Colorado Learning Disabilities Research Center

1Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado; 2Department of Psychology, University of Colorado, Boulder, Colorado; 3Department of Psychology, University of Denver, Denver, Colorado; 4University of Nebraska Medical Center, Omaha, Nebraska; 5University of New England, Armidale Australia

Sally J. Wadsworth1, Erik G. Willcutt1,2, John C. DeFries1,2, Richard K. Olson1,2, Bruce F. Pennington3, Janice M. Keenan3, Shelley D. Smith4 and Brian Byrne5

Overview

Understanding the causes and correlates of cognitive disabilities and testing intervention strategies are essential steps toward the development of assistive technologies. Since 1973, researchers of the Colorado Learning Disabilities Research Center (CLDRC) have been conducting research pertaining to the characterization, amelioration and etiology of learning disabilities (LD). Funded by the National Institute of Child Health and Human Development (NICHD), the CLDRC is a multidisciplinary, multi-site collaborative effort comprised of five component projects at sites in Colorado, Nebraska and Australia. A primary objective of the Center is to assess the genetic and environmental causes of reading deficits, attention deficit-hyperactivity disorder (ADHD) and their comorbidity, as well as their covariation with measures of reading and language processes, mathematics performance and executive functions. A further goal is to assess possible precursors of reading deficits, as well as their genetic and environmental origins. Some of the earliest evidence for genetic etiologies of reading disability (RD) and ADHD, as well as some of the most recent and exciting evidence, has been obtained by co-investigators of the CLDRC.

Between October 1, 1973, and July 30, 1976, 133 reading-disabled children (7.5 to 18 years of age), their parents and siblings, and members of 125 control families were administered an extensive test battery. The reading performance deficits of siblings and parents of probands conclusively demonstrated the familial nature of RD (DeFries et al., 1978). During the next several years these family data were subjected to various genetic analyses. Subsequently, results obtained from a complex segregation analysis of these data by Center co-investigators (Pennington, et al., 1991) provided evidence for a dominant major-gene effect with sex-dependent penetrance, in a substantial proportion of families with RD.

Colorado Reading Project (CRP)In order to obtain data from reading-disabled and control children

on a broader array of measures, a NICHD-funded program project was initiated on July 1, 1979. Between 1979 and 1982, a test battery that included measures of cognitive abilities, reading and language processes, and electro-physiological activity was developed and administered to a sample of 140 reading-disabled children and 140 matched controls. Because of the paucity of well designed twin studies of reading disability, a twin study was initiated in 1982 as a part of the CRP. In order to minimize the possibility of referral bias (Vogel, 1990), twin pairs in this ongoing study are ascertained systematically through 27 cooperating school districts within the state of Colorado.

During this period we developed a new multiple regression analysis of twin data that is highly versatile and statistically more powerful than alternative methods (DeFries & Fulker, 1985; 1988). Use of this method resulted in the first report of definitive evidence for the heritability of RD (DeFries et al., 1987).

Obtaining evidence of heritability is only the first step toward a comprehensive genetic analysis. Therefore, because of its special relevance to the objectives of the CRP, a Genetic Linkage Analysis component was added in 1985. Subsequent analyses of family data provided suggestive evidence for linkage to Chromosome 6 (Smith et al., 1991).

As of August 31, 2001 we have ascertained a total of 267 reading-disabled identical twin pairs and 369 reading-disabled fraternal twin pairs (including 154 pairs of opposite-sex twins) in either the former CRP or the current CLDRC, as well as 117 twin pairs (40 identical, 36 same-sex fraternal, and 41 opposite-sex fraternal) in which at least one member of each pair has ADHD symptoms. A comparison sample of 228 identical twin pairs and 249 fraternal twin pairs (including 99 opposite-sex fraternal twin pairs) has also been ascertained in which neither member of the pair has a school history of reading difficulties or ADHD symptoms. In contrast to previous studies of children with reading difficulties ascertained either by referral or from clinic populations, the gender ratio in our twin sample is approximately 1:1.

Project I: Twin StudiesJ.C. DeFries, S.J. Wadsworth and E.G. Willcutt

The long-range goals of this project are the identification, characterization and validation of etiologically distinct subtypes or dimensions of learning disabilities. To accomplish these goals, the twins and their siblings are administered an extensive psychometric test battery that includes tests of general cognitive ability and academic achievement. In collaboration with investigators from Research Projects II–IV, resulting data are used to assess the genetic and environmental etiologies of reading deficits, ADHD, and their comorbidity, as well as their covariation with measures of other psychopathology, reading, language and perceptual processes, mathematics performance and executive functions. The multiple regression analysis of selected twin data (DeFries & Fulker, 1985, 1988) is used to assess the etiology of group deficits in reading performance, as well as the etiology of individual differences. It has also been used to test novel hypotheses of differential etiology of reading difficulties as a function of ADHD dimensions or subtypes, age, gender, and cognitive ability, and to assess the hypothesis that the etiology of deviant scores differs from that of individual differences within the normal range. Bivariate heritability between RD and other disorders, such as ADHD is also assessed, and QTL analyses are used to assess genetic linkage of reading deficits (Fulker et al., 1991; Cardon et al., 1994).

