The Colorado Learning Disabilities Research Center

A highly collaborative research program on reading disability (the Colorado Reading Project) began as a Program Project in 1979 with funding from the National Institutes of Child Health and Human Development (NICHD). The first three years of the Program Project focused on the validation of various experimental and standardized psychometric measures for the differential diagnosis of reading disability. The most useful measures were then incorporated into a behavioral-genetic study of identical and fraternal twins that began in 1982. A genetic linkage component was added in 1985 and a study of immunological processes was added in 1988. The results obtained in the different components of the Program Project were reviewed by DeFries, Olson, Pennington, & Smith (1991). The Program Project was expanded in 1990 to become the NICHD-funded Colorado Learning Disabilities Research Center, with additional emphasis on mathematics deficits, ADHD, executive functions, brain morphology, and the computer-based remediation of reading disabilities. A review of major results from the different research components of the Center was reported in DeFries, Filipek, Fulker, Olson, Pennington, Smith, and Wise (1997).

For the 2000-2005 funding period, two new components have been added to the Center. Beginning in 2001, a new component of the NIH Center, directed by Janice Keenan at the University of Denver, is focusing on deficits in reading and language comprehension. Keenan is studying the same school-age twins that are tested in Boulder on word-level reading and language skills, so the relative contributions of high-level language skills and word-level reading skills can be understood. A second new component of the NIH Center is focused on the etiology of individual differences in children before they begin formal schooling. Because individual differences in pre-reading skills and environment may have important influences on later reading development in school, we initiated a large longitudinal study of identical and fraternal twins beginning at age 4, with follow-up assessments at the end of kindergarten, first grade, and second grade. A major focus of the study is the assessment of preschool twins’ learning rate from training for the awareness of abstract phonemes in speech. The study includes international collaborations with parallel studies of identical and fraternal preschool twins directed by Brian Byrne in Australia, and Stefan Samuelsson in Norway.

John DeFries is the Director of the Center, and each of the co- investigators are responsible for the direction of their specific component projects. The following individuals are investigators for components of the Center for 2000-2005. John DeFries and Sally Wadsworth are co-investigators on a component that involves the administration of a battery of standardized psychometric tests and the development and application of advanced behavioral-genetic analyses. Richard Olson and Janice Keenan direct the development and administration of experimental measures for component reading, language, and perceptual processes that may play important roles in different reading disabilities. Bruce Pennington and Erik Willcutt are exploring the relations between ADHD, executive functions, and reading disabilities. Shelley Smith is directing research on linkage analysis and physical mapping of associated genes. Richard Olson and Brian Byrne are conducting longitudinal twin studies on pre-reading and early reading development from preschool (age 4) through the end of second grade.

Many important results have been published in numerous articles from the Colorado Reading Project. Some of these are cited in the two review papers mentioned above. I will not attempt to summarize all this work here. Instead, I will focus primarily on some of the major results from our experimental measures of reading, spelling, and language that show significant genetic influence. I will conclude with a discussion of the implications for environmental intervention and briefly review work with Barbara Wise on the computer-based remediation of reading and related phonological disabilities.

The use of a common subject pool of identical and fraternal twins provides an important collaborative link between our component research projects that are focused on school-age twins. The twins are 3rd to 12th graders from 27 Colorado school districts. If one or both members of a twin pair have school records suggesting problems in reading, math, and/or ADHD, they are invited for testing in laboratories at the University of Colorado and the University of Denver. A smaller normal comparison twin sample with no school history of problems in these areas is also tested on the same measures.

Twins are studied because their behavioral data are informative about the relative balance of genetic and environmental influences. Identical or monozygotic (MZ) twins share all their genes and their home environment. Fraternal or dizygotic (DZ) twins also share their home environment, but only half of their segregating genes, on average. Thus, a greater similarity between MZ twins compared to DZ twins provides evidence for a genetic influence on the behavior studied. Behavior-genetic analysis of twin data can also separate the environmental influence that is shared by the twins from that which is not shared: Differences between MZ twins indicate non-shared environment influences and test error; the influence of shared-environment is indicated when the DZ twins’ average similarity is greater than expected from their average 50% genetic similarity.

