Effects of SCA1, MJD, and DPRLA triplet repeat polymorphisms on cognitive phenotypes in a normal population of adolescent twins.

Abstract

The expansion of unstable trinucleotide CAG repeat polymorphisms of a number of genes causes several neurodegenerative disorders with decreased cognitive function, the severity of the disorder being related to allele length at the triplet repeat locus. While the effects of repeat length have been well studied in clinical samples, there has been little investigation of the effects of triplet repeat variation in the normal range for these genes. We have, therefore, examined linkage and association for three CAG triplet repeat markers (Spinocerebellar Ataxia Type 1, SCA1; Machado-Joseph Disease, MJD; Dentatorubro-pallidoluysian Atrophy, DRPLA) to assess their contribution to variation in cognitive ability (IQ, reading ability, processing speed) in a normal, unselected sample of adolescent twins (248 dizygotic (DZ) sibling pairs, aged 16 years). Association tests, performed in Mx and QTDT, showed a consistent positive association of SCA1 with Arithmetic (P = 0.04). While association was supported between SCA1 and Cambridge reading scores and between DRPLA and inspection time, results were inconsistent across software packages. Given the number of statistical tests performed, it is unlikely that trinucleotide repeat variation in the normal range for these genes influences variation in normal cognition.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 144B:95–100 (2007)
Effects of SCA1, MJD, and DPRLA Triplet Repeat
Polymorphisms on Cognitive Phenotypes in
a Normal Population of Adolescent Twins
M. Luciano,1* E. Hine,2M.J. Wright,1D.L. Duffy,1J. MacMillan,3and N.G. Martin1
1Queensland Institute of Medical Research, Brisbane, Australia
2Integrative Biology School, University of Queensland, Brisbane, Australia
3Queensland Clinical Genetics Service, Royal Children’s Hospital, Brisbane, Australia
The expansion of unstable trinucleotide CAG
repeat polymorphisms of a number of genes
causes several neurodegenerative disorders with
decreased cognitive function, the severity of the
disorder being related to allele length at the
triplet repeat locus. While the effects of repeat
length have been well studied in clinical samples,
there has been little investigation of the effects
of triplet repeat variation in the normal range for
thesegenes.Wehave,therefore,examinedlinkage
and association for three CAG triplet repeat
markers (Spinocerebellar Ataxia Type 1, SCA1;
Machado-Joseph Disease, MJD; Dentatorubro-
pallidoluysian Atrophy, DRPLA) to assess their
contribution to variation in cognitive ability
(IQ,readingability,processingspeed)inanormal,
unselected sample of adolescent twins (248 dizy-
gotic (DZ) sibling pairs, aged 16 years). Associa-
tion tests, performed in Mx and QTDT, showed a
consistent positive association of SCA1 with
Arithmetic (P¼0.04). While association was sup-
ported between SCA1 and Cambridge reading
scoresandbetweenDRPLA
time, results were inconsistent across software
packages.Giventhe
tests performed, it is unlikely that trinucleotide
repeat variation in the normal range for these
genesinfluencesvariationinnormalcognition.
? 2006 Wiley-Liss, Inc.
and inspection
numberofstatistical
KEY WORDS:association; cognition; CAG re-
peat polymorphisms
Please cite this article as follows: Luciano M, Hine E,
Wright MJ, Duffy DL, MacMillan J, Martin NG. 2007.
Effects of SCA1, MJD, and DPRLA Triplet Repeat
Polymorphisms on Cognitive Phenotypes in a Normal
PopulationofAdolescentTwins.AmJMedGenetPartB
144B:95–100.
