifies novel associations and Mannuzza, S., Klein, R.G., Bonagura, N., Malloy, P., Giampino, T.L., Addalli, K.A., 1991. confirms candidate gene associations. Am. J. Med. Genet. B Neuropsychiatr. Hyperactive boys almost grown up. V. Replication of psychiatric status. Arch. Genet. 147B, 1345–1354. Gen. Psychiatry 48, 77–83. Lesch, K.P., Bengel, D., Heils, A., Sabol, S.Z., Greenberg, B.D., Petri, S., Benjamin, J., Manolio, T.A., Rodriguez, L.L., Brooks, L., Abecasis, G., Ballinger, D., Daly, M., Muller, C.R., Hamer, D.H., Murphy, D.L., 1996. Association of anxiety-related Donnelly, P., Faraone, S.V., Frazer, K., Gabriel, S., Gejman, P., Guttmacher, A., traits with a polymorphism in the serotonin transporter gene regulatory region. Harris, E.L., Insel, T., Kelsoe, J.R., Lander, E., McCowin, N., Mailman, M.D., Science 274, 1527–1531. Nabel, E., Ostell, J., Pugh, E., Sherry, S., Sullivan, P.F., Thompson, J.F., Warram, J., Lesch, K.P., Timmesfeld, N., Renner, T.J., Halperin, R., Roser, C., Nguyen, T.T., Wholley, D., Milos, P.M., Collins, F.S., 2007. New models of collaboration in Craig, D.W., Romanos, J., Heine, M., Meyer, J., Freitag, C., Warnke, A., Romanos, M., genome-wide association studies: the genetic association information network. Schafer, H., Walitza, S., Reif, A., Stephan, D.A., Jacob, C., 2008. Molecular genetics Nat. Genet. 39, 1045–1051. of adult ADHD: converging evidence from genome-wide association and Manor, I., Tyano, S., Eisenberg, J., Bachner-Melman, R., Kotler, M., Ebstein, R.P., 2002. extended pedigree linkage studies. J. Neural Transm. 115, 1573–1585. The short DRD4 repeats confer risk to attention deficit hyperactivity disorder in Leung, P.W., Lee, C.C., Hung, S.F., Ho, T.P., Tang, C.P., Kwong, S.L., Leung, S.Y., a family-based design and impair performance on a continuous performance Yuen, S.T., Lieh-Mak, F., Oosterlaan, J., Grady, D., Harxhi, A., Ding, Y.C., Chi, H.C., test (TOVA). Mol. Psychiatry 7, 790–794. Flodman, P., Schuck, S., Spence, M.A., Moyzis, R., Swanson, J., 2005. Dopamine Manuck, S.B., Flory, J.D., Ferrell, R.E., Mann, J.J., Muldoon, M.F., 2000. A regulatory receptor D4 (DRD4) gene in Han Chinese children with attention-deficit/ polymorphism of the monoamine oxidase-A gene may be associated with hyperactivity disorder (ADHD): increased prevalence of the 2-repeat allele. Am. variability in aggression, impulsivity, and central nervous system serotonergic J. Med. Genet. B Neuropsychiatr. Genet. 133B, 54–56. responsivity. Psychiatry Res. 95, 9–23. Levin, E.D., Conners, C.K., Silva, D., Canu, W., March, J., 2001. Effects of chronic Masi, G., Perugi, G., Toni, C., Millepiedi, S., Mucci, M., Bertini, N., Pfanner, C., 2006. nicotine and methylphenidate in adults with attention deficit/hyperactivity Attention-deficit hyperactivity disorder – bipolar comorbidity in children and disorder. Exp. Clin. Psychopharmacol. 9, 83–90. adolescents. Bipolar Disord. 8, 373–381. Li, D., Sham, P.C., Owen, M.J., He, L., 2006a. Meta-analysis shows significant asso- McCracken, J.T., Smalley, S.L., McGough, J.J., Crawford, L., Del’Homme, M., ciation between dopamine system genes and attention deficit hyperactivity Cantor, R.M., Liu, A., Nelson, S.F., 2000. Evidence for linkage of a tandem disorder (ADHD). Hum. Mol. Genet. 