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Approximately 60% of children with reading difficulties (RD) meet criteria for at least one co-occurring disorder. The most common of these, attention deficit-hyperactivity disorder (ADHD), occurs in 20-40% of individuals with RD. Recent studies have suggested that genetic influences are responsible. To assess the genetic etiologies of RD and the comorbidity of RD and two ADHD symptom dimensions -- inattention (IN) and hyperactivity/impulsivity (H/I) -- we are conducting the first longitudinal twin study of RD and ADHD. Data from twin pairs in which at least one member of the pair met criteria for proband status for RD at initial assessment, and were reassessed 5 years later, were subjected to DeFries-Fulker (DF) analysis. Analyses of reading composite data indicated that over 60% of the proband deficit at initial assessment was due to genetic influences, and that reading deficits at follow-up were due substantially to the same genetic influences. When a bivariate DF model was fitted to reading performance and IN data, genetic influences accounted for 60% of contemporaneous comorbidity and over 60% of the longitudinal relationship. In contrast, analysis of the comorbidity between reading performance and H/I indicated that common genetic influences accounted for only about 20% of the contemporaneous and about 10% of the longitudinal relationships. Results indicate that (1) genetic influences on RD are substantial and highly stable; (2) the comorbidity between RD and IN is due largely to genetic influences, both contemporaneously and longitudinally; and (3) genetic influences contribute significantly less to the comorbidity between RD and H/I.

Background: Males show higher rates of attention deficit hyperactivity disorder (ADHD) than do females. Potential explanations include genuine etiological differences or artifact., Methods: 2,332 twin and sibling youth participated in behavioral and cognitive testing. Partially competing models of symptom severity distribution differences, the mean difference, and variance difference models, were tested within a randomly selected subsample. The Delta method was used to test for mediation of sex differences in ADHD symptom severity by processing speed, inhibition and working memory., Results: The combined mean difference and variance difference models fully explained the sex difference in ADHD symptom severity. Cognitive endophenotypes mediated 14% of the sex difference effect., Conclusions: The sex difference in ADHD symptom severity is valid and may be due to differing genetic and cognitive liabilities between the sexes., (© 2014 Association for Child and Adolescent Mental Health.)

Despite its high heritability, genetic association studies of attention deficit-hyperactivity disorder (ADHD) have often resulted in somewhat small, inconsistent effects. Refining the ADHD phenotype beyond a dichotomous diagnosis and testing associations with continuous information from the underlying symptom dimensions may result in more consistent genetic findings. This study further examined the association between ADHD and the DRD4, DAT1, and 5HTT genes by testing their association with multivariate phenotypes derived from continuous measures of ADHD symptom severity. DNA was collected in 202 families consisting of at least one ADHD proband and at least one parent or sibling. VNTR polymorphisms of the DRD4 and DAT1 genes were significantly associated with the continuous ADHD phenotype. The association with DRD4 was driven by both inattentive and hyperactive symptoms, while the association with DAT1 was driven primarily by inattentive symptoms. These results use novel methods to build upon important connections between dopamine genes and their final behavioral manifestation as symptoms of ADHD.

In order to test the hypothesis that the genetic etiology of reading disability differs as a function of IQ, composite reading performance data from 308 pairs of identical (monozygotic, MZ) twins and 440 pairs of fraternal (dizygotic, DZ) twins (254 same-sex and 186 opposite-sex) in which at least one member of each pair was classified as reading-disabled were subjected to multiple regression analysis (DeFries and Fulker, Behav Genet 15:467-473, 1985; Acta Genet Med Gemellol 37:205-216, 1988). In the total sample, heritability of the group deficit in reading performance (h(g)(2)) was .61 (±.06). However, results of fitting an extended regression model to reading performance and IQ data suggested that the genetic etiology of reading disability differs as a linear function of IQ (p ≤ .04). When the basic regression model was fitted separately to data from twin pairs with Wechsler (Examiner's manual: Wechsler intelligence scale for children-revised, 1974; Examiner's manual: Wechsler adult intelligence scale-revised, 1981) Full Scale IQ scores in the upper and lower 25% of the sample, resulting estimates of h(g)(2) were .75 (±.12) and .50 (±.10), respectively (p ≤ .045). These results suggest that reading difficulties in children with a higher IQ are due substantially to genetic influences and may require intensive remediation efforts.