INTRODUCTION
The expansion of unstable trinucleotide repeat number
polymorphisms is the cause of a number of neurodegenerative
disorders, such as Huntington’s disease and Spinocerebellar
Ataxia Type 1 (SCA1). These particular disorders are two of
eight known which are caused by the expansion of one of the
most common triplet repeat motifs, CAG, which encodes the
amino acid glutamine [Beckmann and Weber, 1992; Stallings,
1994]. The effect of triplet repeat length in clinical samples is
wellcharacterized;generally,tripletrepeatdisordersdisplaya
positive relationship between number of repeats and the
severity of the symptoms of the disorder [see Monckton and
Caskey, 1995]. The clinical symptoms (e.g., impaired cognitive
ability) of the varying triplet repeat disorders overlap and so
too do the affected brain regions, which include the cerebral
cortex, basal ganglia, brainstem nuclei, cerebellar dentate
nucleus, Purkinje cells of the cerebellum, and spinal and
bulbar motor neurons [Margolis et al., 1999; Koeppen, 2005].
The effect of triplet repeat length in the normal range on
variationinpsychomotorandcognitivefunctionshasbeenless
frequently studied. In the present study, we therefore report
the association between markers for three neurodegenera-
tive disorders: SCA1, Machado-Joseph Disease (MJD), and
Dentatorubro-pallidoluysianAtrophy(DRPLA),andpsychomo-
torandcognitivevariationinanunselectedsampleofadolescent
twins.Thesemarkersweretypedforastudywhichinvestigated
segregation ratio distortion in normal heterozygotes [none was
found; MacMillan et al., 1999]. As IQ and other cognitive data
wereavailableforasubsetofthesegenotypedfamiliesaspartof
alargerstudyofcognition,wehadtheopportunitytoinvestigate
the relationship between expansion length and a variety of
indices of cognitive performance.
Spinocerebellar Ataxia Type 1 is located on chromosome 6
and the triplet repeat marker is polymorphic in the normal
population (alleles in the range of 6–38 repeats), with allele
length ranging from 39 to 83 repeats in clinical samples of
SCA1 individuals [Margolis et al., 1999]. Animal studies have
shown that ataxin-1, the protein affected in SCA1, may be
involved in synaptic plasticity which is important to learning.
Specifically, SCA1-null mice show poor spatial and motor
learning and lower paired-pulse facilitation in a region of the
hippocampus near the dentate gyrus [Matilla et al., 1998].
Chromosome 12 harbors the DRPLA gene, with the repeat
length ranging from 3 to 35 in normal populations and from 49
to 88 in affected populations. The DRPLA gene product,
atrophin-1, is widely expressed in neurons, but its function is
not known [Wood et al., 2000]. MJD is located on chromosome
14 and the allele length of the repeat marker in normal and
affected populations ranges from 12 to 40 and 55 to 84,
respectively [Cummings and Zoghbi, 2000]. While its function
is unknown, ataxin-3, the protein affected in MJD, is widely
expressedinthebrain, andinmostneurons showslocalization
Grant sponsor: ARC; Grant numbers: A79600334, A79906588,
A79801419, DP0212016, DP0343921; Grant sponsor: University
of Queensland; Grant sponsor: Australian Research Council
Postdoctoral Fellowship; Grant number: DP0449598.
*Correspondence to: Dr. M. Luciano, Queensland Institute of
Medical Research, Herston, Brisbane, 4029, Australia.
E-mail: michelle.luciano@qimr.edu.au
Received 23 March 2006; Accepted 13 July 2006
DOI 10.1002/ajmg.b.30413
? 2006 Wiley-Liss, Inc.

Page 2

to cytoplasmic, dendritic, and axonal regions [Trottier et al.,
1998].
Therehavebeenacoupleofstudiesthathavereportedonthe
relationship between triplet repeat length and IQ in non-
clinical samples. Daniels et al. [1994] tested for differences in
Fragile-X CGG repeat length in low, middle, and high IQ
groups of children; null findings were supported in both boys
and girls. In a study where Wechsler Adult Intelligence Test-
Revised (WAIS-R) scores were compared in carriers and non-
carriers of the Huntington’s disease gene, various subtests
were negatively correlated with the number of CAG repeats in
expansion positive but not in expansion negative individuals
[Foroud et al., 1995]. Hence, for the trinucleotide repeat
disorders of Fragile X syndrome and Huntington’s disease,
thereisnoindicationofarepeatlengthrelationshiptoIQinthe
normal population.
