Arch Dis Child: first published as 10.1136/archdischild-2011-300482 on 7 September 2011. Downloaded from Review What causes attention defi cit hyperactivity disorder? A n i t a T h a p a r ,1,2 M i r i a m C o o p e r ,1,2 R a c h e l J e f f e r i e s ,1,2 E v a n g e l i a S t e r g i a k o u l i1,2

1 Department of Psychological A B S T R A C T workplace performance, unemployment, friend- Medicine and Neurology, Attention defi cit hyperactivity disorder (ADHD) affects ship diffi culties and social problems.4 Cardiff University School of Medicine, Cardiff, UK around 1–3% of children. There is a high level of 2 MRC Centre in comorbidity with developmental and learning problems CAUSES OF ADHD Neuropsychiatric Genetics and as well as with a variety of psychiatric disorders. ADHD ADHD, like other common medical and psychiat- Genomics, Cardiff University, is highly heritable, although there is no single causal risk Cardiff, UK ric disorders (eg, asthma, schizophrenia), is infl u- factor and non-inherited factors also contribute to its enced by multiple genes, non-inherited factors and Correspondence to aetiology. The genetic and environmental risk factors their interplay.5 There is no single cause of ADHD Anita Thapar, Child and that have been implicated appear to be associated with and exposure to a risk factor does not necessar- Adolescent Psychiatry Section, a range of neurodevelopmental and neuropsychiatric ily result in disorder. This means that any given Department of Psychological outcomes, not just ADHD. The evidence to date Medicine and Neurology, risk factor will only be observed in a proportion of Cardiff University, School of suggests that both rare and multiple common genetic cases and will also be found in those who are unaf- Medicine, Heath Park, Cardiff, variants likely contribute to ADHD and modify its fected. Also, risk factors that contribute to the ori- CF14 4XN, UK; phenotype. ADHD or a similar phenotype also appears gins of ADHD might not necessarily be the same t h a p a r @ c f . a c . u k to be more common in extreme low birth weight and as those that infl uence its course and outcomes. premature children and those exposed to exceptional A further complexity is that genetic factors can Accepted 20 July 2011 early adversity. In this review, the authors consider exert indirect risk effects through interplay with Published Online First recent developments in the understanding of risk factors 7 September 2011 environmental factors. Genes can alter sensitiv- that infl uence ADHD. ity to environmental risks (gene–environment interaction), for example, environmental toxins or psychosocial adversity.6 Inherited factors can also Hyperkinetic disorder was fi rst described as a infl uence the probability of exposure to certain syndrome in 1902 by George Still, a UK paedia- environmental risks (gene–environment correla- trician. The disorder is characterised by develop- tion; see later). This means that environmental mentally inappropriate hyperactivity, inattention and genetic risk effects cannot be considered as and impulsiveness. These symptoms must be entirely distinct. of early onset, present in more than one setting and associated with impairment in functioning G E N E T I C S (eg, peer relationships, educational achievement). The current diagnostic terms of hyperkinetic dis- Evidence of an inherited contribution to ADHD order, used in the International Classifi cation of There is robust evidence from a wide range of

Diseases, 10th revision (ICD-10) and attention study designs of a strong inherited contribu- http://adc.bmj.com/ defi cit hyperactivity disorder (ADHD), adopted tion to ADHD. Family studies have consistently by the Diagnostic and statistical manual of mental dis- found higher rates of ADHD (twofold to eightfold 7 orders , fourth edition (DSM-IV) are similar but not increased risk) in parents and siblings of affected identical (see table 1 for DSM-IV criteria). ICD-10 probands compared with relatives of unaffected has more strict criteria, with a threshold number controls. Twin studies have shown that monozy- of symptoms in each of the domains of inatten- gotic twin pairs have much higher concordance 8 tion, hyperactivity and impulsivity needed for rates for ADHD than dizygotic twin pairs and on September 28, 2021 by guest. Protected copyright. diagnosis. Prevalence rates overall in the UK vary adoption studies have also found increased rates of from 1.4% for hyperkinetic disorder1 to 2.23% 2 ADHD in the biological parents of ADHD adopt- for ADHD. Those with intellectual disability (ID) ees compared with both the adoptive parents of the and boys (3–4:1 male:female ratio) are more com- probands and with the parents of controls without 9 monly affected. ADHD (eg, Sprich et al ). Mean heritability esti- 10 Comorbidity is typical. ADHD commonly co- mates are around 79%. However, heritability is occurs with specifi c and global developmental and not 100%, suggesting non-inherited factors also learning problems that include autistic spectrum contribute. disorders (ASDs), diffi culties with speech and lan- ADHD also appears to share an inherited liabil- guage, motor co-ordination and reading, as well ity with other neurodevelopmental and psychiatric as with a range of psychiatric disorders notably problems, notably ASDs, developmental coordi- 10 11 12 oppositional defi ant disorder, conduct disorder nation problems, reading ability, IQ, conduct 13 14 and tic disorders. Anxiety, depression and more and mood problems. These fi ndings suggest the rarely bipolar affective disorder can also compli- same inherited and familial risks can result in the cate the clinical presentation. Longitudinal stud- manifestation of different clinical phenotypes. ies show that ADHD symptoms and impairment often persist into adult life and are associated with Searching for ADHD susceptibility genes increased risk of antisocial behaviour and sub- The high heritability of ADHD has fuelled efforts stance misuse, 3 poor educational attainment and to identify susceptibility genes. As is the case for

