Colorado Learning Disabilities Research Center

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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 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 IIIV, 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).
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.
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.
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.
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.
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.
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).
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.
Project III Validity of Subtypes of ADHD B.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.
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. Gay?n, 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., Gayltn, 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).
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 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 11.