Various phenotypes collected in the present study measure
cognitive abilities which have been shown to be affected in the
polyglutamine disorders, including visual reaction time (RT)
and IQ (digit symbol processing, arithmetic, spatial ability,
object assembly, general knowledge, vocabulary). As the
polyglutamine disorders are characterized predominantly by
motor rather than cognitive dysfunction, it is reasonable to
suppose that in our non-clinical sample, the measures requir-
ing motor responses (i.e., visual RT, digit symbol substitution)
will more likely be influenced by triplet repeat variation than
the purely cognitive measures. To test whether normal
variation in triplet repeat length of the SCA1, DRPLA, and
MJD genes is related to variation in these measures, a
combined linkage and association sibling-pair analysis was
performed in a sample of 16-year-old twins for whom both
phenotypes and triplet repeat polymorphism genotypes were
available.
MATERIALS AND METHODS
Sample
The sample comprised a sub-sample of 248 twin pairs
(55 monozygotic (MZ) female, 46 MZ male, 39 dizygotic (DZ)
female, 36 DZ male, 72 DZ opposite sex) who were initially
recruited at age 12 from schools in Brisbane and surrounding
areas to participate in a study investigating melanoma risk
factors [see Zhu et al., 1999]. Twins and their parents were
later genotyped for three triplet repeat loci, SCA1, MJD, and
DRPLA[MacMillanetal.,1999].Fouryearslatermostofthese
twins completed a cognitive battery, which has been fully
described in Wright et al. [2001]. Informed consent to jointly
examine the cognitive and genotype data was obtained within
this phase of the study. The mean age of the twins at time of
cognitive testing was 16.2 years (range: 15.7–17.7 years).
Cognitive Measures
The cognitive assessments included IQ, reading, and
information processing measures. The Multi-dimensional
Aptitude Battery assessed IQ and consisted of five subtests:
information,vocabulary,arithmetic,spatial,andobjectassem-
bly subtests [Jackson, 1984, 1998]. Raw scores of the subtests
and scaled scores for verbal, performance, and full IQ were
examined. The digit symbol test [a subtest of the WAIS-R;
Wechsler, 1981] was also administered. Reading ability tests
included the Cambridge Contextual Reading Test [Nelson and
Willison, 1991] and the Schonell Graded Reading Test
[Schonell and Schonell, 1960] as described in Wainwright
et al. [2004]. Processing speed was measured using a visual
inspection time paradigm [Luciano et al., 2001a] and an eight-
choice RT task [Luciano et al., 2001b].
Zygosity, Genotyping, and IBD Estimation
Blood was obtained from twins and their parents for blood
grouping and DNA extraction, and all families were typed
formarkers including SCA1, DRPLA, and MJD on an ABI
373 sequencer [MacMillan et al., 1999]. Zygosity was diag-
nosed using nine polymorphic DNA microsatellite markers
and three blood groups (ABO, MNS, and Rh) in the twins and
in most cases both parents. Subsequently further microsatel-
lite markers on each of the relevant chromosomes were
available [see Zhu et al., 2004] so that multipoint Identity-by-
Descent (IBD) estimation of the triplet repeat markers was
possible. Hence, for the respective SCA1, MJD, and DRPLA
markers 38 (chromosome 6), 29 (chromosome 14), and 27
(chromosome 12) surrounding microsatellite loci had been
genotyped. Multipoint IBD probabilities were estimated in
Merlin using genotype data of twins and parents [Abecasis
et al., 2002].