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Table 1 DSM-IV criteria for attention defi cit hyperactivity disorder Table 2 Candidate genes associated with ADHD selecting the most Criteria can be met in either or both domains: for inattentive type, hyperactive- consistently replicated fi ndings impulsive type or combined type Gene Polymorphism OR P Consistency Inattention Hyperactivity impulsivity DRD4 7-repeat allele of 1.27 <0.00001 Replicated in four At least six of the following At least six of the following symptoms↓ VNTR in exon III meta-analyses/ symptoms↓ pooled analyses Fails to sustain attention in tasks or Often fi dgets with hands or squirms in DRD5 148-bp microsat- 1.22 0.000095 Replicated in four play activities seat ellite repeat meta-analyses/ Often fails to follow through on Diffi culty remaining seated when pooled analyses instructions from others required DAT1 480-bp VNTR in 1.1 0.002 Replicated in two Often avoids tasks that require Runs about or climbs on things 3’ UTR meta-analyses/ sustained mental effort excessively in situations when it is pooled analyses, did inappropriate not replicate in four Often easily distracted Exhibits a persistent pattern of motor SNAP25 T1065G 1.15 0.03 Replicated in two activity (always on the go) meta-analyses Often loses things that are necessary Often noisy in playing or diffi culty engag- but not same for tasks or activities ing quietly in leisure activities polymorphism Appears not to listen to what is being Diffi culty waiting in turns in games or COMT and Val158Met poly- 2.82 <0.01 Replicated in three said to him/her group situations antisocial morphism large independent behaviour in samples Fails to pay attention to details, or Often blurts out answers before ques- ADHD makes careless mistakes tions have been completed Often forgetful in daily activities Often interrupts or intrudes on others Reported OR and p value are from Gizer et al meta-analysis 19 apart from COMT , for 26 Often has diffi culty organising tasks Often talks excessively which OR and p value are taken from Langley et al. and activities ADHD, attention defi cit hyperactivity disorder; COMT, catechol-O-methyltrans- ferase; DAT1, dopamine transporter gene; DRD4, dopamine D4 receptor gene; Additional criteria required: Onset before the age of 7 years, functional impairment, DRD5, dopamine D5 receptor gene; SNAP25, synaptosomal-associated protein of impairment present in more than one setting 25 kD; UTR, untranslated region; VNTR, variable number tandem repeat. DSM-IV, Diagnostic and statistical manual of mental disorders, fourth edition

knockout mouse exhibits hyperactivity and defi cits in inhibi- other complex disorders, molecular genetic studies of ADHD tory behaviour.21 In the most recent meta-analysis,19 signifi - have so far mainly been based on examining common DNA cant evidence of association was found with the 480-bp allele variation (the common disease–common variant hypoth- of the most commonly studied polymorphism (a VNTR in esis). This was originally investigated using candidate gene the 3’ untranslated region (UTR) region of the gene) as well as approaches, in which assumptions about the pathophysiology with other polymorphisms in the same gene. The substantial of the disorder are made, and more recently with ‘hypothesis- heterogeneity reported could be the result of multiple poly- free’ genome wide association studies (GWAS), in which the morphisms in this gene increasing risk to ADHD or gene–en- frequencies of thousands of single nucleotide polymorphisms vironment interaction between the 3’ UTR VNTR and prenatal (SNPs) across the genome are compared between cases and factors, such as maternal alcohol consumption 22 or maternal 15 23 controls. There is also emerging interest in the contribution smoking during pregnancy, although these associations have http://adc.bmj.com/ of rare genetic variants to ADHD. not been widely replicated. The gene encoding catechol O methyl transferase ( COMT ), Examining specifi c genes of interest: candidate gene which catalyses the degradation of dopamine, has also been association studies studied extensively in ADHD. A functional polymorphism in There is a very large volume of literature on candidate genes the gene, which results in a valine–methionine transition and reported to be associated with ADHD, but only a few have con- affects enzyme activity, has been the focus of many genetic