Project II: Reading and Language ProcessesR.K. Olson, D. Compton and J.M. Keenan

The objectives of this project are to measure component processes and knowledge in reading and related language skills, and to assess genetic and environmental etiologies of group deficits in these processes. In addition, the etiologies of covariation among these measures, and between these measures and the measures of cognitive abilities and academic achievement administered in Project I, as well as with measures of ADHD administered in Project III. Behavior genetic analyses are also used to validate subtypes and/or dimensions of individual differences among children with reading deficits. In collaboration with investigators from research projects I and IV, QTL analyses are used to assess genetic linkage for deficits in different reading and language skills.

Project III: Validity of Subtypes of ADHDB.F. Pennington and E.G. Willcutt

The overall goal of this project is to test the internal and external validity of subtypes of ADHD. To accomplish this goal, a battery of neuropsychological and psychiatric measures is administered to twins with RD, ADHD, and to unaffected control twins and their siblings. Reliability and internal validity of ADHD subtypes is assessed by examining inter-rater agreement and test-retest reliability and conducting factor and cluster analyses of individual symptoms. Diagnostic and discriminant validity are tested by comparing subtypes on measures of functional impairment and other clinical correlates. Etiological relations among the subtypes are tested using multiple regression analysis of selected twin data and molecular genetic linkage and association analysis.

Project IV: Genomic Analyses S.D. Smith, R.B. Barber and J.E. Eudy

The goal of this project is to identify specific regions of the genome which contribute to learning disabilities. In collaboration with investigators from Research Projects I-III, linkage and association analyses reveal relations between the various phenotypes and 1) DNA markers and 2) specific gene mutations. By evaluating the contributions of each gene region or gene to specific phenotypes, we can determine the extent to which the phenotypes are genetically distinct, or share genetic influences. The adaptation of the multiple regression analysis of selected twin data for use in linkage/QTL analyses has shown that there is a gene located on Chromosome 6 which influences both phonological and orthographic abilities (Gayn et al., 1999) as well as ADHD (Willcutt et al., in press). Identification of the genes influencing reading disability and ADHD will help delineate the basic functions and neurological mechanisms important in the development of these disorders.

Project V: Early Reading, Language and Attention Development R.K. Olson and B. Byrne

As a new addition to the CLDRC, this project is a collaboration with the University of New England in Australia. By testing 340 preschool-aged twin pairs in Australia, and combining these data with a companion study in Colorado, the goal of this project is to assess genetic and environmental influences on early reading and attention development, as well as on their responsiveness to instruction, and to identify the specific psychological processes which mediate these influences. In addition, the twins will be retested at the end of kindergarten, first, and second grades, so that growth and development may be monitored during this critical period of early reading development.

Numbers of Twin Pairs Ascertained in the Colorado Learning Disabilities Research Center

Ascertained as Identical (MZ) Fraternal (DZ)

RD 267 369

ADHD 40 77

Neither (Control) 228 249

Estimates of Heritability for RD and ADHD

Phenotype h2g

RD .59Word Recognition .54Orthographic Coding .67Phonological Decoding .71Phoneme Awareness .72Reading Comprehension .32

ADHD symptoms .92Inattention .94Hyperactivity/Impulsivity .78

Bivariate Heritability Estimates

Phenotypes h2g

RD/Cognitive Ability .28RD/Rapid Naming .20Phonological Decoding/Rapid Naming .21Orthographic Coding/Rapid Naming .40Reading Comprehension/Word Recog. .52RD/Inattention .39RD/Hyperactivity .05

Differential Genetic Etiology of RD

As a function of h2g p

Age < 11.5 yrs = .61 > 11.5 yrs = .49 .25

Sex Males = .58 Females = .59 > .90

IQ < 100 = .43 > 100 = .72 < .03

Colorado Learning Disabilities Research Center (CLDRC) The ongoing NICHD-funded CLDRC was initiated in 1990. A

major goal of this more comprehensive program is to assess the genetic and environmental etiologies of reading disabilities, ADHD and their comorbidity, as well as their covariation with measures of reading, language and perceptual processes, mathematics deficits, executive functions, and other psychopathology. To accomplish this goal, staff of an Administrative Core Unit ascertain and schedule twin pairs and siblings that are tested in individual research projects.