Structural Equation Modeling
Combined tests of linkage and association were performed
using maximum-likelihood based structural equation model-
ing in the Mx software package [Neale et al., 1999]. Within
this framework, a variance components model was specified
to include the effect of the QTL (linkage) and a means
model was specified to include the fixed effect of association
as well as sex and age effects [Fulker et al., 1999; Zhu et al.,
1999]. Hence, observed variances and covariances for MZ
and DZ twins were partitioned into four components:
additive genetic variance (A), common environmental var-
iance (C), unique environmental variance (E), and QTL
variance (Q). The expected covariance structure for MZ
twins was AþCþQ, and for DZ twins was 0.5AþCþ^ pQ,
where ^ p (pi-hat) is the estimated proportion of genes shared
identical by descent at the marker locus. Pi-hat is equivalent
to the probability of sharing two genes IBD plus half the
probability of sharing one gene IBD, that is, p(IBD2)þ0.5
p(IBD1) [Amos, 1994; Boomsma, 1996; Eaves et al., 1996].
To test for linkage, Q was fixed to zero and the fit of this
reduced model was compared to the fit of the saturated
model using the w2likelihood ratio test. In this test the
difference in minus two times the log likelihood (?2 LL)
between the saturated and reduced model is compared to the
critical value of a w2distribution, with degrees of freedom
equal to the difference in degrees of freedom between the
models. In the univariate case, this likelihood ratio statistic
is a mixture of a w2on 1 df and a point mass of 0, so the
probability related to the w2should be halved. To determine
whether a cognitive measure was associated with triplet
repeat length at any of the three loci, the phenotype was
linearly regressed onto mean allele length (rallele) at the
relevant locus. The test of association was considered under
an ACE model by fixing the allele-length regression coeffi-
cient to zero. A significance level of 0.05 was used for our test
of association (rallele), corresponding to a critical value of 3.84
with 1 df.
Asfamily-based datawere used,wefurther testedforeffects
of population stratification and within family effects using
QTDT [Abecasis et al., 2000]. The binned allele length for each
marker was re-coded into three categories representing short,
medium, and long allele length. This was done to avoid QTDT
combining low frequency alleles (<5%) of differing repeat
length. Significant associations were inspected for linearity of
tripletrepeatsizebyre-codingeachofthethreecategoriesinto
a binary trait (presence vs. absence of allele) and checking
whether the chi-squares (obtained from the association test’s
P-value on 1 df) form a linear relationship between the ordinal
categories.
96 Luciano et al.

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RESULTS
Preliminary
Outlier screening and transformations of data distributions
followed the procedures adopted throughout our previous
studies, which were based on larger sample sizes [see Luciano
et al., 2001a, 2004a; Wainwright et al., 2004]. Post hoc
examination of inspection time data indicated that 24
participants did not perform the task properly and their
measurements were excluded. Following log10transformation
of inspection time, 16 outlying cases were removed. Choice RT
was considered for an 8-choice condition, with the index
measure calculated as the mean of log RT across 96 trials. A
significant correlation between mean log RT and accuracy
(r¼0.49) indicated the presence of a speed-accuracy trade-off
effect, so a regression term for accuracy was included in the
means model of the ensuing genetic analysis. The Schonell
readingvariablewasreverselog10transformedduetonegative
skewness in the data.
Prior to genetic analysis, assumptions about equality of
meansandvariancesacrossbirth-order,sex,andzygositywere
tested for each variable. The means of 7 of the 13 variables
differed significantly between males and females, necessitat-
ing the inclusion of an additional term to adjust the means
model for the genetic analyses. Also taken into account in the
genetic analyses performed in Mx were the significantly
different variances between males and females for three
variables:IQsubtests, informationandspatial, andinspection
time.Adifferenceinmeansacrossbirth-orderwasdetectedfor
verbal IQ, but with no other IQ variables showing this trend—
in particular vocabulary, information, and arithmetic (subt-
ests of verbal IQ)—this was assumed to be a type I error and
was not corrected for in the genetic analysis of this variable.