19 17 on September 28, 2021 by guest. Protected copyright. sistently withstood replication (table 2) and meta-analyses. studies. Neither meta-analysis nor pooled analysis has The most robust evidence of association with ADHD has found any evidence of association with ADHD. There is how- been shown for a dopamine D4 receptor gene ( DRD4 ) variant. ever evidence that COMT could have a modifying effect on the This receptor binds both dopamine and norepinephrine and ADHD phenotype rather than increase the risk of the disorder there is a functional polymorphism (variable number tandem itself. The COMT val/val genotype (associated with greater repeat—VNTR) in exon III of the gene that has been exten- enzyme activity) was found to be associated with antisocial 24 sively studied. The seven-repeat allele of this polymorphism behaviour in patients with ADHD, then replicated in two has been found to be associated with ADHD in different meta- independent populations as well as shown in a pooled analy- 25 analyses.16 – 18 The latest meta-analysis shows signifi cant asso- sis. The association fi nding has been subsequently replicated ciation of small effect size, 19 although there is also evidence of in other studies and the link with antisocial behaviour appears 26 substantial heterogeneity across studies. to be mediated through impaired social understanding. This Another dopamine receptor gene, DRD5 , has also been con- association is specifi c to antisocial behaviour in ADHD because 25 26 sistently implicated. A microsatellite genetic marker located it has not been observed with antisocial behaviour alone. close (18.5 kb) but outside the gene region has also been found to be associated with ADHD in several meta-analyses,19 although Searching across the genome for common genetic risk again with evidence of moderate heterogeneity across studies. variants: GWAS The dopamine transporter gene (DAT1) was originally con- Candidate gene association studies were relatively successful sidered the most likely ADHD candidate gene because it is for ADHD compared with other neuropsychiatric/develop- responsible for the reuptake of dopamine in the presynaptic mental disorders. However, GWAS fi ndings for ADHD are cleft, 20 inhibited by stimulants and also because the DAT1 still at an early stage, with no common gene variant having

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yet been identifi ed.27 The same has been true for autism. The lack of genome-wide signifi cant results may be because of the large sample sizes required. Because of the heavy mul- tiple testing burden and the small effect sizes expected, tens of thousands of cases and controls are likely to be required, as has been shown in other complex disorders such as dia- betes.28 None of the four published GWAS of ADHD has achieved genome-wide signifi cant results.29 – 32 A meta-analy- sis of these studies that included 2064 parent–child trios, 896 cases and 2455 controls had a best p value of 1.2×10 −6 and no SNP reached genome-wide signifi cance (p=5×10−8 ). 33 Although these results appear disappointing, it has to be remembered that ADHD GWAS studies are still in their infancy. Apart from sample sizes, which are clearly important, there is the issue of sample heterogeneity, which has also been Figure 1 Mother’s genes can infl uence ADHD as well as exposure to highlighted by meta-analyses of candidate gene studies 19 and c e r t a i n e n v i r o n m e n t a l f a c t o r s . can make collaboration and replication of signifi cant results diffi cult. 27 Another view is that disorders such as ADHD and Table 3 Environmental factors reported to be associated with ADHD autism may be better explained by the effect of rare genetic Maternally related prenatal risks Alcohol in pregnancy variants. Smoking in pregnancy Drug use in pregnancy The contribution of rare genetic variants: chromosomal Maternal stress in pregnancy anomalies, genetic syndromes and copy number variants Maternal health in pregnancy (obesity) A number of different chromosomal anomalies including Pregnancy and birth complications Bleeding in pregnancy abnormalities in the number of chromosomes (notably sex Protracted/complicated delivery chromosome aneuploidies) and chromosomal structure as well Prematurity/low birth weight/intrauterine as some single gene disorders have been found to be associ- growth restriction ated with higher rates of ADHD. Fragile X syndrome, tuber- Low APGAR score ous sclerosis and several microdeletion syndromes including External agents Infections Smith Magenis and Velocardiofacial (VCFS; 22q11 microdele- Exposure to lead and other toxins eg, PCB tion) syndromes are associated with ADHD (more commonly Nutritional factors inattentive type). They are also associated with other neurode- Psychosocial adversities velopmental and psychiatric disorders (eg, ASD, psychosis in ADHD, attention defi cit hyperactivity disorder; PCB, polychlorinated biphenyl. VCFS). However routine screening in those without ID does not appear to be indicated.34 35 or from unmeasured confounders that can include inherited Copy number variants (CNVs) are a type of chromosomal factors (see fi gure 1 ).45 Interestingly, time trends studies have structural variant. These DNA segments vary in size between