15, 2276–2284. duplication polymorphism upstream of the dopamine D4 receptor gene Li, J., Wang, Y., Zhou, R., Zhang, H., Yang, L., Wang, B., Faraone, S.V., 2006b. Asso- (DRD4) with attention deficit hyperactivity disorder (ADHD). Mol. Psychiatry ciation between tryptophan hydroxylase gene polymorphisms and attention 5, 531–536. deficit hyperactivity disorder in Chinese Han population. Am. J. Med. Genet. B McLoughlin, G., Ronald, A., Kuntsi, J., Asherson, P., Plomin, R., 2007. Genetic support Neuropsychiatr. Genet. 141B, 126–129. for the dual nature of attention deficit hyperactivity disorder: substantial Lim, M.H., Kim, H.W., Paik, K.C., Cho, S.C., Yoon, D.Y., Lee, H.J., 2006. Association of genetic overlap between the inattentive and hyperactive-impulsive compo- the DAT1 polymorphism with attention deficit hyperactivity disorder (ADHD): nents. J. Abnorm. Child. Psychol. 35, 999–1008. a family-based approach. Am. J. Med. Genet. B Neuropsychiatr. Genet. 141B, Merikangas, K.R., Leckman, J.F., Prusoff, B.A., Pauls, D.L., Weissman, M.M., 1985. 309–311. Familial transmission of depression and alcoholism. Arch. Gen. Psychiatry 42, Loo, S.K., Specter, E., Smolen, A., Hopfer, C., Teale, P.D., Reite, M.L., 2003. Functional 367–372. effects of the DAT1 polymorphism on EEG measures in ADHD. J. Am. Acad. Merikangas, K.R., Gelernter, C.S., 1990. Comorbidity for alcoholism and depression. Child. Adolesc. Psychiatry 42, 986–993. Psychiatr. Clin. North Am. 13, 613–632. Loo, S.K., Fisher, S.E., Francks, C., Ogdie, M.N., MacPhie, I.L., Yang, M., McCracken, J.T., Mick, E., Wozniak, J., Wilens, T.E., Biederman, J., Faraone, S.V., 2009. Family-based McGough, J.J., Nelson, S.F., Monaco, A.P., Smalley, S.L., 2004. Genome-wide scan association study of the BDNF, COMT and serotonin transporter genes and DSM- of reading ability in affected sibling pairs with attention-deficit/hyperactivity IV bipolar-I disorder in children. BMC Psychiatry 9, 2. disorder: unique and shared genetic effects. Mol. Psychiatry 9, 485–493. Milin, R., Halikas, J.A., Meller, J.E., Morse, C., 1991. Psychopathology among Loo, S.K., Hale, T.S., Macion, J., Hanada, G., McGough, J.J., McCracken, J.T., substance abusing juvenile offenders. J. Am. Acad. Child. Adolesc. Psychiatry 30, Smalley, S.L., 2009. Cortical activity patterns in ADHD during arousal, activation 569–574. and sustained attention. Neuropsychologia 47, 2114–2119. Mulligan, A., Anney, R.J., O’Regan, M., Chen, W., Butler, L., Fitzgerald, M., Buitelaar, J., Lotrich, F.E., Pollock, B.G., 2004. Meta-analysis of serotonin transporter poly- Steinhausen, H.C., Rothenberger, A., Minderaa, R., Nijmeijer, J., Hoekstra, P.J., morphisms and affective disorders. Psychiatr. Genet. 14, 121–129. Oades, R.D., Roeyers, H., Buschgens, C., Christiansen, H., Franke, B., Gabriels, I., S.I. Sharp et al. / Neuropharmacology 57 (2009) 590–600 599

Hartman, C., Kuntsi, J., Marco, R., Meidad, S., Mueller, U., Psychogiou, L., Reif, A., 2009. Is NOS1 a genetic link between RLS and ADHD? J. Psychiatr. Res. Rommelse, N., Thompson, M., Uebel, H., Banaschewski, T., Ebstein, R., Reif, A., Herterich, S., Strobel, A., Ehlis, A.C., Saur, D., Jacob, C.P., Wienker, T., Eisenberg, J., Manor, I., Miranda, A., Mulas, F., Sergeant, J., Sonuga-Barke, E., Topner, T., Fritzen, S., Walter, U., Schmitt, A., Fallgatter, A.J., Lesch, K.P., 2006. A Asherson, P., Faraone, S.V., Gill, M., 2009. Autism symptoms in Attention-Deficit/ neuronal nitric oxide synthase (NOS-I) haplotype associated with schizophrenia Hyperactivity Disorder: a familial trait which correlates with conduct, opposi- modifies prefrontal cortex function. Mol. Psychiatry 11, 286–300. tional defiant, language and motor disorders. J. Autism Dev. Disord. 