The prevalence of reading difficulties is typically higher in males than females in both referred and research-identified samples, and the ratio of males to females is greater in more affected samples. To explore possible gender differences in reading performance, we analysed data from 1133 twin pairs in which at least one member of each pair had a school history of reading problems and from 684 twin pairs from a comparison sample with no reading difficulties. Although the difference between the average scores of males and females in these two samples was very small, the variance of reading performance was significantly greater for males in both groups. We suggest that a greater variance of reading performance measures in males may account at least in part for their higher prevalence of reading difficulties as well as for the higher gender ratios that are observed in more severely impaired samples., ((c) 2009 John Wiley & Sons, Ltd.)

There is significant comorbidity between attention-deficit/hyperactivity disorder (ADHD) and conduct disorder (CD). The conclusions of studies that examined the causes of comorbidity between ADHD and CD conflict, with some researchers finding support for the three independent disorders model and others finding support for the correlated risk factors model. We tested these models and eleven alternative hypotheses using the same analytical approach. The participants were 110 monozygotic twin pairs and 181 dizygotic twin pairs recruited from the Colorado Learning Disabilities Research Center Twin Study. The three independent disorders model did not fit the data, whereas the correlated risk factors model fit the data well. Several other comorbidity models fit the data as well as or better than the correlated risk factors model. The results suggest that correlated risk factors are a better explanation for the comorbidity between ADHD and CD than a third, independent ADHD+CD subtype.

The primary objectives of the present study are to introduce the Colorado Longitudinal Twin Study of Reading Disability, the first longitudinal twin study in which subjects have been specifically selected for having a history of reading difficulties, and to present some initial assessments of the stability of reading performance and cognitive abilities in this sample. Preliminary examination of the test scores of 124 twins with a history of reading difficulties and 154 twins with no history of reading difficulties indicates that over the 5- to 6-year interval between assessments, cognitive and reading performance are highly stable. As a group, those subjects with a history of reading difficulties had substantial deficits relative to control subjects on all measures at initial assessment, and significant deficits remained at follow-up. The stability noted for all cognitive and achievement measures was highest for a composite measure of reading, whose average stability correlation across groups was 0.80. Results of preliminary behavior genetic analyses for this measure indicated that shared genetic influences accounted for 86% and 49% of the phenotypic correlations between the two assessments for twin pairs with and without reading difficulties, respectively. In addition, genetic correlations reached unity for both groups, suggesting that the same genetic influences are manifested at both time points.

Background: Neurocognitive deficits associated with attention-deficit/hyperactivity disorder (ADHD) might be useful intermediate endophenotypes for determining specific genetic pathways that contribute to ADHD., Methods: This study administered 17 measures from prominent neuropsychological theories of ADHD (executive function, processing speed, arousal regulation and, motivation/delay aversion) in dizygotic (DZ) twin pairs discordant for ADHD and control twin pairs (ages 8-18 years) to compare performance between twins affected with ADHD (n = 266), their unaffected co-twins (n = 228), and control children from twin pairs without ADHD or learning difficulties (n = 332)., Results: The ADHD subjects show significant impairment on executive function, processing speed, and response variability measures compared with control subjects. Unaffected co-twins of ADHD subjects are significantly impaired on nearly all the same measures as their ADHD siblings, even when subclinical symptoms of ADHD are controlled., Conclusions: Executive function, processing speed, and response variability deficits might be useful endophenotypes for genetic studies of ADHD.