shown no increase in the population rate of ADHD over time, http://adc.bmj.com/ people and can be either duplications, when there is a gain although identifi cation has increased.46 Cross-national studies of DNA, or deletions, when there is a loss of DNA. They are have not yet found consistent evidence of lower ADHD rates in part of the normal variation of the human genome. 36 Large certain countries. These fi ndings contrast with data on child- (>500 kb), rare (<1% frequency) duplications and deletions hood behavioural problems for which rates have risen in the have been implicated in the aetiology of neurodevelopmental last 50 years46 47 and vary geographically. These results sug- disorders, such as autism, 37 schizophrenia and ID.38 Studies gest that for ADHD there are more likely to be multiple envi- that have examined rare CNVs of all sizes in ADHD have ronmental risks, each of small effect, with the overall burden on September 28, 2021 by guest. Protected copyright. not found an increased rate of deletions or duplications in of these risks remaining similar over time and between coun- cases39 40 but have found CNVs to be enriched for neurode- tries. Some of these risk effects might be modifi ed by genetic velopmental genes. In a UK study that focused on large, rare infl uences (gene–environment interaction). Environmental CNVs in ADHD (410 cases and 1156 controls), there was a risks can also alter gene function through tissue-specifi c epi- signifi cantly increased rate in cases compared with controls.41 genetic mechanisms. For example, animal studies have dem- This rate was especially high in those with ADHD and ID onstrated how adverse early rearing has an impact on stress but was not restricted to this group. Restricting analysis to responses through such mechanisms and that these biological those without ID, this study also reported an overlap of CNVs changes can be transmitted to subsequent generations.48 found in ADHD with both autism and schizophrenia, further strengthening the notion of ADHD being a neurodevelop- mental disorder. 41 Maternal smoking, alcohol, drug use and stress/anxiety in pregnancy ENVIRONMENTAL RISK FACTORS Clinical and epidemiological associations show a consis- Inherited factors are not the only explanation of ADHD. tent association (OR=2.39)49 and dose–response relationship Although there are a number of environmental risk factors between prenatal exposure to maternal cigarette smoking that are associated with ADHD ( table 3), identifying which of (maternal reports and urinary cotinine levels) and offspring these are causal is challenging. This is because many observed ADHD. Although biologically plausible, because smoking associations might arise as a result of symptoms/disorder in the is known to have an effect on physiological processes that child or the parent (reverse causation eg, peer rejection, fam- may create risks relevant to the origins of ADHD, it is dif- ily adversity, 42 low socioeconomic status 43 or head injury),44 fi cult to adequately control for familial and social confounds