39, 197–209. Reif, A., Jacob, C.P., Rujescu, D., Herterich, S., Lang, S., Gutknecht, L., Baehne, C.G., Munafo, M.R., Clark, T.G., Roberts, K.H., Johnstone, E.C., 2006. Neuroticism mediates Strobel, A., Freitag, C.M., Giegling, I., Romanos, M., Hartmann, A., Rosler, M., the association of the serotonin transporter gene with lifetime major depres- Renner, T.J., Fallgatter, A.J., Retz, W., Ehlis, A.C., Lesch, K.P., 2009. Influence of sion. Neuropsychobiology 53, 1–8. functional variant of neuronal nitric oxide synthase on impulsive behaviors in Neale, B.M., Lasky-Su, J., Anney, R., Franke, B., Zhou, K., Maller, J.B., Vasquez, A.A., humans. Arch. Gen. Psychiatry 66, 41–50. Asherson, P., Chen, W., Banaschewski, T., Buitelaar, J., Ebstein, R., Gill, M., Rietveld, M.J., Hudziak, J.J., Bartels, M., van Beijsterveldt, C.E., Boomsma, D.I., 2003. Miranda, A., Oades, R.D., Roeyers, H., Rothenberger, A., Sergeant, J., Heritability of attention problems in children: I. cross-sectional results from Steinhausen, H.C., Sonuga-Barke, E., Mulas, F., Taylor, E., Laird, N., Lange, C., a study of twins, age 3–12 years. Am. J. Med. Genet. B Neuropsychiatr. Genet. Daly, M., Faraone, S.V., 2008. Genome-wide association scan of attention 117B, 102–113. deficit hyperactivity disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. Rietveld, M.J., Hudziak, J.J., Bartels, M., van Beijsterveldt, C.E., Boomsma, D.I., 2004. 147B, 1337–1344. Heritability of attention problems in children: longitudinal results from a study O’Neill, M.F., Heron-Maxwell, C.L., Shaw, G., 1999. 5-HT2 receptor antagonism of twins, age 3 to 12. J. Child. Psychol. Psychiatry 45, 577–588. reduces hyperactivity induced by amphetamine, cocaine, and MK-801 but not Roman, T., Schmitz, M., Polanczyk, G.V., Eizirik, M., Rohde, L.A., Hutz, M.H., 2003. Is D1 agonist C-APB. Pharmacol. Biochem. Behav. 63, 237–243. the alpha-2A adrenergic receptor gene (ADRA2A) associated with attention- Ogdie, M.N., Macphie, I.L., Minassian, S.L., Yang, M., Fisher, S.E., Francks, C., deficit/hyperactivity disorder? Am. J. Med. Genet. B Neuropsychiatr. Genet. Cantor, R.M., McCracken, J.T., McGough, J.J., Nelson, S.F., Monaco, A.P., 120B, 116–120. Smalley, S.L., 2003. A genomewide scan for attention-deficit/hyperactivity Roman, T., Polanczyk, G.V., Zeni, C., Genro, J.P., Rohde, L.A., Hutz, M.H., 2006. Further disorder in an extended sample: suggestive linkage on 17p11. Am. J. Hum. evidence of the involvement of alpha-2A-adrenergic receptor gene (ADRA2A) in Genet. 72, 1268–1279. inattentive dimensional scores of attention-deficit/hyperactivity disorder. Mol. Ogdie, M.N., Fisher, S.E., Yang, M., Ishii, J., Francks, C., Loo, S.K., Cantor, R.M., Psychiatry 11, 8–10. McCracken, J.T., McGough, J.J., Smalley, S.L., Nelson, S.F., 2004. Attention deficit Romanos, M., Freitag, C., Jacob, C., Craig, D.W., Dempfle, A., Nguyen, T.T., Halperin, R., hyperactivity disorder: fine mapping supports linkage to 5p13, 6q12, 16p13, and Walitza, S., Renner, T.J., Seitz, C., Romanos, J., Palmason, H., Reif, A., Heine, M., 17p11. Am. J. Hum. Genet. 