Introduction
The co-occurrence between attention deficit-hyperactivity disorder (ADHD), which is characterized by developmentally inappropriate levels of inattentive and/or hyperactive-impulsive behaviours (American Psychiatric Association (APA)
2000), and reading disability, whether defined as diagnostic categories or quantitative traits, is well documented (August and Garfinkel
1990; Dykman and Ackerman
1991; Trzesniewski et al.
2006; Willcutt and Pennington
2000a,
b). It reflects a strong phenotypic association between reading disability and ADHD inattention symptoms, which has been largely attributed to shared genes (Martin et al.
2006; Willcutt and Pennington
2000a; Willcutt et al.
2000,
2007b). The present study, using a genetically informative design, extends this research by investigating to what extent the common genetic variability between reading difficulties and ADHD inattention symptoms is also shared with general cognitive ability, as measured by IQ.
Previous twin studies have shown that both reading ability/disability (Alarcon and DeFries
1997; Byrne et al.
2008; Gayan and Olson
2003; Harlaar et al.
2005a; Tiu et al.
2003; Wadsworth et al.
2000) and ADHD symptoms (Kuntsi et al.
2004; Wood et al.
2009) share genetic variability with IQ. Therefore, it is possible that any shared genetic variability between inattention symptoms and reading disability could reflect a common genetic association shared with general intelligence. This idea was supported by evidence that genetic and environmental influences shared with IQ accounted for the covariance between reading performance and a cognitive attention measure (Zumberge et al.
2007). However, it is not possible to generalize directly from cognitive attention processes to behavioural inattention problems (Marzocchi et al.
2009; Warner-Rogers et al.
2000). Similar manifestations of inattention problems may reflect diverse cognitive deficits, and the relationship between overt behavioural inattention and deficits in cognitive attention is neither simple nor direct (Marzocchi et al.
2009; Warner-Rogers et al.
2000).
Indeed, behavioural and genetic evidence at the overt symptom level suggests that shared aetiological influences between inattention symptoms and reading disability are likely to be independent of IQ. A recent study reported similar estimates of common genetic influences between a brief measure of hyperactive/inattentive behaviours and a composite measure of academic achievement (including reading) before and after adjusting the latter for IQ (Saudino and Plomin
2007). Other studies have shown that early inattention symptoms predicted later reading achievement even after controlling for prior reading ability and IQ (Rabiner and Coie
2000; Rabiner and Malone
2004).
There is a need to understand better the aetiology of the covariance between ADHD inattention symptoms and reading disability because, to be effective at improving reading performance in the context of inattention problems, intervention programs need to address the specific deficits giving rise to the covariance between these disorders (Rabiner and Malone
2004). If the covariance could be attributed to shared aetiological influences that are independent of IQ, this would indicate the presence of specific neurocognitive deficits contributing to these disorders that were independent of possible “generalist” mechanisms spanning cognitive processes and learning abilities/disabilities across domains (Haworth et al.
2009).
Bivariate studies allow the parsing of the covariance between two phenotypes into distinct genetic and environmental components. The genetic and environmental correlations provide estimates of the degree to which the covariance between two phenotypes reflects shared genes or environmental factors, respectively. The inclusion of additional variables of interest in the multivariate case makes possible the estimation of the extent to which the genetic (or environmental) overlap is further shared with the additional variables (such as IQ). Multivariate designs offer improved power by decreasing the rate of false positive type I error rate (by decreasing the number of tests) and by taking into account the covariance among traits for each individual (Hottenga and Boomsma
2008).
Existing studies have employed bivariate designs, examining the aetiology between reading deficits and a single ADHD subtype, or ADHD symptom dimension, at a time, excluding IQ (Martin et al.
2006; Willcutt et al.
2000,
2007b). In the present study we replicate and extend previous research by using a general population sample and employing a multivariate design, including measures of IQ and both ADHD inattention and hyperactivity-impulsivity symptoms. The use of an unselected, general population sample avoids possible selection biases associated with clinic-referred or selected community samples and allows the generalization of findings to the general population. Inattention, hyperactivity-impulsivity and reading disability are all considered to be the tails of normally distributed traits, reflecting the normal distribution of genetic risk in the population (Chen et al.
2008; Harlaar et al.
2005b; Levy et al.
1997; Shaywitz et al.
1992). Studying general population samples is useful in understanding the extremes, as quantitative genetic and epidemiological evidence supports the validity of making inferences from population data to clinical cases in ADHD (Chen et al.