DeFries and Fulker (1985) developed a powerful method, now referred to as DF analysis, for assessing genetic influence on a group deficit when twin pairs are selected for one or both member’s deviant position on a normally distributed dimension such as reading. DF analysis compares the average regression toward the normal population mean for MZ and DZ cotwins who do not meet the affected severity criterion. From this information, it is possible to derive estimates of the average genetic, shared environment, and non-shared environment influences on deviant group membership. DF analyses have been used to assess average genetic influence on the group deficit (below the local 10th percentile) for a composite measure of word recognition, reading comprehension, and spelling from the Peabody Individual Achievement Test (Dunn & Markwardt, 1970). The most recent analysis by DeFries and Alarcon (1996) estimated that the heritability of the group deficit in this composite measure was h2g = .56. This means that approximately half of the group deficit is due to genetic factors.

DF analyses have also been conducted for group deficits in phoneme awareness, phonological decoding, and orthographic coding (Olson, Wise, Conners, Rack, & Fulker, 1989; Olson, Forsberg, & Wise, 1994; Gayan & Olson, 2001). Phoneme awareness is measured by language tasks that require the isolation and manipulation of phonemes within spoken words or nonwords. Performance in these tasks is highly correlated with reading skill, particularly with the component reading skill of phonological decoding. We measure phonological decoding through both the oral and silent reading of nonwords. Our orthographic coding measures assess subjects’ sensitivity to the precise spelling patterns for words in the comparison of a word with a homophonic nonword (e.g., rain rane) and in the choice between homophones (bear bare) to fit the meaning of a spoken sentence. All of these tasks are significantly correlated with each other and with measures of printed word recognition. Olson et al. (1989) suggested that the group deficit in orthographic coding might have a lower heritability than the other component skills. We argued that accurate recognition of the precise spelling for a word would depend more on the environmental effects of exposure to that word in print, and we inferred that print exposure would be more likely mediated by environmental factors than by genes. However, a trend toward lower heritability in the small sample of twins analyzed by Olson et al. (1989) was not replicated in larger samples (Gayan & Olson, 2001). In these later analyses, group accuracy deficits in the orthographic tasks have heritability levels that range between h2g = .6-.7

Bivariate DF analyses were employed by Olson et al. (1994) and Gayan and Olson (2001) to assess the degree of common genetic influence on the shared variance among the above measures: The question was, to what degree are the group deficits in the measures due to the same or different genetic influences? The results indicated that there were significant common genetic effects on group deficits in all the measures, but there was also evidence of some independent genetic effects on each measure. Shared and independent genetic effects on individual differences in each of the measures have recently been confirmed in both normal and reading disabled groups using appropriate factor models (Gayan & Olson, under review). The partial genetic independence of phonological and orthographic skills is of particular interest to researchers who study individual differences or subtypes within the reading disabled population and who wonder about the role of genes and environment in these differences (c.f., Castles and Coltheart, 1993; Castles et al., 1999; Olson et al., 1985).

The DF analyses for group deficits described above do not provide evidence on the genetic influence for any individual disabled reader within the group. We could begin to make more accurate predictions about the degree of genetic influence on individual deficits if we found evidence that the level of heritability varies, depending on individual variables such as age, gender, or IQ. Fortunately, DF analyses can be extended to assess the size and statistical significance of such effects on the average level of heritability. Gender does not appear to be related to the degree of genetic influence on reading deficits (DeFries, Gillis, & Wadsworth, 1993). Nonsignificant trends in relation to age reported by Wadsworth, Gillis, DeFries, & Fulker (1989) have been further explored by DeFries, Alarcon, and Olson (1997). The latter study found trends toward decreasing heritability with age for word recognition and increasing heritabiltiy with age for spelling. The opposing direction of these trends resulted in a statistically significant interaction. In addition, there is now significant evidence for the importance of IQ in the genetic etiology of deficits in word recognition: Disabled readers with relatively high IQ scores tend to have a stronger genetic etiology than those with relatively low IQ (Olson, Datta, Gayan, & DeFries, 1999; Wadsworth, Olson, Pennington, & DeFries, 2000). The concurrence of low IQ and low reading may be more likely due to some shared family environment that constrains both reading and general cognitive development. With high IQ, the reading environment may tend to be better, and reading failure more likely due to genetic constraints. We are currently conducting additional analyses to better understand this apparent relation between IQ and genetic influence on reading deficits.