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in observational designs. Recent studies suggest that the asso- alertness being most reliably affected.66 There is also emerging ciation with ADHD (but not with lower birth weight) may evidence from several studies that lead could be implicated in wholly or substantially represent familial and inherited con- ADHD even at low levels, but causality cannot be assumed founds (gene–environment correlation). 50 51 from the evidence to date. Similarly, further work is needed Alcohol is a known teratogen and prenatal exposure to to draw fi rm conclusions about how important pesticides and heavy maternal drinking can cause foetal alcohol syndrome, PCBs are as causes of ADHD. the behavioural aspects of which include symptoms of inat- Dietary constituents that have been studied in relation to tention and hyperactivity. However, associations between less ADHD symptoms include sugar, artifi cial food colourings, zinc, extreme alcohol use in pregnancy and offspring ADHD/ADHD iron, magnesium and omega-3 fatty acids. There is no convinc- symptoms are inconsistent.52 53 Findings are also inconsistent ing evidence yet that diet plays a major causal role in ADHD. with regard to links with prenatal exposure to illicit drugs. 52 However, a separate issue relates to using dietary change to Maternal stress in pregnancy has also been reported to be modify symptoms. Overall, the value of the studies looking associated with offspring ADHD symptoms, although recent at diet and ADHD are limited by small sized trials, subjective work suggests that for ADHD (but not antisocial behaviour measures of outcome and varied protocols for intervention, and or anxiety), this might also refl ect inherited links between on this basis there has been inadequate evidence to suggest mother and child (gene–environment correlation) rather than that dietary manipulation can ameliorate ADHD symptoms being causal.54 In summary, with the exception of the extreme in children.68 However, a recent randomised controlled trial of phenotype of foetal alcohol syndrome, the evidence that a restricted elimination diet based on high or low IgG foods maternally related cigarette and substance use and stress in suggests a benefi cial effect of a restricted elimination diet on pregnancy play a major causal role in ADHD remains equivo- ADHD and oppositional defi ant disorder symptoms. 69 cal, although many of these factors are clearly detrimental for other offspring outcomes. Psychosocial adversity Adverse social and family environments such as low parental Low birth weight and prematurity education, social class, poverty, bullying/peer victimisation, Most studies, including meta-analyses of premature and/ negative parenting, maltreatment and family discord are asso- or low birth weight children, fi nd evidence of an association ciated with ADHD. However, the designs used so far have not with ADHD (relative risk of 2.64 for ADHD in premature been able to show that these are defi nite causes of ADHD. For children)55 and ADHD symptoms/attentional problems.56 example, longitudinal and treatment studies suggest that nega- The risk appears to be strongest for extreme prematurity and tive mother/son70 and peer relationships arise in response to very low birth weight in relation to inattention symptoms child ADHD symptoms. This contrasts with fi ndings for child and ADHD inattentive subtype.57 58 Some preliminary stud- antisocial behaviour/conduct disorder in which a variety of ies also suggest the likely importance of intrauterine growth designs including treatment trials have consistently found that restriction (small for gestational age). 59 60 However it is not adverse social and family environments are causal. However, known whether low birth weight and/or prematurity and psychosocial factors might modify ADHD expression espe- other associated pre/perinatal risks (see table 3) are risk mark- cially in those who are genetically susceptible, for example ers of ADHD or whether they are causal. The fi ndings at least by infl uencing comorbidities such as conduct disorder, depres-

suggest the need for heightened awareness of possible ADHD sion symptoms and level of impairment. This needs further http://adc.bmj.com/ in very premature/low birth weight children. investigation. One exception is exposure to extreme early deprivation. Toxins and diet A study of Romanian orphans adopted in the UK found a Specifi c environmental exposures that seem to have relevance deprivation-specifi c inattentive and overactive pattern of 71 to the ADHD phenotype include organic pollutants (eg, pes- behaviour. It remains to be examined whether a similar pat- ticides, polychlorinated biphenyl (PCBs)) and lead. These may tern of defi cits arises in response to less extreme adversity.

damage cognitive and neural systems known to be implicated on September 28, 2021 by guest. Protected copyright. in ADHD.61 C O N C L U S I O N Associations between organophosphate pesticide exposure In summary, there is strong evidence of an inherited contri- and ADHD have been investigated cross-sectionally, 62 and bution to ADHD, although non-inherited factors that likely prospectively (eg, Eskenazi et al , Marks et al , Rauh et al63 – 65 ) include environmental risks and chance events (including de using assessments of prenatal and postnatal (childhood) uri- novo genetic changes) are also important. There is no single nary organophosphate metabolites and umbilical cord plasma cause of ADHD and the risk factors that have been identifi ed levels of pesticides. so far appear to be non-specifi c. That is, risks such as chro- PCBs are a large group of toxic manufactured organic com- mosomal microdeletions (eg, VCFS), large, rare CNVs, extreme pounds that were previously mass produced. Both human low birth weight and prematurity appear to affect a range of and animal studies have examined the effect of PCB expo- different neurodevelopmental and psychiatric phenotypes. sure on neurobehavioural outcomes similar to those affected Genetic risks likely also include multiple common gene vari- in ADHD, and these have found evidence of impairments in ants of small effect size that have yet to be identifi ed, with working memory, response inhibition and cognitive fl exi- the possible exception of a few dopaminergic genes. With the bility.66 A recent prospective study also found a positive costs of DNA sequencing dropping, there is likely to be an association between low-level prenatal PCB exposure and increasing focus on identifying rare genetic variants, including ADHD-type behaviour in middle childhood, with a dose–re- structural variants such as CNVs and other rare mutations sponse relationship.67 Both human and animal studies of lead with larger risk effects. exposure have shown similar impairments in executive func- Despite the rapid advances in genetics, there is still a need tions and attention, with cognitive fl exibility, vigilance and for further research into environmental risks. Although many