The means and variances of the cognitive variables are
presented in Table I separately for males and females. Similar
sex effects have been observed in our previous studies of these
measures which have used larger sample sizes [Luciano et al.,
2001a, 2004a; Wainwright et al., 2004]. However, our larger
studies show no sex differences in the variance of IQ subtests
and no mean difference between males and females for the
reading tests; additionally, sex effects for all MAB IQ subtests
and inspection time are significant, with increased perfor-
mance bymales.The observation of higherthan average mean
IQ scores in our sample may be an artefact of using non-
Australiannorms.Asthedigitsymbolmeanscoreisconsistent
with the average normative WAIS-R score, this indicates that
the finding is MAB-specific.
Linkage and Association
The distribution of alleles for each triplet repeat locus in the
twin sample (includes both DZ co-twins and a single MZ co-
twin)is showninFigure 1.These frequency distributions were
similar to those reported in other studies focusing on healthy
individuals of Caucasian descent [e.g., Watkins et al., 1995;
Takano et al., 1998]. MJD was shown to have the most
variation with 21 alleles and a heterozygosity of 0.84, while
SCA1 and DRPLA had 13 and 17 alleles, respectively, with
heterozygosities of 0.75 and 0.80.
Tests of the significance of the QTL variance component and
the association effect (mean regression) are presented in
TableII.Linkageresultswerenon-significantforallmeasures,
except arithmetic, which demonstrated significant linkage to
SCA1 (P¼0.03); although this result would not withstand
correction for multiple testing. The lack of power for this
analysis is evidenced by the wide confidence interval on the
estimate of QTL variance of 32% (95% confidence intervals
ranging 0–64%).
Tests of population stratification were significant for digit
symbol (MJD, P¼0.005), vocabulary (DRPLA, P¼0.03), and
verbal IQ (DRPLA, P¼0.047), but the within family tests of
associationforthesemeasureswerenotsignificant.TheQTDT
totalassociationresultswereconsistentwithMxresultsforthe
association of SCA1 with arithmetic (P<0.05), the combined
allelesexplaining2.1%ofvariance(estimatederivedfromMx).
The direction of the effect was positive, so that longer repeats
were associated with higher IQs. QTDT results also supported
this linear effect with the linear trend line fitted to the chi-
squarevalues(fromassociationanalysesoftheshort,medium,
andlongallelebinarycategories)givinganR2of0.92.Marginal
TABLE I. Means and Variances for the Cognitive Measures Separately for Males (N Range:
193–236) and Females (N Range: 234–260)
Means Variances
Female MaleFemaleMale
IQ raw scores
Information
Vocabulary
Arithmetic
Spatial
Object assembly
Digit symbol
IQ scaled scores
Verbal IQ
Performance IQ
Full-scale IQ
Reading
Cambridge
Schonella
Speed
Choice RTb
Inspection timec
21.14
17.60
12.06
29.52
12.62
65.34
21.06
17.18
12.58
32.12
13.24
55.28
23.06
25.85
7.46
91.20
13.98
96.46
34.22
23.62
7.44
63.68
14.36
118.63
110.28
110.27
111.04
111.27
114.48
113.76
116.74
279.66
168.04
126.83
245.43
157.41
31.59
10.39
29.68
11.06
63.37
11.61
57.99
11.95
27.47
19.02
27.43
18.85
0.47
2.93
0.59
4.35
Significant differences between the sexes (P-value of 0.05) are indicated in bold.
Inspection time and RT variables have been multiplied by 10 to facilitate maximum-likelihood estimation.
aReverse log10transformed.
bChoice RT is the mean of log10transformed RT trials.
cLog10transformed.
Association Between CAG Repeats and Cognitive Measures97

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association of SCA1 repeat length with Cambridge Reading
testscores(P¼0.054)wasfoundinMxbutnotQTDT,withthe
direction of the effect also being positive. While association of
DRPLA and inspection time was supported in the QTDT
analyses (P¼0.01), this result may be less reliable than that
from Mx where unequal variances between males and females
were explicitly modeled. The relationship between repeat
length and IT was quadratic so that those with medium length
alleles had faster IT scores.
