It is well established that attention deficit hyperactivity disorder (ADHD) is a familial and highly heritable disorder. Consequently, much effort is being directed towards searching for specific susceptibility genes. There is a growing trend, across the field of complex disease genetics, towards undertaking secondary analyses based on refined phenotypic definitions and in testing whether specific susceptibility genes modify the phenotypic presentation of the disorder in question. It is crucial that good, empirically derived arguments are made before undertaking multiple analyses on different phenotype refinements. In this review article, we consider the evidence from genetic epidemiological studies as well as key clinical studies that provide guidance on examining the ADHD phenotype for the purpose of molecular genetic studies. Specifically, findings on categorical versus dimensional conceptualisations of ADHD, reporter effects, comorbidity, ADHD subtypes and persistence are reviewed. Current evidence suggests that for the purpose of identifying susceptibility genes for ADHD, parent and teachers should be used as informants and that focusing on the clinical diagnosis of ADHD is useful. There is also good empirical support in favour of examining antisocial behaviour in ADHD. Genetic studies of dimensional ADHD are useful for other complementary purposes.
The importance of phenotype definition
Considerable international effort is being channelled into molecular genetic studies of attention deficit hyperactivity disorder (ADHD). Encouragingly there have been a number of replicated findings, although thus far all these results have come from functional candidate gene association studies.1, 2 Increasingly, researchers are attempting to fine tune molecular genetic findings for complex disorders by refining the phenotype in secondary analyses.3, 4 Given the risks of multiple testing, especially in the context of emerging whole genome association studies and the importance of replicating findings in other samples, it is advisable to base such analyses on firm empirical foundations.
There are many different approaches to validating phenotypes5 but for the purpose of molecular genetic studies, phenotypes should at least be heritable as well as reliably measured. In this paper, we consider what classical genetic studies tell us about heritable ADHD-related phenotypes. Our focus is on phenotypes defined by reported signs and symptoms. We discuss dimensional and categorical conceptualisations, the utility of Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) subtypes, the role of comorbidity, and the persistence of disorders and symptoms as valid phenotype definitions of ADHD and markers of heterogeneity. We recognise the intense interest in intermediate measures, for example neurocognitive tasks. This area of research is out with the remit of the present review and we direct the interested to authoritative reviews elsewhere.6, 7
Dimensional or categorical definitions of attention deficit hyperactivity disorder
The reliability, validity as well as clinical utility of categorically defined ICD-10 hyperkinetic disorder and DSM-IV ADHD are very well established.8, 9 Although there have been relatively few twin studies of categorically defined ADHD,10, 11, 12 these have consistently shown that this phenotype is heritable, a finding supported by family and adoption studies.13 Thus, in principle, ADHD defined as a category is appropriate for molecular genetic investigation.
However, there are also strong arguments for considering ADHD defined as a dimensional measure.14 Total ADHD symptom scores have predictive validity with longitudinal epidemiological studies showing that ADHD defined in such a way predicts a variety of adverse outcomes.15, 16 The dimension also has aetiological validity since genetic and many putative environmental risk factors influence ADHD across the continuum of severity.17, 18 Thus, there is specific evidence that ADHD scores within the normal range as well as high scores are equally heritable. There is also evidence of a dose–response relationship between some environmental risk factors, notably maternal smoking in pregnancy and ADHD symptom scores across the range of severity.19 However, that does not necessarily mean that the same genes influence low/normal range scores and high scores. Nevertheless, there is enough to suggest that setting out to identify susceptibility genes for ADHD defined dimensionally, that is, quantitative trait loci (QTL) studies represents a valid approach.
Which approach is to be preferred in the search for attention deficit hyperactivity disorder susceptibility genes?
