Colorado Learning Disabilities Research Center
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
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
Project I: Twin Studies
J.C. DeFries, S.J. Wadsworth and E.G. Willcutt
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 coinvestigators of the CLDRC.
History
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).
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
Numbers of Twin Pairs Ascertained in the
Colorado Learning Disabilities Research Center
Ascertained as
(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.
Identical (MZ)
Fraternal (DZ)
RD
267
369
ADHD
40
77
228
249
Neither (Control)
Bivariate Heritability Estimates
Phenotypes
h2g
RD/Cognitive Ability
RD/Rapid Naming
Phonological Decoding/Rapid Naming
Orthographic Coding/Rapid Naming
Reading Comprehension/Word Recog.
RD/Inattention
RD/Hyperactivity
.28
.20
.21
.40
.52
.39
.05
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 (Gayn 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.
1973
1979
1982
1985
1987
1990
1991
1994
Colorado Family
Reading Study
Colorado
Reading Project
Twin Study of
RD Initiated
Mult. Reg. Anal.
of Selected
Twin Data
Definitive
evidence for
heritable
nature of RD
Colorado
Learning
Disabilities
Research Center
Evidence for
Major Gene
for RD
Linkage of RD
to Chrom. 6p
Between October 1, 1973, and July 30, 1976, 133 readingdisabled 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 coinvestigators (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).
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.
As of August 31, 2001 we have ascertained a total of 267 readingdisabled 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.
1997, 1999
Confirmation of
RD linkage to
Chrom. 6p
2001
Bivariate
Linkage of RD
& ADHD to
Chrom. 6p
Project II: Reading and Language Processes
R.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 V: Early Reading, Language and Attention Development
R.K. Olson and B. Byrne
Estimates of Heritability for RD and ADHD
Phenotype
h2g
RD
Word Recognition
Orthographic Coding
Phonological Decoding
Phoneme Awareness
Reading Comprehension
.59
.54
.67
.71
.72
.32
ADHD symptoms
Inattention
Hyperactivity/Impulsivity
.92
.94
.78
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.
Project III: Validity of Subtypes of ADHD
B.F. Pennington and E.G. Willcutt
References
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.
Differential Genetic Etiology of RD
h2 g
As a function of
p
Age
< 11.5 yrs = .61
> 11.5 yrs = .49
.25
Sex
Males = .58
Females = .59
> .90
IQ
< 100 = .43
> 100 = .72
< .03
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