1979

Colorado Reading Project

1990

Colorado Learning

Disabilities Research Center

1982

Twin Study of RD Initiated

1973

Colorado Family Reading Study

1994

Linkage of RD to Chrom. 6p

2001

Bivariate Linkage of RD

& ADHD to Chrom. 6p

1985

Mult. Reg. Anal. of Selected

Twin Data

1991

Evidence for Major Gene

for RD

1987

Definitive evidence for

heritable nature of RD

1997, 1999Confirmation of RD linkage to

Chrom. 6p

References

Cardon, L.R., Smith, S.D., Fulker, D.W., Kimberling, W.J., Pennington, B.F., & DeFries, J.C. (1994). Quantitative trait locus for reading disability on chromosome 6. Science, 226, 276-279.

DeFries, J.C. (1985). Colorado Reading Project. In D.B. Gray, & J.F. Kavanagh (Eds.), Biobehavioral measures of dyslexia. Parkton, MD: York Press. 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 Disabilities: A Multidisciplinary Journal, 8, 7-19.DeFries J.C., & Fulker, D.W. (1985). Multiple regression analysis of twin data. Behavior Genetics, 15, 467-473.DeFries, J.C., & Fulker, D.W. (1988). Multiple regression analysis of twin data: Etiology of deviant scores versus individual

differences. Acta Geneticae Medicae et Gemellologiae: Twin Research, 37, 205-216.DeFries, J.C., Fulker, D.W., & LaBuda, M.C. (1987). Evidence for a genetic aetiology in reading disability of twins. Nature,

329, 537-539.DeFries, J.C., Singer, S.M., Foch, T.T., & Lewitter, F.I. (1978). Familial nature of reading disability. British Journal of

Psychiatry, 132, 361-367.DeFries, J.C., Vogler, G.P., & LaBuda, M.C. (1986). Colorado family reading study: An overview. In J.L. Fuller, & E.C.

Simmel (Eds.), Behavior genetics: Principles and applications II. Hillsdale, NJ: Lawrence Erlbaum Associates. Fisher, S.E., Marlow, A. J., Lamb, J., Maestrini, E., Williams, D. F., Richardson, A. J., Weeks, D. E., Stein, J. F., & Monaco,

A.P. (1999). A quantitative trait locus on chromosome 6p influences different aspects of developmental dyslexia. American Journal of Human Genetics, 64, 146-156.

Fulker, D.W., Cardon, L.R., DeFries, J.C., Kimberling, W.J., Pennington, B.F., & Smith, S.D. (1991). Multiple regression analysis of sib-pair data on reading to detect quantitative trait loci. Reading and Writing: An Interdisciplinary Journal, 3, 299-313. [Reprinted in B.F. Pennington (Ed.), Reading disabilities: Genetic and neurological

influences (pp. 111-125). Dordrecht, The Netherlands: Kluwer Academic Publishers.]Gayn, J., Smith, S.D., Cherny, S.S., Cardon, L.R., Fulker, D.W., Bower, A.M., Olson, R.K., Pennington, B.F., & DeFries, J.C. (1999). Quantitative-trait locus for specific language and reading deficits on chromosome 6p. American Journal of Human Genetics, 64, 157-164.Grigorenko, E. L., Wood, F. B., Meyer, M. S., Hart, L. A., Speed, W. C., & Shuster, A. (1997). Susceptibility loci for distinct

components of developmental dyslexia on chromosomes 6 and 7. American Journal of Human Genetics, 60, 27-39.

Pennington, B.F., Gilger, J., Pauls, D., Smith, S.A., Smith S.D., & DeFries, J.C. (1991). Evidence for major gene transmission of developmental dyslexia. Journal of the American Medical Association, 266, 1527-1534.Smith, S.D., Kimberling, W.J, Pennington, B.F. (1991). Screening for multiple genes influencing dyslexia. Reading and

Writing: An Interdisciplinary Journal, 3, 285-298.Vogel, S.A. (1990). Gender differences in intelligence, language, visual-motor abilities, and academic achievement in

students with learning disabilities: A review of the literature. Journal of Learning Disabilities, 23, 44-52.Willcutt, E.G., Pennington, B.F., Smith, S.D., Cardon, L.R., Gay<n, J., Knopik, 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).

History

Colorado Family Reading Study (CFRS) Our first attempt to investigate the etiology of a learning disability

was the Colorado Family Reading Study, initiated in 1973 by a grant from the Spencer Foundation. The primary objectives of that study were

(1) to construct a short battery of tests that differentiates children with a diagnosed reading disability from matched controls(2) to assess possible deficits in parents and siblings of affected children(3) to study the transmission of reading disability in families of affected children.