Based on the classical genetic and clinical evidence, it can be seen that there are not the data to support one approach over the other for molecular genetic studies. Clearly both categorical and dimensional approaches can be regarded as showing validity. However, there are additional issues that favour traditional genetic studies based on clinical cases. First, for ADHD, the use of categorical diagnoses has yielded significant replicated evidence for association to several genes1, 2 indicating that this approach is fruitful in practice. In contrast, association with these gene variants for ADHD trait measures have either not been consistently detected or have been very much weaker,20 or researchers have imposed cut-points on their quantitative measure to generate extreme categories (e.g. Payton et al.21 and Cornish et al.22). However, there are some exceptions23 and the weakness of evidence may be because there have been fewer QTL studies. A more important concern, in terms of its implications for future studies, is the possibility that susceptibility genes for clinical ADHD are not the same as those that influence dimensional ADHD represented by total symptom scores.
Another important reason for retaining categorical approaches in research is that molecular genetic studies aspire to pave the way to prevention and improved treatments in clinical settings. Thus genetic studies, like randomised-controlled trials of treatments, should ideally relate to phenotypes that are meaningful in a clinical context and currently clinicians use categories not dimensions. Although it is unlikely that DSM or ICD-10 diagnostic categories will neatly index genetic liability, there must be an initial starting point and genetic findings, together with results from other types of studies can in turn be used to inform new classificatory systems.
In summary, there are arguments supporting both the use of categorical and dimensional approaches to defining ADHD. It is however far from clear whether the theoretical power advantages that follow from the latter can be realised. At any rate, the key point is perhaps not which is best but rather what is the nature of the relationship between ADHD and a given susceptibility variant.24 Given that it is impossible to know this before the variant is identified, ideally we need studies that incorporate both approaches (an extremely large population study with sufficient clinical cases as well as dimension ratings) to allow for testing of association with clinical diagnosis and dimensions simultaneously. As a study on such a large scale is unlikely to be feasible, it is desirable that QTL studies of ADHD include multiple dimensions (symptom-based and other associated measures e.g. cognitive, temperamental attributes) and clinical studies should also include the same set of dimensional measures to enable comparisons across different study designs. While necessary, we would note that the increased phenotypic efforts may compromise sample collection and as a result, power despite the theoretical attractions. Overall, where the primary aim is to identify ADHD susceptibility genes, current evidence supports the use of catetorical clinical diagnosis for defining the phenotype.
Attention deficit hyperactivity disorder symptoms can be assessed on the basis of reports from parents, teachers, the affected child or adult, or a mixture of the above. However a key problem is that agreement between different raters is at best modest, thereby creating a potential source of differences between genetic studies.
There is highly consistent evidence that maternal reports of ADHD whether symptom scores or categorical are highly heritable (heritability estimates ranging from 60 to 91%).13 Asking mothers about their children's symptoms is also practical and, from the clinical management perspective, is intuitively clinically meaningful. However, there are a number of problems. The use of single rater assessment (and single measures) can result in unacceptable measurement error variance,25 which in turn can adversely influence power to detect susceptibility genes. Importantly from the molecular genetics perspective, many twin studies have found zero or even negative dizygotic (DZ) twin correlations and concordance rates for maternally reported ADHD defined using questionnaire measures and interviews.18 Low DZ twin correlations could possibly arise from sibling competition, with increased ADHD scores in one twin leading to lower scores in the co-twin26 or rater contrast effects27 whereby mothers maximise the contrast between their DZ twin children. However rater contrast effects have not been found in all studies and may differ depending on the type of measure used. Overall, this uncertainty about validity and measurement suggests that molecular genetic studies of ADHD should not rely on maternal reports alone.
Teacher reports of ADHD have been shown to have greater phenotypic and genetic stability in the short term28 as well as a stronger association with neurocognitive correlates29 than parent reports. Moreover, twin studies of teacher reports have shown no evidence of rater contrast effects. However, environmental factors seem to contribute more strongly to teacher ratings of ADHD13 and heritability estimates are highly variable. More importantly, for clinical translational purposes, in the only studies to examine high teacher-rated ADHD scores, the heritabilities were low (16 and 20%).30, 31 This contrasts with teacher-rated categorical ADHD (DSM-III-ADDH or DSM-III-R ADHD12; cut-point on questionnaire11) where heritability was high. Given these variable findings, together with the problems of using a single rater, using teacher reports alone for molecular genetic studies of ADHD is not recommended.
