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 i 1,2 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 260 Arch Dis Child 2012;97:260–265. doi:10.1136/archdischild-2011-300482 20_archdischild-2011-300482.indd 260 2/12/2012 7:28:43 PM Arch Dis Child: first published as 10.1136/archdischild-2011-300482 on 7 September 2011. Downloaded from Review 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 22 (SNPs) across the genome are compared between cases and factors, such as maternal alcohol consumption or maternal 15 23 controls.