Results obtained from previous longitudinal studies of reading difficulties indicate that reading deficits are generally stable. However, little is known about the etiology of this stability. Thus, the primary objective of this first longitudinal twin study of reading difficulties is to provide an initial assessment of genetic and environmental influences on the stability of reading deficits. Data were analyzed from a sample of 56 twin pairs, 18 identical (monozygotic, MZ) and 38 fraternal (dizygotic, DZ), in which at least one member of each pair was classified as reading-disabled in the Colorado Learning Disabilities Research Center, and on whom follow-up data were available. The twins were tested at two time points (average age of 10.3 years at initial assessment and 16.1 years at follow-up). A composite measure of reading performance (PIAT Reading Recognition, Reading Comprehension and Spelling) was highly stable, with a stability correlation of .84. Data from the initial time point were first subjected to univariate DeFries-Fulker multiple regression analysis and the resulting estimate of the heritability of the group deficit (h2g) was .84 (+/-.26). When the initial and follow-up data were then fitted to a bivariate extension of the basic DF model, bivariate heritability was estimated at .65, indicating that common genetic influences account for approximately 75% of the stability between reading measures at the two time points.

Results obtained from previous studies of word recognition, reading component skills, and reading composite measures suggest that genetic factors may be more important as a cause for reading disability among children with higher IQ scores than among those with lower IQ scores. To investigate the genetic etiology of reading disability further, measures of word recognition, phonological decoding, orthographic coding, and phoneme awareness were obtained from a total of 465 twin pairs with a positive school history of reading problems. The basic and extended DeFries and Fulker (DF) multiple regression models for the analysis of selected twin data were employed to investigate the etiology of group deficits in reading and language skills, as well as to assess differential genetic etiology for the reading-related measures as a function of IQ. Data from 168 sibling pairs (drawn from the twins' families), including fraternal twin pairs and their siblings, as well as non-twin siblings of identical twins were subjected to single-marker analyses using the DF basic linkage model to examine evidence for linkage of a quantitative-trait locus (QTL) for reading and language deficits to the short arm of chromosome 6. Lastly, to investigate the possible differential influence of this QTL as a function of IQ, the sibling pair data were fitted to an extension of the DF basic linkage model. Results indicated that reading and language deficits are significantly heritable and that differential genetic influences as a function of IQ are evident for measures of word recognition and phonological decoding. Results obtained from linkage analyses confirmed the presence of a QTL on chromosome 6p that influences phonological and orthographic skills, as well as phoneme awareness measures, and suggest that this QTL may influence phoneme awareness differentially as a function of IQ: however, future analyses with considerably larger samples are needed to test the hypothesis of differential QTL influence more rigorously.

Children with reading deficits perform more slowly than normally-achieving readers on speed of processing measures, such as rapid naming (RN). Although rapid naming is a well-established correlate of reading performance and both are heritable, few studies have attempted to assess the cause of their covariation. Measures of rapid naming (numbers, colors, objects, and letters subtests), phonological decoding, orthographic choice, and a composite variable (DISCR) derived from the reading recognition, reading comprehension, and spelling subtests of the Peabody Individual Achievement Test were obtained from a total of 550 twin pairs with a positive school history of reading problems. Basic DeFries and Fulker (DF) multiple regression models for the analysis of selected twin data confirmed the heritable nature of phonological decoding, orthographic choice, DISCR, and rapid-naming composites. Bivariate DF models were employed to examine the extent to which deficits in the three reading-related measures covary genetically with rapid naming. Significant bivariate heritability estimates for each of the reading measures with the numbers and letters rapid-naming composite were also obtained. As expected, univariate sib-pair linkage analyses indicated the presence of a quantitative trait locus (QTL) on chromosome 6p21.3 for phonological decoding and orthographic choice deficits. Bivariate linkage analyses were then conducted to test the hypothesis that this QTL for reading difficulties is pleiotropic for slower performance on RN tasks. The results obtained from these analyses did not provide substantial evidence that the 6p QTL for reading difficulties has significant effects on rapid naming; however, larger samples would be required to test this hypothesis more rigorously.