To our knowledge there has only been one twin study of self-reported ADHD and this study in adolescence yielded 0% heritability.32 Longitudinal and clinical studies have additionally suggested that self-reports of ADHD do not show as good predictive validity as parent reports.33 These data cast doubts about the utility of self-reports of ADHD in molecular genetic studies.
Combined parent and teacher reports
For diagnostic purposes, both ICD-10 and DSM-IV require the presence of ADHD symptoms or impairment in more than one setting. For children, this usually involves obtaining information about the symptoms at school. Whether or not the measures are categorical or dimensional, as we have seen, there are problems with using single-source reports alone and merits of using multiple raters in defining ADHD in terms of decreased measurement error and higher reliability. However, before combining the data from different raters for genetic studies, an important question is whether or not mothers and teachers are rating constructs with a common underlying aetiology, especially given the modest levels of agreement. It appears from twin studies that this is partially true, with studies consistently showing genetic influences common to both reports (e.g. Thapar et al.11, Nadder et al.34 and Martin et al.32). However, the same studies show informant-specific effects suggesting that some genes contribute to phenotypes differentially indexed by informant sources, an observation that should be borne in mind when comparing molecular genetic data derived from different study designs using different reporters.
While this does not clarify whether there are genuine situational influences on the phenotype or merely informant effects,35 there is good evidence that pervasive ADHD (ADHD problems endorsed by both mother and teacher) shows greater predictive validity than home-based or school-based ADHD alone.36, 29 It is also highly heritable12, 11 and does not appear to be subject to rater contrast effects. These findings together with the general benefits from using multiple raters provide a compelling argument for using both mother and teacher reports to generate a diagnosis of ADHD in molecular genetic studies. However, it is less straightforward deciding how exactly to combine data from parents and teachers and different research groups may integrate data from different informants differently to yield categorical clinical diagnoses. There is even greater uncertainty as to how best to integrate scores from different reporters in QTL studies. Some researchers have generated dimensional composite scores in different ways, for example factor score-based measures (e.g.Curran et al.37 and Boomsma and Dolan 38) so replication of genetic findings in such QTL studies could prove even more difficult.
In conclusion, there is evidence across clinical and twin studies that for studies adopting a categorical approach, pervasive ADHD defined using cut-points on mother and teacher reports is valid, heritable, does not appear to be influenced by rater contrast effects, and is clinically relevant. Finally, it needs to be borne in mind that if single raters are used, studies based on maternal reports and studies based on teacher ratings may yield different findings.
Comorbidity, notably with conduct disorder (CD) and reading disability (RD), is a common phenomenon in ADHD and an important consideration for molecular genetic studies in several respects. First, there is evidence that the power of affected sib pair linkage studies of categorically defined phenotypes can be enhanced by inclusion of clinical covariates.39 There should be good a priori evidence for the inclusion of a covariate; heritability, predictive validity and ideally, clinical meaning are important. Covariates such as bronchial responsiveness in asthma have been included to refine linkage or association findings for the key phenotype and indeed in the case of asthma led to identification of a susceptibility gene ADAM33.3 Second, identifying modifying genetic loci that influence the comorbid condition or covariate itself; for example the development of CD in ADHD, can be important.40 Finally for QTL studies also, there is theoretical evidence that statistical power can, in some instances, be increased when multiple covarying phenotypes are examined together.38, 41 With these issues in mind, we consider more specific findings on ADHD and the key comorbid conditions of conduct disorder and RD.
ADHD commonly co-occurs with antisocial behaviour that conforms to the clinical diagnoses of oppositional defiant disorder and CD. Children with both CD and ADHD show greater ADHD and CD symptom severity than children with either disorder alone, a stronger association with neurobiological correlates,42, 14 and a poorer outcome. These observations have thus led to consideration of ADHD accompanied by CD, notably when it is of childhood onset, as a useful subtype and this is reflected in the ICD-10 subcategory of Hyperkinetic Conduct Disorder. Genetic epidemiological studies also suggest that CD in children with ADHD indexes a more strongly familial subtype of ADHD43 that differs quantitatively (in terms of genetic loading) but not qualitatively in aetiology from ADHD alone.44 Jointly, all these data suggest that comorbid CD in ADHD needs to be considered as a potential index of heterogeneity (in a quantitative sense) in molecular genetic studies of ADHD.