DISCUSSION
This is the first report to characterize the relationship of
trinucleotide repeat length of the markers predisposing to
SCA1, MJD, and DRPLA disorders with cognitive phenotypes
inalarge,non-clinicalsample.Withamaximumnumberof229
DZ twin pairs for SCA1, our power to detect linkage at any of
the triplet repeat marker loci was low, though the sample size
was reasonable for detecting association [Risch and Teng,
1998]. Linkage of SCA1 to arithmetic was nominally signifi-
cant, but no other linkage effects for the other markers or
measures approached significance. Association of the CAG
repeat loci with the measures was tested using a linear
regression on number of CAG repeats. The only significant
association—consistentacross
packages—was for SCA1 and arithmetic. Interestingly, this
relationship was positive which contrasts the findings in
clinical samples that increased repeat length predicts
increasedseverityofsymptoms(i.e.,poorercognitivefunction).
The significant association component of our joint linkage and
association results suggests that either SCA1 or one or more
variants in linkage disequilibrium with SCA1 influences
arithmetic performance.
There is existing evidence implicating the region on 6p in
which SCA1 lies in influencing cognition. For instance, a QTL
for dyslexia has been mapped to 6p21 [Cardon et al., 1994] and
associationofthesuccinate-semialdehydedehydrogenasegene
(on 6p22) to IQ has been reported [Plomin et al., 2004]. The
present study uncovered weak evidence for linkage to SCA1,
butasthelinkagewasmodeledinthepresenceofassociationit
is unlikely that SCA1 is the causative gene. A genome-wide
studyconductedinasamplewhichpartlyincludesparticipants
from the present study shows suggestive linkage in a region
near the SCA1 marker to arithmetic [Luciano et al., 2006],
strengthening support that a marker in close proximity to
SCA1influences arithmetic. Unlike the linkage, the statistical
Mx andQTDTsoftware
power of our association tests was reasonable. If the positive
association of SCA1 repeat length with arithmetic is a true
effect, this suggests that a threshold exists at which having
larger repeats becomes detrimental to cognitive performance.
SCA1 disease genes show a CAG repeat range of 39–82, while
the largest repeat length observed in our sample was 37.
Obviously, this association requires replication in an indepen-
dentsampletoexcludespuriousassociationsandgiventhatwe
performed a large number of statistical tests, it is possible that
the positive findings reflect type 1 error, especially in view of
the counterintuitive direction of the association.
Our combined tests of linkage and association generally
indicatedthatvariationatthetripletrepeatmarkersforSCA1,
MJD, and DRPLA diseases did not influence measures of IQ,
reading ability, or processing speed in a non-clinical popula-
tion. The exception was arithmetic which showed a positive
association with SCA1. While Cambridge reading and inspec-
tion time showed significant associations with SCA1 and
DRPLA, respectively, the association results were quite
inconsistent between software packages. Our results, then,
suggest that length of the CAG repeats investigated do not
influence variation in cognitive function when the expansion
lengthisinthenormalrange.TheCAGtripletrepeatdisorders
show various clinicopathologies, and while we focused on
cognitive function, it is possible that trinucleotide expansion
length in the normal range or in other genes does influence
other behavioral functions, symptoms of psychopathology, or
motor function. Some research[e.g., Wangetal., 1996; Ritsner
et al., 2002; Medland et al., 2005; Swift-Scanlan et al., 2005]
supports the association between CAG repeats and risk of
schizophrenia,bipolar disorder,
although these effects, like those found in the present study,
require replication and further study.
andleft-handedness,
ACKNOWLEDGMENTS
Phenotype
(A79600334,
DP0343921) and genotyping by a University of Queensland
grant to JC MacMillan and NG Martin. Dr. Luciano is
supported by an Australian Research Council Postdoctoral
Fellowship (DP0449598). We thank the twins and their
parents for their co-operation, and Gu Zhu and Dr. Dale
Nyholt for their helpful advice on data analysis and inter-
pretation.
collection
A79906588,
wasfunded
A79801419,
by ARC
DP0212016,
grants
Fig. 1.Distribution of CAG repeat numbers in the SCA1, MJD, and DRPLA genotype data.