2008).
Specifically, our study aimed to: (1) Confirm the substantially larger phenotypic and genetic correlations between reading difficulties and ADHD inattention symptoms, compared to hyperactivity-impulsivity symptoms. (2) Investigate, for the first time, to what extent the common genetic variability between ADHD inattention symptoms and reading difficulties is also shared with IQ and hyperactivity-impulsivity symptoms. (3) Assess how much of the variance in reading difficulties could be attributed to aetiological influences shared with the ADHD symptom domains and IQ, thus providing an estimate of their relative importance in understanding the aetiology of reading difficulties. (4) Finally, examine the possibility of gender differences in the aetiology for the covariation between reading difficulties and inattention symptoms.
Results
A medium phenotypic correlation between reading difficulties and inattention symptoms was observed, which was substantially and significantly higher than the correlation with hyperactivity-impulsivity symptoms (
p<.001) (Table
2). The association between IQ and reading difficulties was similar to what has been previously reported in the larger TEDS sample using a composite index of reading ability (
r = .43; Harlaar et al.
2005a). The correlation between IQ and ADHD inattention symptoms was small but significant, while the correlation with hyperactivity-impulsivity symptoms, although also significant, was less than half the size of the association with inattention. Heritability estimates ranged from 55% for inattention to 74% for reading difficulties (Table
3). The genetic correlation between reading difficulties and inattention was moderately high at 0.60, 2.5 times the size of the genetic correlation with hyperactivity-impulsivity (Table
3). The phenotypic correlation of reading difficulties with both inattention and hyperactivity-impulsivity symptoms was largely attributable to shared genetic effects (75% and 92% respectively; Table
3).
Table 2
Phenotypic Correlations (with 95% Confidence Intervals in Brackets) Across IQ, Inattention, Hyperactivity-Impulsivity and Reading Difficulties Ratings
Inattentiona
| .51 (.47,.55) | | |
Hyperactivity-impulsivitya
| .22 (.16,.28) | .60 (.56,.64) | |
IQ | −.37 (−.42, −.31) | −.19 (−.24, −.13) | −.08 (−.14, −.02) |
Table 3
Standardized Parameter Estimates (with 95% Confidence Intervals) from the Correlated Factors Solution of the Full Cholesky Model Within and Across IQ, Hyperactivity-Impulsivity, Inattention and Reading Difficulties Ratings
Genetic influences (broad sense) |
IQ |
.61 (.47,.76)
| −0.05 (66%) | −0.10 (55%) | −0.33 (89%) |
Hyperactivity-impulsivitya
| −.07 (−.17,.04) |
.72 (.66,.77)
| 0.47 (78%) | 0.18 (92%) |
Inattentiona
| −.17 (−.29, −.05) | .74 (.66,.81) | .55 (.45,.63) | 0.38 (75%) |
Reading difficulties | −.49 (−.60, −.40) | .24 (.15,.33) | .60 (.51,.68) |
.74 (.68,.79)
|
Child-specific environmental influences |
IQ |
.21 (.17,.26)
| −0.02 (34%) | −0.08 (45%) | −0.04 (11%) |
Hyperactivity-impulsivitya
| −.10 (−.22,.02) | .28 (.23,.34) | 0.13 (22%) | 0.02 (8%) |
Inattentiona
| −.26 (−.38, −.14) | .38 (.27,.48) |
.45 (.37,.55)
| 0.13 (25%) |
Reading difficulties | −.17 (−.29, −.04) | .06 (−.06,.18) | .37 (.26,.48) |
.26 (.20,.32)
|
Shared environment influences (IQ only) |
IQ |
.18 (.04,.31)
| | | |
Comparing the AIC values of the three multivariate models, including the common-pathway and independent-pathway models, showed that the ACE-AE Cholesky model provided the best fit to the data (Table
4). This indicated that the covariance between the four phenotypes could not be best explained by genetic and environmental factors that are common among all traits. Using the parameter estimates from the best-fitting Cholesky decomposition model (Fig.
1), we estimated that 45% of the covariance between reading difficulties and inattention was due to genetic effects not shared with any of the other phenotypes: (3.20*1.80)/[3.20*1.80+1.24*1.98+(−2.89)*(−0.47)+2.22*1.19+0.16*0.87+(−0.57)*(−0.65)]. Similarly, we calculated that a fifth (19%) of the covariance was due to genetic effects shared with both inattention and hyperactivity-impulsivity, but not IQ, and only 11% of the covariance was due to genetic effects shared among all four phenotypes. These estimates added up to 75%, which was the percentage of the phenotypic correlation between reading difficulties and inattention due to shared genetic effects (Table
3). The remaining 25% percent could be attributed to child-specific environment effects (21% not being shared with hyperactivity-impulsivity or IQ).