Twin studies have also consistently shown that ADHD and antisocial behaviour share a common genetic aetiology.44, 45 This additionally suggests that gene variants influencing ADHD may also influence antisocial behaviour. It is however important to consider the possibility that there will be some modifying gene variants that influence the development of antisocial behaviour in ADHD but that are not susceptibility genes for ADHD itself, and there are emerging data to suggest that this the case (see later).
Thus far, there has been relatively little published molecular genetics work focusing on CD in those with ADHD. In a joint analysis of data from the UK and Eire, the subgroup of ADHD with CD was significantly associated with the DRD4 7 repeat allele,46 whereas association was not detected in the full ADHD sample. That this is a genuine rather than chance finding is supported by similar observations in a follow-up study in an expanded Irish sample.47 There is also reported association between the COMT val/val genotype, previously found to be linked to prefrontal cognition, and CD symptoms in clinical ADHD40 and this finding has been recently replicated (Caspi et al., 2005, Personal communication). Interestingly, there is no evidence showing that this is a risk genotype for ADHD itself.1
In summary, twin, clinical and epidemiological data as well as emerging molecular genetic evidence suggest that measures of antisocial behaviour (the most convincing data so far are for accompanying childhood-onset CD) should be included in genetic studies of ADHD.
Attention deficit hyperactivity disorder commonly co-occurs with RD, and this is in part the result of a shared genetic aetiology, at least between RD and inattention symptoms.48 These findings from twin studies suggest that susceptibility genes for RD should be tested in ADHD cases and vice versa. Interestingly, genome-wide linkage studies49, 50have now found a number of suggestive areas of linkage common to both ADHD and RD, although specific variants that increase susceptibility to both disorders have yet to be identified.
There is no substantive evidence however that RD in those affected by ADHD identifies a distinct phenotype or that it reliably indexes heterogeneity in ADHD.
Attention deficit hyperactivity disorder subtypes
DSM-IV, unlike ICD-10, allows for further defining ADHD as inattentive, hyperactive–impulsive and combined subtypes, but whether these are genetically distinct is unclear. One study51 found no evidence of familial distinction between subtypes, a finding supported by analyses both of sibling pairs collected for a molecular genetic study52 and of a twin sample.53 In contrast, some twin studies based on general population samples54, 55, 56 have found distinct genetic (and environmental) influences on the different subtype symptom scores.
Although existing sample sizes might lack power, and the number of definitive or even highly probably confirmed ADHD loci is small, the distinction of DSM-IV ADHD subtypes also has no strong support from molecular genetic studies to date. The meta-analysis of a DRD5 gene variant57 found that the significant association with ADHD came predominantly from the combined and inattentive subtypes. Another group58 found a stronger association between inattentive symptoms of ADHD and DAT1 compared to combined or hyperactive/impulsive symptoms but these findings have not been replicated. Another approach to defining subtypes involves the use of latent class analysis of symptoms to separate individuals into subtypes. This statistical method creates phenotypically similar subgroups that may reflect aetiological homogeneity.59 Eight latent classes found through twin analysis55 have been broadly replicated in both extensions of the original and independent samples.60, 61 The latent classes so defined are familial, heritable and unlike the DSM-IV subtypes are more consistently reported to be independently transmitted.53, 56 Molecular genetic studies based on these classes have so far yielded negative findings apart from a reported significant association between the severely inattentive subtype and a variant within the nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4).62 One problem is that latent class genetic findings could be difficult to replicate if class structures vary in different types of populations.