75, 661–668. Windemuth-Kieselbach, C., Vogler, C., Sigmund, J., Warnke, A., Schafer, H., Ohannessian, C.M., Stabenau, J.R., Hesselbrock, V.M., 1995. Childhood and adulthood Meyer, J., Stephan, D.A., Lesch, K.P., 2008. Genome-wide linkage analysis of temperament and problem behaviors and adulthood substance use. Addict. ADHD using high-density SNP arrays: novel loci at 5q13.1 and 14q12. Mol. Behav. 20, 77–86. Psychiatry 13, 522–530. Ohlmeier, M.D., Peters, K., Te Wildt, B.T., Zedler, M., Ziegenbein, M., Wiese, B., Rowe, D.C., Van den Oord, E.J., Stever, C., Giedinghagen, L.N., Gard, J.M., Emrich, H.M., Schneider, U., 2008. Comorbidity of alcohol and substance Cleveland, H.H., Gilson, M., Terris, S.T., Mohr, J.H., Sherman, S., Abramowitz, A., dependence with attention-deficit/hyperactivity disorder (ADHD). Alcohol Waldman, I.D., 1999. The DRD2 TaqI polymorphism and symptoms of attention Alcohol. 43, 300–304. deficit hyperactivity disorder. Mol. Psychiatry 4, 580–586. Okuyama, Y., Ishiguro, H., Toru, M., Arinami, T., 1999. A genetic polymorphism in the Rubino, I.A., Frank, E., Croce Nanni, R., Pozzi, D., Lanza di Scalea, T., Siracusano, A., promoter region of DRD4 associated with expression and schizophrenia. Bio- 2009. A Comparative study of Axis I Antecedents before age 18 of unipolar chem. Biophys. Res. Commun. 258, 292–295. depression, bipolar disorder and schizophrenia. Psychopathology 42, 325–332. Ouellet-Morin, I., Wigg, K.G., Feng, Y., Dionne, G., Robaey, P., Brendgen, M., Vitaro, F., Schinka, J.A., Busch, R.M., Robichaux-Keene, N., 2004. A meta-analysis of the Simard, L., Schachar, R., Tremblay, R.E., Perusse, D., Boivin, M., Barr, C.L., 2008. association between the serotonin transporter gene polymorphism (5-HTTLPR) Association of the dopamine transporter gene and ADHD symptoms in and trait anxiety. Mol. Psychiatry 9, 197–202. a Canadian population-based sample of same-age twins. Am. J. Med. Genet. B Sheehan, K., Lowe, N., Kirley, A., Mullins, C., Fitzgerald, M., Gill, M., Hawi, Z., 2005. Neuropsychiatr. Genet. 147B, 1442–1449. Tryptophan hydroxylase 2 (TPH2) gene variants associated with ADHD. Mol. Pacholczyk, T., Blakely, R.D., Amara, S.G., 1991. Expression cloning of a cocaine- and Psychiatry 10, 944–949. antidepressant-sensitive human noradrenaline transporter. Nature 350, 350–354. Shiow, L.R., Paris, K., Akana, M.C., Cyster, J.G., Sorensen, R.U., Puck, J.M., 2009. Severe Pastor, P.N., Reuben, C.A., 2008. Diagnosed attention deficit hyperactivity disorder combined immunodeficiency (SCID) and attention deficit hyperactivity disorder and learning disability: United States, 2004–2006. Vital Health Stat. 10, 1–14. (ADHD) associated with a Coronin-1A mutation and a chromosome 16p11.2 Patel, S.D., Chen, C.P., Bahna, F., Honig, B., Shapiro, L., 2003. Cadherin-mediated cell– deletion. Clin. Immunol. 131, 24–30. cell adhesion: sticking together as a family. Curr. Opin. Struct. Biol. 13, 690–698. Simon, V., Czobor, P., Balint, S., Meszaros, A., Bitter, I., 2009. Prevalence and corre- Payton, A., Holmes, J., Barrett, J.H., Hever, T., Fitzpatrick, H., Trumper, A.L., lates of adult attention-deficit hyperactivity disorder: meta-analysis. Br. J. Harrington, R., McGuffin, P., O’Donovan, M., Owen, M., Ollier, W., Psychiatry 194, 204–211. Worthington, J., Thapar, A., 2001. Examining for association between candidate Simsek, M., Al-Sharbati, M., Al-Adawi, S., Lawatia, K., 2006. The VNTR poly- gene polymorphisms in the dopamine pathway and attention-deficit hyperac- morphism in the human dopamine transporter gene: improved detection and tivity disorder: a family-based study. Am. J. Med. Genet. 