Table 4
Statistics for the Relative Fit of the Multivariate Genetic Models
1 | Saturated | 32323.17 | 5024 | – | – | – | – | – | – | – | – | – |
2
|
ACE-AE (scalar)
|
32596.76
|
5212
|
273.58
|
188
|
<.001
| −102.417
| – | – | – | – | 1 |
3 | ACE/AE: common pathway (scalar) | 32795.59 | 5218 | 472.42 | 194 | <.001 | 84.415 | 198.84 | 6 | <.001 | 186.84 | 1/2 |
4 | ACE/AE: independent pathways (scalar) | 32759.70 | 5216 | 436.52 | 192 | <.001 | 52.522 | 162.94 | 4 | <.001 | 154.94 | 1/2 |
Individual differences in reading difficulties scores were largely attributed to genetic factors (heritability h
2=74%; Table
3). Of the total variance for reading difficulties, 31% [3.77
2/(3.77
2+3.20
2+1.24
2+(−2.89)
2 +3.17
2+1.19
2+0.16
2+(−0.57)
2)] (or 42% of the heritability) was attributed to unique genetic effects (see Fig.
1), 22% to genetic effects shared only with inattention (A3), 3% to genetic effects shared with both inattention and hyperactivity-impulsivity (A2), and 18% to genetic effects shared among all phenotypes (A1). Unique child—specific environment influences accounted for 22% of the total variance in reading difficulties, whereas the sum of child-specific environment influences shared with the other phenotypes accounted for only 4% of the total variance.
The lack of qualitative and quantitative sex differences in the univariate analyses, together with the absence of any indication of sex differences in the cross-twin cross-trait correlations for reading difficulties and inattention symptoms between males (MZ: r = .39, 95% confidence intervals (CI95):.31 to .46; DZ: r = .02, CI95: −.15 to .19) and females (MZ: r = .41, CI95:.34 to .47; DZ: r = .04, CI95: −.12 to .20), provided no indication for further testing this aim in the multivariate analysis.
Discussion
Using an unselected general population sample, we confirmed previous reports that reading difficulties show higher phenotypic and genetic correlations with ADHD inattention symptoms, compared to hyperactivity-impulsivity symptoms (Martin et al.
2006; Willcutt et al.
2000,
2007b). This study further showed, for the first time, that the covariance between reading difficulties and ADHD inattention symptoms is largely (66%) driven by aetiological factors (genetic, 45%, and child-specific environment, 21%) that are
not shared with IQ or hyperactivity-impulsivity. Almost half (47%) of the variance in reading difficulties was attributed to components shared with other phenotypes, mainly genetic influences shared with inattention (22%) or inattention, hyperactivity-impulsivity and IQ (18%), attesting to the multifactorial nature of the deficits underlying reading disability (Bosse et al.
2007; Vellutino et al.
2004).
This study extends findings from bivariate twin studies that used extreme selected groups (Willcutt et al.
2000,
2007b) to the full distribution of ADHD symptom ratings and reading disability scores in the general population. The similarity of findings across selected and general population samples supports the notion that inattention and hyperactivity-impulsivity symptoms and reading disability are the tails of normally distributed traits, reflecting normally distributed risk factors in the population (Chen et al.
2008; Harlaar et al.
2005b; Levy et al.
1997; Shaywitz et al.
1992).
A novel finding in this study was that the aetiological factors linking reading difficulties with inattention symptoms were largely independent from factors affecting general cognitive ability. This is consistent with evidence from behavioural genetic (Saudino and Plomin
2007) and longitudinal studies (Rabiner and Coie
2000; Rabiner and Malone
2004). Moreover, accumulating evidence from reading disability studies has challenged the role of IQ as a useful marker in the diagnosis of reading disability and the prognosis of outcome (Stuebing et al.
2002; Vellutino et al.
2004). For example, IQ-discrepancy scores did not distinguish cases according to the potential benefit they would receive from an intervention program (Vellutino et al.
2004; Vellutino et al.
2000). In a behavioural intervention study, teacher attention ratings predicted reading outcome better than verbal IQ did (Stage et al.