This study utilized a sample of 313 eight- to sixteen-year-old same-sex twin pairs (183 monozygotic, 130 dizygotic) to assess the etiology of comorbidity between reading disability (RD) and attention-deficit/hyperactivity disorder (ADHD). RD was assessed by a discriminant function score based on the Peabody Individual Achievement Test, a standardized measure of academic achievement. The DSM-III version of the Diagnostic Interview for Children and Adolescents was used to assess symptoms of ADHD, and separate factor scores were computed for inattention and hyperactivity/impulsivity (hyp/imp). Individuals with RD were significantly more likely than individuals without RD to exhibit elevations on both symptom dimensions, but the difference was larger for inattention than hyp/imp. Behavior genetic analyses indicated that the bivariate heritability of RD and inattention was significant (h(2)(g(RD/Inatt)) = 0.39), whereas the bivariate heritability of RD and hyp/imp was minimal and nonsignificant (h(2)(g(RD/Hyp)) = 0.05). Approximately 95% of the phenotypic covariance between RD and symptoms of inattention was attributable to common genetic influences, whereas only 21% of the phenotypic overlap between RD and hyp/imp was due to the same genetic factors.

Parents of 323 twin pairs with reading disability (RD) reported significantly more problems learning to read (16% of mothers and 33% of fathers) than parents of 309 twin pairs without reading difficulties (6% of mothers and 9% of fathers). These rates of self-reported reading problems in parents of twins are highly similar to those previously obtained in parents of non-twin children with RD and controls, suggesting that the etiology of reading deficits in twin and non-twin children may also be highly similar. Moreover, within both the RD and control samples, twins whose parents self-reported a positive history of reading problems had lower reading performance test scores, on average, than those whose parents reported no reading problems. Therefore, results of the present twin study support those of previous studies with non-twin children in which parental self-reports have been found to provide a valid index of family history status for reading difficulties.

A community sample of 373 8 to 18 year-old twin pairs in which at least one twin in each pair exhibited a history of learning difficulties was utilized to examine the etiology of inattention and hyperactivity/impulsivity (hyp/imp). Symptoms of attention-deficit/hyperactivity disorder (ADHD) were assessed by the DSM-III Diagnostic Interview for Children and Adolescents. Inattention and hyp/imp composite scores were created based on results of a factor analysis. Results indicated that extreme ADHD scores were almost entirely attributable to genetic influences across several increasingly extreme diagnostic cutoff scores. Extreme inattention scores were also highly heritable whether or not the proband exhibited extreme hyp/imp. In contrast, the heritability of extreme hyp/imp increased as a linear function of the number of inattention symptoms exhibited by the proband. This finding suggests that extreme hyp/imp may be attributable to different etiological influences in individuals with and without extreme inattention. If this result can be replicated in other samples, it would provide evidence that the hyp/imp symptoms exhibited by individuals with Combined Type ADHD and Predominantly Hyp/Imp Type ADHD may be attributable to different etiological influences.

Objective: To test for brain structure differences in reading disability (RD) by means of MRI-based morphometry., Background: Consensus is lacking on the brain structural correlates of RD. The current study reports on a wider set of structures in the largest sample yet studied, controlling for age, gender, IQ, and attention deficit hyperactivity disorder (ADHD)., Methods: A case-control study was performed that was comprised of 75 individuals with RD (mean age, 17.43+/-4.29 years) and 22 control subjects without RD (mean age, 18.69+/-3.75 years), each a single member of a twin pair. The two groups were similar in age, gender, and handedness, but differed in full-scale IQ (FSIQ), with the RD group having a lower mean FSIQ (101.8+/-9.9 versus 118.3+/-10.3). Using three group-by-structure analyses of covariance, groups were compared in terms of volume (in cubic centimeters) of major neocortical subdivisions, subcortical structures, and midsagittal areas (in square millimeters) of three subdivisions of the corpus callosum., Results: Controlling for age, gender, and IQ, the authors found a significant group-by-structure interaction for the major neocortical subdivisions (p = 0.002), reflecting a different developmental pattern in the RD group, with the insula and anterior superior neocortex being smaller and the retrocallosal cortex being larger in the RD group. In contrast, they found no group main or interaction effects for the subcortical or callosal structures. The pattern of results was essentially the same in subjects without ADHD., Conclusions: Most brain structures do not differ in size in RD, but cortical development is altered subtly. This study replicates in a larger sample previous findings of insular differences in RD and demonstrates further that those differences are not attributable to comorbid ADHD.