Overall the evidence that DSM-IV subtypes are genetically distinct, or that they access substantially different sets of risk or modifier genes, is far from compelling. Thus, there is little support for selecting specific ADHD subtypes in molecular genetic studies or examining clinical subtypes separately at present to refine the phenotype definition. In general population samples, there is some evidence that latent class analysis could provide more homogenous subtypes that better index genetic liability or the presence of modifier loci but further molecular genetic findings are awaited and it is not known whether these latent classes behave similarly in clinical samples.
Persistence and continuity
It is now recognised that ADHD can persist into adolescence and adulthood.63 Persistence of ADHD may define a much more highly familial variant (λr=17.2–19.7) than childhood ADHD (λr=4–5.4).64 So should molecular genetic studies preferentially include subjects with adult ADHD? Caution is warranted for several reasons. First, there have been no twin or adoption studies of adult ADHD and therefore we cannot know that increased familiality reflects increased heritability. Second, defining the adult ADHD phenotype poses its own set of challenges that have not yet been resolved.65 Finally, there has been no evidence from data published so far that molecular genetic studies of adult ADHD yield more success than those based on samples of children (e.g. Inkster et al.66 and De Luca et al.67) although this may be because there have been fewer studies in this age group.
A related issue is whether genes that influence the origins of ADHD also influence continuity of ADHD symptom scores. Here, twin studies have all shown that it is genetic factors that mainly account for continuity of ADHD symptoms over time.28, 68, 69, 70 However, there is some additional genetic contribution specific to symptoms at the later time point in longitudinal studies.28, 68 This suggests that susceptibility genes for ADHD may also influence its continuity over time but that there may be additional genetic modifier loci that specifically influence the presence of symptoms at later ages. So far there has been one published longitudinal study that found association of the DRD4 7 repeat allele with ADHD and ADHD persistence in boys aged 4 and 11 years.71
Finally, there is increasing generalised interest in using longitudinal, repeated measures for the purpose of increasing the statistical power of molecular genetic studies. Some have found that the weighted average of repeated measures of quantitative variables such as fasting glucose levels increases power to detect QTLs in linkage studies72 but this approach has not been uniformly successful in general medicine with others (e.g. North et al.73) finding greater success in examining each time point separately (either because of reduced power or time-/age-specific effects). Moreover it is not yet clear what is the best approach to combining data from different occasions. Given these concerns, although there are clearly strong arguments for longitudinal studies with regard to examining specific questions (for example, what gene variants influence continuity), since the equivalent resources could alternatively allow recruitment of a much larger and thereby more powerful sample, much more work is needed before the expense of longitudinal measures gathered specifically and only to improve the power of a molecular genetic study can be justified.
Taking a clinical perspective, evidence from epidemiological and classical genetic studies together with emerging molecular genetic data suggests that for the purpose of identifying susceptibility genes, there is strong support for focusing on categorically defined, clinical diagnoses of ADHD. However, as there is empirical evidence that ADHD defined as a dimension is also valid in terms of correlates, outcome and genetic aetiology, further consideration of the measurement and methodological complexities of dimensional QTL studies of ADHD are warranted. Based on the evidence to date, we suggest that QTL studies of ADHD are more useful for examining different questions to those of traditional clinical case-based designs, for example testing for gene × environment interaction across a spectrum of environmental exposures or examining specific developmental questions in the general population and for investigating the pathway from gene to intermediate phenotypes in unaffected individuals once ADHD susceptibility genes are identified. We also conclude that multiple raters (mothers and teachers for child ADHD) should be used in molecular genetics studies of ADHD and that there is good support for examining accompanying childhood-onset CD in ADHD. However, the lack of evidence for RD, DSM-IV subtypes and persistence indexing heterogeneity suggests that these subtypes are not a priority for sample collection or analysis in molecular genetic studies of ADHD, unless the aim is to test a hypothesis specifically about those subtypes.
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KL is funded by the Wellcome Trust (Value in Person Award). Part of this paper is based upon a presentation made by AT at the EUNETHYDIS meeting, Santorini, Greece, September 2003. We thank Professor Jim Stevenson for his suggestion to develop this paper.
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