2003).
Another novel finding in this study was that child-specific environment factors (including possible error) were uniquely shared between reading difficulties and inattention symptoms, making a significant contribution (21%) to their covariance. This confirms previous evidence from TEDS showing a child-specific environment contribution to the covariation between a brief ADHD measure and a composite measure of teacher-assessed scholastic achievement (including reading) (Saudino and Plomin
2007). Other studies, though, have reported minimal or no contributions of child-specific environment influences (Martin et al.
2006; Willcutt et al.
2000). Possibly, the use of the full range of scores that is available with an unselected general population sample and the multivariate design may have increased power to detect this effect. Saudino and Plomin (
2007) suggested that such factors are likely to operate across family and school environments. An intriguing prospect for future research would be to replicate this finding and identify such factors using objective readings measures, as they might provide useful targets for intervention.
Consistent with previous reports (Saudino and Plomin
2007; Willcutt et al.
2000), our findings did not provide any indication for gender differences in the aetiology of the covariance between reading difficulties and inattention symptoms. Further, while our data confirmed the low phenotypic and genetic correlations between reading difficulties and hyperactivity-impulsivity symptoms, it suggested that the phenotypic association was almost entirely due to shared genetic effects (92%), unlike previous reports (Willcutt et al.
2000,
2007b). It is possible that the use of the full range of scores in an unselected sample may have made possible the detection of this effect in the present study.
The evidence from this and previous studies (Martin et al.
2006; Willcutt et al.
2000,
2007b) is supportive of the idea that pleiotropic gene effects drive the covariance between inattention symptoms and reading difficulties. Further support is provided by molecular genetic studies, which have identified genetic variants likely to increase susceptibility to both reading disability and ADHD or show bivariate linkage to both disorders (Couto et al.
2009; Gayan et al.
2005; Loo et al.
2004; Wigg et al.
2008; Willcutt et al.
2002). Current twin and genetic data cannot distinguish, though, between different causal pathways; phenotypic covariance could result either from deficits in distinct neurocognitive mechanisms underlying each disorder, or deficits in common processes acting as vulnerability factors for both disorders, or both. Existing evidence from neuropsychological, medical treatment and behavioural intervention studies, while consistent with the idea of pleiotropic gene effects, is supportive of both possible patterns of causal relatedness.
Neuropsychological deficits in the comorbid group are mostly a combination of deficits observed when either disorder is present alone (Bental and Tirosh
2007; Rommelse et al.
2009; Shanahan et al.
2006; Willcutt et al.
2001,
2005). Processing speed and rapid naming emerge as strong candidates for shared risk factors, sharing all the common genetic influences contributing to the covariance between performance in objective reading tests and ADHD symptoms (Willcutt et al.
2010a). The same executive and motor endophenotypes have also been associated with both reading difficulties and ADHD (Rommelse et al.
2009).
Pharmacological studies have shown that despite improvements in ADHD symptoms, methylphenidate and atomoxetine effects on reading performance depended on the nature of the drug, and possibly the reading test that was used. Methylphenidate improved reading performance only in cases of reading disability comorbid with ADHD, despite similar improvements in inattention symptoms in single-disorder groups (Keulers et al.
2007). Similarly, a behavioural intervention program failed to improve reading performance only in those cases with both inattention symptoms and reading difficulties (Rabiner and Malone
2004). This evidence is suggestive of deficits in neurocognitive processes specific to the comorbid cases. Improvement in reading performance effected by atomoxetine treatment either did not correlate (or did so weakly) with improvement in ADHD symptoms (Sumner et al.
2009), or atomoxetine did not affect reading performance despite reducing ADHD symptoms (de Jong et al.
2009). This dissociation of atomoxetine effects on reading performance and ADHD symptoms suggests that distinct neurocognitive mechanisms may also contribute to the covariance between these traits.
Nevertheless, alternative explanations would also be consistent with a shared genes account. Methodological/sampling issues, such as symptom overlap or shared method variance could mimic shared gene effects. The similarity of findings across studies using objective measures (Willcutt et al.
2000,
2007b) or parent ratings (this study and Martin et al.
2006) of reading difficulties makes it unlikely that such factors made an important contribution in this study. The use of only parent ratings of reading difficulties is a limitation of this study though. Cross-assortative mating could be another possible confounding factor, yet initial evidence (Faraone et al.
1993) was not replicated (Friedman et al.
2003). Besides, cross-assortative mating would actually decrease estimates of shared genetic effects (Willcutt et al.