98Luciano et al.

Page 5

REFERENCES
AbecasisGR,CardonLR,CooksonWO.2000.Ageneraltestofassociationfor
quantitative traits in nuclear families. Am Journal Hum Genet 66:279–
292.
Abecasis GR, Cherny SS, Cookson WO, Cardon LR. 2002. Merlin-rapid
analysis of dense genetic maps using sparse gene flow trees. Nat Genet
30:97–101.
Amos CI.1994. Robustvariance-components approach forassessinggenetic
linkage in pedigrees. Am J Hum Genet 54:535–543.
Beckmann JS, Weber JL. 1992. Survey of human and rat microsatellites.
Genome 12:627–631.
Boomsma DI. 1996. Using multivariate genetic modeling to detect
pleiotropic quantitative trait loci. Behav Genet 26:161–166.
CardonLR,SmithSD,FulkerDW,KimberlingWJ,PenningtonBF,DeFries
JC. 1994. Quantitative trait locus for reading disability on chromosome
6. Science 266:276–279.
Cummings CJ, Zoghbi HY. 2000. Trinucleotide repeats: Mechanisms and
pathophysiology. Annu Rev Genomics Hum Genet 1:281–328.
Daniels JK, Owen MJ, McGuffin P, Thompson L, Detterman DK,
Chorney M, Chorney K, Smith D, Skuder P, Vignetti S, McClearn
GE, Plomin R. 1994. IQ and variation in the number of fragile X
CGG repeats: No association in a normal sample. Intelligence 19(1):
45–50.
Eaves LJ, Neale MC, Maes H. 1996. Multivariate multipoint linkage
analysis of quantitative trait loci. Behav Genet 26:519–525.
Foroud T, Siemers E, Kleindorfer D, Bill DJ, Hodes ME, Norton JA,
Conneally PM, Christian JC. 1995. Cognitive scores in carriers of
Huntington’s disease gene compared to noncarriers. Ann Neurol
37(5):657–664.
Fulker DW, Cherny SS, Sham PC, Hewitt JK. 1999. Combined linkage and
association sib-pair analysis for quantitative traits. Am J Hum Genet
64:259–267.
Jackson DN. 1984. Manual for the multidimensional aptitude battery. Port
Huron, MI: Research Psychologists Press.
Jackson DN. 1998. Multidimensional aptitude battery II. Port Huron, MI:
Sigma Assessment Systems, Inc.
Koeppen AH. 2005. The pathogenesis of spinocerebellar ataxia. Cerebellum
4(1):62–73.
Luciano M, Smith GA, Wright MJ, Geffen GM, Geffen LB, Martin NG.
2001a.OntheheritabilityofinspectiontimeainitscovariancewithIQ:A
twin study. Intelligence 29:443–457.
Luciano M, Smith GA, Wright MJ, Geffen GM, Geffen LB, Martin NG.
2001b. Genetic covariance among measures of information processing
speed, working memory, and IQ. Behav Genet 31(6):581–592.
LucianoM,WrightMJ,GeffenGA,GeffenLB,SmithGA,MartinNG.2004a.
A genetic investigation of the covariation among Inspection Time,
Choice Reaction Time and IQ subtest scores. Behav Genet 34(1):
41–50.
Luciano M, Wright MJ, Duffy DL, Wainwright MA, Zhu G, Evans DM,
GeffenGM,MontgomeryGW,MartinNG.2006.Genome-widescanofIQ
finds significant linkage to a Quantitative Trait Locus on 2q. Behav
Genet 36(1):45–55.
MacMillan JC, Voisey J, Healey SC, Martin NG. 1999. Mendelian
segregation of normal CAG trinucleotide repeat alleles at three
autosomal loci. J Med Genet 36(3):258–259.