Behavioral comparisons of MZ and DZ twins has yielded valuable information about the balance of genetic and environmental influence on group deficits in reading and related language skills. Further analyses of genetic influence on reading disabilities in relation to IQ and other individual characteristics will provide more specific information about this balance across individuals. However, the further specification and understanding of genetic mechanisms at the individual level will ultimately depend on the identification of specific genes that are associated with reading disability. Recent linkage analyses suggest that a gene or genes on the short arm of chromosome 6, close to the HLA region, may account for a significant proportion of reading disabilities. Preliminary evidence for this linkage was first obtained by Smith, Kimberling, & Pennington (1991) using data from 19 extended families with a history of reading problems. Cardon, Smith, Fulker, Kimberling, Pennington, & DeFries (1994) applied more powerful linkage analyses to these family data and added a sample of 46 DZ twin families from the Colorado Reading Project. Taken together, the extended family and twin data provided highly significant evidence for a genetic linkage to reading disability near the HLA region of chromosome 6.

Reading disability in the above linkage studies was ascertained through a composite measure of word recognition, reading comprehension, and spelling from the Peabody Individual Achievement Test (Dunn & Markwardt, 1970). Gayan et al. (1999) used the same analytic methods with an expanded DZ twin and sibling sample to look for linkage to deficits in the specific skills of phoneme awareness, phonological decoding, orthographic coding, and fluent word recognition. These results and recent unpublished analyses of a new DZ twin and sibling sample suggest that deficits in phoneme awareness, phonological decoding, and orthographic coding show strong evidence for linkage to genetic markers in the HLA region of chromosome 6. The evidence was less strong for two measures of word recognition. A similar pattern of results for phoneme awareness and word recognition has been reported by Grigorenko et al. (1997). They used data from extended families with a history of reading disabilities and found strong linkage for deficits in phoneme awareness to the same HLA region of chromosome 6. Linkage appeared to be weaker in this region for deficits in word recognition, which were more strongly linked to a region on chromosome 15. The possibility of differential genetic linkages for different component skills in reading and language is intriguing, but a much larger subject sample is needed to test the statistical significance of these differences. This additional data is now being collected by our Center, with additional genetic markers including other regions of the genome. Most recently, DNA from the Colorado sample and an independent sample collected in England were subjected to a whole-genome scan to search for linkage in other regions of the genome. Fisher et al. (in press) found evidence in both samples for linkage to the HLA region on chromosome 6, and even stronger evidence for linkage in both samples to a region on chromosome 18.

A strong genetic linkage for deficits in phoneme awareness and orthographic coding has now been confirmed in two independent laboratories for the same regions of chromosomes 6 and 18. The next step is to more precisely specify the gene or genes’ location(s) and ultimately clone the gene(s), identify the coded protein(s), and determine the influence of the protein(s) on the developing nervous system and related behavior. Much more research will be needed to reach the latter goal, but recent advances in methods for locating genes may soon allow us to identify individuals who have a gene or genes that place them at risk for reading disability. Early information about a genetic risk could be used to provide additional support in a child’s early language and reading environment. Providing support prior to school entry could help avoid the stigmatizing effect of school failure in reading.

It should be emphasized that having a genetic risk does not imply that a reading disability is inevitable. All genetic effects are mediated by the environment. For example, phenylketonuria is a genetic disorder that can lead to severe mental retardation, but restricting the child’s diet to reduce the ingestion of an amino acid called phenylalanine can substantially reduce or eliminate the deleterious effects of this genetic disorder. There is no evidence that such a simple dietary control could reduce a specific genetic influence on reading disability, but other forms of environmental intervention can have a significant impact. Since 1986, we have been exploring the use of talking computers in the schools to support 2nd to 5th grade children with reading disabilities in their word decoding while reading stories. The programs allow children with reading disabilities to read interesting stories on the computer that are more appropriate for their age level, and independently obtain spoken decoding support by targeting difficult words with a mouse. More recently, we have incorporated additional programs designed to improve disabled readers’ phoneme awareness and phonological decoding (Wise and Olson, 1995; Wise, Ring, & Olson, 1999, 2000). The main point to be made here is that these and other programs can substantially improve disabled readers’ phoneme awareness and phonological decoding, skills that are critical for reading development and that have a very strong genetic influence on their group deficits. It is clear that the improvement of these and other reading-related skills in children with reading disabilities often requires extraordinary environmental support. Computer programs incorporating both synthetic and digitized speech can efficiently provide much of this support.