We conducted a study of the association between developmental reading disability (DRD) and immune disorders (ID) using both survey and immunoassay data in two separate samples of families. One sample was made up of twins and their parents and was ascertained through a population-based sampling scheme. The other sample was a set of extended pedigrees selected for apparent autosomal dominant transmission of DRD. We failed to find an association between DRD and ID in either sample, regardless of the method used to assess immune system function. Even though our twin sample provided evidence that both DRD and immune conditions were significantly heritable, there was no evidence for a genetic correlation between ID and DRD nor was there any clear indication that a special subgroup of individuals may be comorbid for these conditions because of genetic reasons. How these negative findings can be reconciled with the developmental hypothesis of Geschwind, Behan, Galaburda, and colleagues, and how they may relate to the gene locus influencing DRD that has been recently located in the HLA region of the short arm of chromosome 6 is discussed., (Copyright 1998 Academic Press.)

Although results obtained from recent twin and adoption studies suggest that individual differences in mathematics performance are due in part to heritable influences, no genetic analysis of mathematics disability (MD) has been previously reported. In this article we present data from the first twin sample ascertained for mathematics deficits (40 identical and 23 same-sex fraternal twin pairs in which at least one member had MD). When mathematics performance data from these twin pairs were subjected to a multiple regression analysis, evidence for a significant genetic etiology was obtained. However, tests for the differential etiology of MD as a function of reading performance level were nonsignificant. Results of this first twin study of MD indicate that the condition is significantly heritable, but data from additional twin pairs will be required to test hypotheses of differential etiology more rigorously.

In order to assess the genetic etiology of the comorbidity of reading and mathematics difficulties, data were ascertained from two samples: (1) 102 identical and 77 same-sex fraternal twin pairs in which at least one member of each pair is reading disabled and (2) 42 identical and 23 same-sex fraternal twin pairs in which at least one member is math disabled. Composite reading and mathematics performance data from each sample were fitted to the basic multiple regression model for the analysis of selected twin data and its bivariate extension. Resulting estimates of bivariate heritability and the genetic correlation between the reading and the mathematics performance measures suggest that the comorbidity between mathematics and reading difficulties is due in part to genetic influences.

Although children with learning disabilities frequently manifest comorbid reading and mathematics deficits, the cause of this comorbidity is unknown. To assess the extent to which comorbidity between reading and mathematics deficits is due to genetic and environmental influences, we conducted a twin study of reading and mathematics performance. Data from 148 identical and 111 fraternal twin pairs in which at least one member of the pair had a reading disability were subjected to a cross-concordance analysis and also fitted to a bivariate extension of the basic multiple regression model for the analysis of selected twin data. Results of these analyses suggest that genetic and shared-environmental influences both contribute to the observed covariance between reading and mathematics deficits.

To test the hypothesis that the etiology of individual differences in reading performance differs in males and females, reading performance data from twin pairs tested in the Colorado Learning Disabilities Research Center were fitted to structural equation models of sex limitation. The sample included 513 pairs of twins in which at least one member of each pair has a positive school history of reading problems [228 monozygotic (MZ), 176 same-sex dizygotic (DZ), and 109 opposite-sex DZ pairs] and 302 matched control pairs [148 MZ, 98 same-sex DZ, and 56 opposite-sex DZ pairs]. Estimates of the genetic correlation between performance in males and females were obtained by analysis of data from both same-sex and opposite-sex twin pairs (Neale and Cardon, 1992). The full model fit the data well (chi 2 = 17.74, df = 16, p = 0.340), and the resulting genetic parameter estimates were highly similar in males and females in both the proband and the control samples. The correlations between genetic influences in males and females do not differ among groups (change in chi 2 = 0.95, df = 1, p > or = 0.25), and the resulting pooled estimate is about .5. Thus, results of this analysis suggest that the etiology of individual differences in reading performance may differ to some extent in males and females.

Wechsler Intelligence Scale for Children--Revised (WISC-R) factor scores (Verbal Comprehension, Perceptual Organization, and Freedom from Distractibility) were obtained from 574 twin pairs in the Colorado Reading Project and subjected to multivariate genetic analysis. Variances were partitioned into components common to the three WISC-R factors and to those specific to each factor. Substantial commonality, both genetic and environmental, was found among the three factors. The full model fit the data well, and estimates of heritability and environmentality indicated that about half of the phenotypic variance for each factor is due to additive genetic effects. These results were compared to those obtained in a previous twin study of the three Wechsler Adult Intelligence Scale (WAIS) factors by Tambs et al. (1986).