2000); evidently, this cannot have played an important role in this study.
Another possible explanation that would mimic shared gene effects is the phenocopy hypothesis, whereby disorder B is caused by the deficits associated with disorder A, in the absence of the normal aetiological antecedents for the former (Pennington et al.
1993). Initially, based on the resemblance of the neurocognitive profile of the comorbid group with that of the pure reading disability group, it was suggested that ADHD is a secondary outcome of reading disability (Pennington et al.
1993). This hypothesis was not supported by later neuropsychological studies though (discussed earlier), or by evidence from separate lines of research. First, it is not consistent with evidence for small to moderate phenotypic and genetic correlations between inattention symptoms and prereading skills in preschool children, before the onset of formal reading instruction (Willcutt et al.
2007a,
b). Second, ADHD symptom ratings before or at school entry predicted scholastic achievement in later years (Fantuzzo et al.
2003; Horn and Packard
1985; Merrell and Tymms
2001; Newman et al.
1998; Rabiner and Coie
2000). Third, this and other studies have found that parent as well as teacher ratings of ADHD symptoms predict reading difficulties, showing that this association was not restricted to the classroom (Fergusson and Horwood
1992; Saudino and Plomin
2007).
Yet this evidence is not inconsistent with the hypothesis that attention deficits could lead to reading difficulties. This idea makes intuitive sense, as it is plausible that inattention problems might interfere with reading instruction. It is known that inadequate experience or instruction in reading accounts for most cases of early reading difficulties, which can be rectified through additional tutoring (Vellutino et al.
2004). Such deficiencies would mimic deficits observed in cases of pure reading disability, which reflect cognitive deficits of biological origin (Vellutino et al.
2004). Inattention symptoms do indeed moderate the effect of early tutoring on reading development (Stage et al.
2003), and studies have shown that early inattention deficits could predict later reading achievement even after controlling for concurrent reading ability (Rabiner and Coie
2000; Rabiner and Malone
2004). In particular, Rabiner and Coie (
2000) found that one third of a group of inattentive kindergarten children whose standardized reading achievement scores at grade 5 were substantially (>1 SD) below those of their peers had normal reading scores at the post-kindergarten assessment. However, existing evidence suggests that reading difficulties in the context of inattention symptoms may not be caused by inadequate tutoring, given the failure of a behavioural intervention program to improve reading performance only in the comorbid cases (Rabiner and Malone
2004).
The findings from the current study can only apply to reading difficulties and ADHD inattention symptoms as reflected in parent and teacher ratings; they cannot be extrapolated to any specific process in either domain. ADHD inattention ratings represent pervasive inattentiveness across different domains in real life over an extended period of time. Therefore our conclusions cannot be extended to any specific cognitive attention process, as overt behavioural problems cannot be linked in a simple and direct manner to possible underlying deficits in cognitive attention processes, while similar manifestations of inattention problems may reflect diverse cognitive deficits (Marzocchi et al.
2009; Warner-Rogers et al.
2000). Studies using specific cognitive attention measures may lead to different conclusions regarding the extent of shared aetiological influences with IQ, depending on what particular measure in used (Zumberge et al.
2007).
It is important to understand the causal links between inattention problems or deficits in cognitive attention processes and the development of normal reading skills or the act of reading. Reading disability is a multifactorial disorder (Bosse et al.
2007; Vellutino et al.
2004), and for behavioural interventions to be effective they need to address the specific aetiological factors involved in each case (e.g. focusing on self-regulation versus targeting a specific neurocognitive process) (Rabiner and Malone
2004; Stage et al.
2003). Inattention is unlikely to be associated with reading difficulties only at the behavioural level and, in line with existing research, our findings are consistent with the idea that specific neurocognitive processes underlie the covariance between these two traits, which reflects shared genetic and child-specific environment influences that are largely independent from IQ. Indeed, cognitive attentional processes are being recognized as being involved in many stages of the reading process (Bosse et al.
2007; Reynolds and Besner
2006; Shaywitz and Shaywitz
2008; Vidyasagar and Pammer
2010). In the future we need evidence from longitudinal twin studies, measuring objectively a range of specific reading skills as well as of processes likely to contribute to behavioural inattention problems. Such studies will identify with greater specificity the neurocognitive processes that link behavioural inattention with deficits in specific reading skills, and examine causal relationships between these traits though development, as well as examine whether the contribution of IQ differs throughout development.