The varied and convergent research perspectives on reading disability in the Colorado Learning Disabilities Research Center and the other NICHD- sponsored centers have resulted in some major advances over the past decade. As this work continues, with continued collaboration of investigators in the U.K. and other countries, we look forward to learning much more about the causes and optimal treatment of different reading disabilities.

References

Cardon, L. R., Smith, S., Fulker, D., Kimberling, W., Pennington, B. & DeFries, J. (1994). Quantitative trait locus for reading disability on chromosome 6. Science, 266, 276-279.

Castles, A., & Coltheart, M. (1993). Varieties of developmental dyslexia. Cognition, 47, 149-180.

Castles, A., Datta, H., Gayan, J., & Olson, R.K. (1999). Varieties of developmental reading disorder: Genetic and environmental influences. Journal of Experimental Child Psychology, 72, 73-94.

Davis, C.J., Gayan, J., Knopik, V.S., Smith, S.D., Cardon, L.R., Pennington, B.F., Olson, R.K., & DeFries, J.C. (2001). Etiology of reading difficulties and rapid naming: The Colorado Twin Study of Reading Disability. Behavior Genetics, 31 (6), 625-635.

DeFries, J. C., & Alarcon, M. (1996). Genetics of specific reading disability. Mental Retardation and Developmental Disabilities Research Reviews, 2, 39-47.

DeFries, J. C., Alarcon, M., & Olson, R. K. (1997). Genetics and dyslexia: Developmental differences in the etiologies of reading and spelling deficits. in C. Hulme & M. Snowling (Eds.), Dyslexia: Biology, cognition, and intervention (pp. 20-37). London: Whurr Publishers Ltd.

Defries, J. C., Filipek, P. A., Fulker, D. W., Olson, R. K., Pennington, B. F., Smith, S. D., & Wise, B. W. (1997). Colorado Learning Disabilities Research Center. Learning Disability Quarterly, 7-8, 19.

DeFries, J. C., & Fulker, D. W. (1985). Multiple regression analysis of twin data. Behavior Genetics, 15, 467-473.

DeFries, J.C., Gillis, J.J., & Wadsworth, S.J. (1993). Genes and genders: A twin study of reading disability. In A.M. Galaburda (Ed.), Dyslexia and development: Neurobiological aspects of extra- ordinary brains (pp. 187-204).

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Olson, R. K., Wise, B., Conners, F., Rack, J., and Fulker, D. (1989). Specific deficits in component reading and language skills: Genetic and environmental influences. Journal of Learning Disabilities, 22, 6, 339- 348.

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Smith, S.D., Kelley, P.M., Askew, J.W., Hoover, D.M., Deffenbacher, K.E., Gayan, J., Brower, A., & Olson, R.K. (2001). Reading disability and chromosome 6p21.3: Evaluation of MOG as a candidate gene. Journal of Learning Disabilities, 34, 512-519.

Wadsworth, S.J., Gillis, J.J., DeFries, J.C., & Fulker, D.W. (1989). Differential genetic aetiology of reading disability as a function of age. Irish Journal of Psychology, 10, 509-520.

Wilcutt, E.G., Pennington, B.F., Smith, S.D., Cardon, L.R., Gayan, J., Knopic, V.S., Olson, R.K., & DeFries, J.C. (in press). Quantitative trait locus for reading disability on chromosome 6p is pleiotropic for attention-deficit/hyperactivity disorder. American Journal of Medical Genetics (Neuropsychiatric Genetics)

Wise, B. W., & Olson, R. K. (1995). Computer-based phonological awareness and reading instruction. Annals of Dyslexia, 45, 99- 122.

Wise, B.W., Ring, J., & Olson, R.K. (1999). Training phonological awareness with and without attention to articulation. Journal of Experimental Child Psychology, 72, 271-304.

Wise, B.W., Ring, J., & Olson, R.K. (2000). Individual differences in gains from computer-assisted remedial reading with more emphasis on phonological analysis or accurate reading in context. Journal of Experimental Child Psychology, 77, 197-235.