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factors are associated with ADHD, different designs are needed 1 8 . Li D, S h a m P C , O w e n M J , et al. Meta-analysis shows signifi cant association to test which are causal.45 The strongest evidence relates to the between dopamine system genes and attention defi cit hyperactivity disorder (ADHD). Hum Mol Genet 2 0 0 6; 15 : 2 2 7 6– 8 4. links between ADHD/ADHD-like behaviours and relatively 1 9 . Gizer IR, Ficks C, Waldman ID. Candidate gene studies of ADHD: a meta-analytic rare extreme adversities, specifi cally extreme prematurity, review. Hum Genet 2 0 0 9; 126 : 5 1– 9 0. very low birth weight, foetal alcohol syndrome and a pat- 2 0 . DiMaio S, G r i z e n k o N , J o o b e r R . D o p a m i n e g e n e s a n d a t t e n t i o n - d e fi c i t tern of behaviours associated with institutional deprivation in hyperactivity disorder: a review. J Psychiatry Neurosci 2 0 0 3; 28 : 2 7– 3 8. the early years. Less is known about risk factors that modify 2 1 . Gainetdinov RR. Dopamine transporter mutant mice in experimental n e u r o p h a r m a c o l o g y . Naunyn Schmiedebergs Arch Pharmacol ADHD outcomes. One exception is the association between 2 0 0 8; 377 : 3 0 1– 1 3. COMT and antisocial behaviour in ADHD that is well repli- 2 2 . Brookes KJ, M i l l J , G u i n d a l i n i C , et al. A common haplotype of the dopamine cated now and highlights that behavioural problems in those transporter gene associated with attention-defi cit/hyperactivity disorder and with ADHD may have different origins to behavioural prob- interacting with maternal use of alcohol during pregnancy. Arch Gen Psychiatry 2 0 0 6; 63 : 7 4– 8 1. lems in general. 2 3 . Becker K, E l - F a d d a g h M , S c h m i d t M H , et al. Interaction of dopamine transporter Cumulatively, the available evidence goes some way genotype with prenatal smoke exposure on ADHD symptoms. J Pediatr towards highlighting groups who are at higher risk; specifi - 2 0 0 8; 152 : 2 6 3– 9 . cally those who have a family history of ADHD and/or neu- 2 4 . Thapar A, L a n g l e y K , F o w l e r T , et al. Catechol O-methyltransferase gene variant rodevelopmental or learning problems, and those who have and birth weight predict early-onset antisocial behavior in children with attention- defi cit/hyperactivity disorder. Arch Gen Psychiatry 2 0 0 5; 62 : 1 2 7 5– 8 . been exposed to the environmental adversities described ear- 2 5 . Caspi A, L a n g l e y K , M i l n e B , et al. A replicated molecular genetic basis for lier. However, none of these risks, including the genetic ones, subtyping antisocial behavior in children with attention-defi cit/hyperactivity provide tests or biomarkers of ADHD. It is hoped that, in the disorder. Arch Gen Psychiatry 2 0 0 8; 65 : 2 0 3– 1 0. future, improved identifi cation of ADHD risk factors and path- 2 6 . Langley K, H e r o n J , O ’ D o n o v a n M C , et al. Genotype link with extreme antisocial behavior: the contribution of cognitive pathways. Arch Gen Psychiatry ways will increase our understanding of the as yet unknown 2 0 1 0; 67 : 1 3 1 7– 2 3. pathogenesis of ADHD and pave the way for improving diag- 2 7 . Franke B, Neale BM, Faraone SV. Genome-wide association studies in ADHD. nosis and treatment. Hum Genet 2 0 0 9; 126 : 1 3– 5 0. 2 8 . Pe’er I, Y e l e n s k y R , A l t s h u l e r D , et al. Estimation of the multiple testing A c k n o w l e d g e m e n t s Ongoing ADHD research supported by the Wellcome Trust. burden for genomewide association studies of nearly all common variants. Competing interests None. Genet Epidemiol 2 0 0 8; 32 : 3 8 1– 5 . 2 9 . Lasky-Su J, N e a l e B M , F r a n k e B , et al. 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