Interval mapping of data from two independent samples of sib pairs, at least one member of whom was reading disabled, revealed evidence for a quantitative trait locus (QTL) on chromosome 6. Results obtained from analyses of reading performance from 114 sib pairs genotyped for DNA markers localized the QTL to 6p21.3. Analyses of corresponding data from an independent sample of 50 dizygotic twin pairs provided evidence for linkage to the same region. In combination, the replicate samples yielded a chi 2 value of 16.73 (P = 0.0002). Examination of twin and kindred siblings with more extreme deficits in reading performance yielded even stronger evidence for a QTL (chi 2 = 27.35, P < 0.00001). The position of the QTL was narrowly defined with a 100:1 confidence interval to a 2-centimorgan region within the human leukocyte antigen complex.

The influence of genetic factors in the comorbidity of spelling disability and hyperactivity was investigated in two samples of 190 and 260 same sex twin pairs. The method of bivariate group heritability was used to estimate the genetic correlation for spelling disability and hyperactivity. A similar though not statistically significant value for the genetic correlation was obtained for the two samples (0.29 and 0.42). It was estimated that approximately 75% of the co-occurrence of these two conditions was due to shared genetic influences.

Recent research has raised the question of whether age- and IQ-discrepancy forms of reading disability (RD) are distinguishable in terms of either their underlying linguistic deficit or their response to treatment, thus threatening the external validity of the traditional distinction between specific reading retardation and reading backwardness. The present study pursued the external validity of this distinction in three domains: (a) genetic etiology, (b) sex ratio and clinical correlates, and (c) neuropsychological profiles. Each of these domains was explored in the RD (n = 640) and control (n = 436) twins participating in the Colorado Reading Project (514 males, 562 females, with an overall mean age of 12.42 years). Little evidence for external validity was found in terms of the clinical correlates of attention deficit-hyperactivity disorder (ADHD), immune disorders, or handedness. Most importantly, there was no evidence of differential genetic etiology of the two phenotypes in this sample, in that deficits in both phenotypes were similarly heritable (h2g = .40 and .46 for age and IQ phenotypes, respectively) and the genetic correlation between them was high (rG = .88 to .96). However, the genetic and neuropsychological profile analyses did suggest that age- and IQ-discrepancy definitions of RD may relate differentially to component reading processes, such as phonological awareness and orthographic coding.

Monozygotic and dizygotic twin pairs, in which at least one member of each pair is reading disabled (RD), were assessed for attention-deficit hyperactivity disorder (ADHD). Within pair cross-concordances of the RD and ADHD qualitative diagnoses for monozygotic twins were larger than for dizygotic twins, although not significantly so (p less than 0.10). Thus, the data suggest that RD and ADHD may be primarily genetically independent. However, trends in the data and subtype analyses suggest that in some cases RD and ADHD may occur together because of a shared genetic etiology and that a genetically mediated comorbid subtype may exist.

The multiple regression analysis of twin data in which a cotwin's score is predicted from that of a proband (the member of a twin pair selected because of a deviant score) and the coefficient of relationship provides a powerful test of genetic etiology (DeFries and Fulker: Behav Genet 15:467-473, 1985). Moreover, when an augmented model containing an interaction term is fitted to the same data set, direct estimates of heritability (h2) and the proportion of variance owing to shared environmental influences (c2) are also obtained. In the present paper, the expected partial regression coefficients estimated from these models are derived, and the flexibility of the general approach is illustrated. An extended model is formulated for the analysis of data from combined samples of affected and control twin pairs that yields tests for differential h2 and c2 in the two groups as well as pooled estimates of these parameters. The application of these models is illustrated by an analysis of data from reading-disabled and control twin pairs. Because of the ease, flexibility, and utility of the multiple regression analysis of twin data, it is an appealing alternative to more traditional model-fitting approaches.