105, 464–470. absence of association of VNTR alleles with attention-deficit hyperactivity Polanczyk, G., de Lima, M.S., Horta, B.L., Biederman, J., Rohde, L.A., 2007. The disorder. Genet. Test. 10, 31–34. worldwide prevalence of ADHD: a systematic review and metaregression Smalley, S.L., Kustanovich, V., Minassian, S.L., Stone, J.L., Ogdie, M.N., McGough, J.J., analysis. Am. J. Psychiatry 164, 942–948. McCracken, J.T., MacPhie, I.L., Francks, C., Fisher, S.E., Cantor, R.M., Monaco, A.P., Ponce, G., Hoenicka, J., Rubio, G., Ampuero, I., Jimenez-Arriero, M.A., Rodriguez- Nelson, S.F., 2002. Genetic linkage of attention-deficit/hyperactivity disorder on Jimenez, R., Palomo, T., Ramos, J.A., 2003. Association between cannabinoid chromosome 16p13, in a region implicated in autism. Am. J. Hum. Genet. 71, receptor gene (CNR1) and childhood attention deficit/hyperactivity disorder in 959–963. Spanish male alcoholic patients. Mol. Psychiatry 8, 466–467. Smith, K.M., Daly, M., Fischer, M., Yiannoutsos, C.T., Bauer, L., Barkley, R., Navia, B.A., Ponce, G., Hoenicka, J., Rodriguez-Jimenez, R., Gozalo, A., Jimenez, M., Monasor, R., 2003. Association of the dopamine beta hydroxylase gene with attention deficit Aragues, M., Rubio, G., Jimenez-Arriero, M.A., Ramos, J.A., Palomo, T., 2004. hyperactivity disorder: genetic analysis of the Milwaukee longitudinal study. DRD2 TaqIA polymorphism is associated with urinary homovanillic acid levels Am. J. Med. Genet. B Neuropsychiatr. Genet. 119B, 77–85. in a sample of Spanish male alcoholic patients. Neurotox. Res. 6, 373–377. Smoller, J.W., Biederman, J., Arbeitman, L., Doyle, A.E., Fagerness, J., Perlis, R.H., Ponce, G., Hoenicka, J., Jimenez-Arriero, M.A., Rodriguez-Jimenez, R., Aragues, M., Sklar, P., Faraone, S.V., 2006. Association between the 5HT1B receptor gene Martin-Sune, N., Huertas, E., Palomo, T., 2008. DRD2 and ANKK1 genotype in (HTR1B) and the inattentive subtype of ADHD. Biol. Psychiatry 59, 460–467. alcohol-dependent patients with psychopathic traits: association and interac- Solanto, M.V., 1998. Neuropsychopharmacological mechanisms of stimulant drug tion study. Br. J. Psychiatry 193, 121–125. action in attention-deficit hyperactivity disorder: a review and integration. Pottenger, M., McKernon, J., Patrie, L.E., Weissman, M.M., Ruben, H.L., Newberry, P., Behav. Brain Res. 94, 127–152. 1978. The frequency and persistence of depressive symptoms in the alcohol Sonuga-Barke, E.J., Lasky-Su, J., Neale, B.M., Oades, R., Chen, W., Franke, B., abuser. J. Nerv. Ment. Dis. 166, 562–570. Buitelaar, J., Banaschewski, T., Ebstein, R., Gill, M., Anney, R., Miranda, A., Preisig, M., Fenton, B.T., Stevens, D.E., Merikangas, K.R., 2001. Familial relationship Mulas, F., Roeyers, H., Rothenberger, A., Sergeant, J., Steinhausen, H.C., between mood disorders and alcoholism. Compr. Psychiatry 42, 87–95. Thompson, M., Asherson, P., Faraone, S.V., 2008. Does parental expressed Qian, Q.J., Wang, Y.F., Zhou, R.L., Yang, L., Li, J., 2004. Association studies of G352A emotion moderate genetic effects in ADHD? An exploration using a genome polymorphism of dopamine transporter gene in Han Chinese attention deficit wide association scan. Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B, hyperactivity disorder patients. Beijing Da Xue Xue Bao 36, 626–629. 1359–1368. Quist, J.F., Barr, C.L., Schachar, R., Roberts, W., Malone, M., Tannock, R., Basile, V.S., Sprich, S., Biederman, J., Crawford, M.H., Mundy, E., Faraone, S.V., 2000. Adoptive Beitchman, J., Kennedy, J.L., 2003. The serotonin 5-HT1B receptor gene and and biological families of children and adolescents with ADHD. J. Am. Acad. attention deficit hyperactivity disorder. Mol. Psychiatry 8, 98–102. Child. Adolesc. Psychiatry 39, 1432–1437. Reiersen, A.M., Constantino, J.N., Volk, H.E., Todd, R.D., 2007. Autistic traits in Swanson, J.M., Flodman, P., Kennedy, J., Spence, M.A., Moyzis, R., Schuck, S., a population-based ADHD twin sample. J. Child. Psychol. Psychiatry 48, 464–472. Murias, M., Moriarity, J., Barr, C., Smith, M., Posner, M., 2000. Dopamine genes Reiersen, A.M., Constantino, J.N., Grimmer, M., Martin, N.G., Todd, R.D., 2008. and ADHD. Neurosci. Biobehav. Rev. 24, 21–25. Evidence for shared genetic influences on self-reported ADHD and autistic Takeuchi, T., Misaki, A., Liang, S.B., Tachibana, A., Hayashi, N., Sonobe, H., Ohtsuki, Y., symptoms in young adult Australian twins. Twin Res. Hum. Genet. 11, 579–585. 2000. Expression of T-cadherin (CDH13, H-Cadherin) in human brain and its 600 S.I. Sharp et al. / Neuropharmacology 57 (2009) 590–600

characteristics as a negative growth regulator of epidermal growth factor in Han children: case-control and family-based studies. Kobe J. Med. Sci. 53, neuroblastoma cells. J. Neurochem. 74, 1489–1497. 327–333. Thapar, A., Langley, K., Fowler, T., Rice, F., Turic, D., Whittinger, N., Aggleton, J., Van Wood, A.C., Rijsdijk, F., Asherson, P., Kuntsi, J., 2009. Hyperactive-impulsive den Bree, M., Owen, M., O’Donovan, M., 2005. Catechol O-methyltransferase symptom scores and oppositional behaviours reflect alternate manifestations of gene variant and birth weight predict early-onset antisocial behavior in chil- a single liability. Behav. Genet. dren with attention-deficit/hyperactivity disorder. Arch. Gen. Psychiatry 62, Yan, T., McQuillin, A., Thapar, A., Asherson, P., Hunt, S., Stanford, S., Gurling, H., 2009. 1275–1278. NK1 (TACR1) receptor gene ‘knockout’ mouse phenotype predicts genetic Todd, R.D., Jong, Y.J., Lobos, E.A., Reich, W., Heath, A.C., Neuman, R.J., 2001. No association with ADHD. J. Psychopharmacol. association of the dopamine transporter gene 30 VNTR polymorphism with Yang, J.W., Jang, W.S., Hong, S.D., Ji, Y.I., Kim, D.H., Park, J., Kim, S.W., Joung, Y.S., ADHD subtypes in a population sample of twins. Am. J. Med. Genet. 105, 2008. A case-control association study of the polymorphism at the promoter 745–748. region of the DRD4 gene in Korean boys with attention deficit-hyperactivity Uhl, G.R., Drgon, T., Liu, Q.R., Johnson, C., Walther, D., Komiyama, T., Harano, M., disorder: evidence of association with the -521 C/T SNP. Prog. Neuro- Sekine, Y., Inada, T., Ozaki, N., Iyo, M., Iwata, N., Yamada, M., Sora, I., Chen, C.K., psychopharmacol. Biol. Psychiatry 32, 243–248. Liu, H.C., Ujike, H., Lin, S.K., 2008. Genome-wide association for methamphet- Zametkin, A., Rapoport, J.L., Murphy, D.L., Linnoila, M., Ismond, D., 1985. Treatment amine dependence: convergent results from 2 samples. Arch. Gen. Psychiatry of hyperactive children with monoamine oxidase inhibitors. I. Clinical efficacy. 65, 345–355. Arch. Gen. Psychiatry 42, 962–966. van ’t Ent, D., Lehn, H., Derks, E.M., Hudziak, J.J., Van Strien, N.M., Veltman, D.J., De Zametkin, A.J., Nordahl, T.E., Gross, M., King, A.C., Semple, W.E., Rumsey, J., Geus, E.J., Todd, R.D., Boomsma, D.I., 2007. A structural MRI study in mono- Hamburger, S., Cohen, R.M., 1990. Cerebral glucose metabolism in adults with zygotic twins concordant or discordant for attention/hyperactivity problems: hyperactivity of childhood onset. N. Engl. J. Med. 323, 1361–1366. evidence for genetic and environmental heterogeneity in the developing brain. Zhou, K., Chen, W., Buitelaar, J., Banaschewski, T., Oades, R.D., Franke, B., Sonuga- Neuroimage 35, 1004–1020. Barke, E., Ebstein, R., Eisenberg, J., Gill, M., Manor, I., Miranda, A., Mulas, F., Waldman, I.D., Rowe, D.C., Abramowitz, A., Kozel, S.T., Mohr, J.H., Sherman, S.L., Roeyers, H., Rothenberger, A., Sergeant, J., Steinhausen, H.C., Lasky-Su, J., Cleveland, H.H., Sanders, M.L., Gard, J.M., Stever, C., 1998. Association and Taylor, E., Brookes, K.J., Xu, X., Neale, B.M., Rijsdijk, F., Thompson, M., linkage of the dopamine transporter gene and attention-deficit hyperactivity Asherson, P., Faraone, S.V., 2008a. Genetic heterogeneity in ADHD: DAT1 gene disorder in children: heterogeneity owing to diagnostic subtype and severity. only affects probands without CD. Am. J. Med. Genet. B Neuropsychiatr. Genet. Am. J. Hum. Genet. 63, 1767–1776. 147B, 1481–1487. Walitza, S., Renner, T.J., Dempfle, A., Konrad, K., Wewetzer, C., Halbach, A., Herpertz- Zhou, K., Dempfle, A., Arcos-Burgos, M., Bakker, S.C., Banaschewski, T., Biederman, J., Dahlmann, B., Remschmidt, H., Smidt, J., Linder, M., Flierl, L., Knolker, U., Buitelaar, J., Castellanos, F.X., Doyle, A., Ebstein, R.P., Ekholm, J., Forabosco, P., Friedel, S., Schafer, H., Gross, C., Hebebrand, J., Warnke, A., Lesch, K.P., 2005. Franke, B., Freitag, C., Friedel, S., Gill, M., Hebebrand, J., Hinney, A., Jacob, C., Transmission disequilibrium of polymorphic variants in the tryptophan Lesch, K.P., Loo, S.K., Lopera, F., McCracken, J.T., McGough, J.J., Meyer, J., Mick, E., hydroxylase-2 gene in attention-deficit/hyperactivity disorder. Mol. Psychiatry Miranda, A., Muenke, M., Mulas, F., Nelson, S.F., Nguyen, T.T., Oades, R.D., 10, 1126–1132. Ogdie, M.N., Palacio, J.D., Pineda, D., Reif, A., Renner, T.J., Roeyers, H., Walther, D.J., Bader, M., 2003. A unique central tryptophan hydroxylase isoform. Romanos, M., Rothenberger, A., Schafer, H., Sergeant, J., Sinke, R.J., Smalley, S.L., Biochem. Pharmacol. 66, 1673–1680. Sonuga-Barke, E., Steinhausen, H.C., van der Meulen, E., Walitza, S., Warnke, A., Wang, Y., Wang, Z., Yao, K., Tanaka, K., Yang, Y., Shirakawa, O., Maeda, K., Lewis, C.M., Faraone, S.V., Asherson, P., 2008b. Meta-analysis of genome-wide 2008. Lack of association between the dopamine transporter gene 30 VNTR linkage scans of attention deficit hyperactivity disorder. Am. J. Med. Genet. B polymorphism and attention deficit hyperactivity disorder in Chinese Neuropsychiatr. Genet. 147B, 1392–1398.