Margolis RL, McInnis MG, Rosenblatt A, Ross CA. 1999. Trinucleotide
repeat expansion and neuropsychiatric disease. Arch Gen Psychiatry
56(11):1019–1031.
MatillaA,RobersonED,BanfiS,MoralesJ,ArmstrongDL,etal.1998.Mice
lacking ataxin-1 display learning deficits and decreased hippocampal
paired-pulse facilitation. J Neurosci 18:5508–5516.
Medland SE, Duffy DL, Spurdle AB, Wright MJ, Geffen GM, Montgomery
GW,MartinNG.2005.OppositeeffectsofandrogenreceptorCAGrepeat
length on increased riskofleft-handednessinmales andfemales.Behav
Genet 35(6):735–744.
Monckton DG, Caskey CT. 1995. Unstable triplet repeat diseases. Circula-
tion 91:513–520.
Neale MC, Boker SM, Xie G, Maes HH. 1999. Mx: Statistical Modeling,
5th edition. VCU Box 900126, Richmond, VA 23298: Department of
Psychiatry.
Nelson HE, Willison JR. 1991. National adult reading test. Berkshire:
NFER-Nelson Publishing Company.
TABLE II. Chi-Squares (and P-values) for the Tests of Linkage (QTL) and Allelic Association (Mx: rallele;) of the Triplet Repeat Markers to the Cognitive Measures
SCA1
MJD
DRPLA
Mx
QTDTa
%Var
Mx
QTDTa
%Var
Mx
QTDTa
%Var
QTL (P)
rallele(P)
rallele(P)
QTL (P)
rallele(P)
rallele(P)
QTL (P)
rallele(P)
rallele(P)
IQInformation
0.73 (0.19)
1.36 (0.24)
0.78 (0.68)
0
0 (0.50)
0.09 (0.76)
0.05 (0.97)
0
0 (0.50)
0.28 (0.59)
1.86 (0.39)
0
Vocabulary
0 (0.50)
2.76 (0.10)
4.74 (0.09)
1
0 (0.50)
0.02 (0.90)
0.05 (0.97)
0.02
0 (0.50)
0.24 (0.62)
0.61 (0.74)
0.13
Arithmetic
3.79 (0.03)
4.02 (0.04)
7.18 (0.03)
2.1
0.70 (0.20)
.00 (0.95)
0.30 (0.86)
0.02
0 (0.50)
0.89 (0.34)
2.36 (0.31)
0.18
Object assembly
0 (0.50)
0.01 (0.92)
2.29 (0.32)
0
0 (0.50)
1.28 (0.26)
2.23 (0.33)
0.46
0 (0.50)
0.34 (0.56)
0.94 (0.62)
0.07
Spatial
0 (0.50)
1.98 (0.16)
1.71 (0.42)
0.25
0 (0.50)
1.22 (0.27)
1.38 (0.50)
0.66
0.27 (0.30)
0.81 (0.37)
3.81 (0.15)
0.07
Verbal IQ
1.97 (0.08)
2.42 (0.12)
4.91 (0.09)
1.31
0 (0.50)
0.02 (0.90)
0.11 (0.95)
0.05
0 (0.50)
0.85 (0.35)
1.15 (0.56)
0.11
Performance IQ
0 (0.50
0.12 (0.73)
0.07 (0.97)
0.07
0 (0.50)
1.71 (0.19)
1.94 (0.38)
0.70
0.25 (0.31)
0.01 (0.93)
2.82 (0.24)
0
Full-scale IQ
1.67 (0.10)
0.91 (0.34)
1.79 (0.41)
0.50
0 (0.50)
0.67 (0.41)
0.66 (0.72)
0.16
0 (0.50)
0.46 (0.50)
2.47 (0.29)
0.02
Digit symbol
0 (0.50)
0.38 (0.54)
0.79 (0.67)
0.04
0.07 (0.39)
1.02 (0.31)
1.15 (0.56)
0.44
0 (0.50)
0 (0.95)
1.67 (0.43)
0.01
Reading
Cambridge
0 (0.50)
3.70 (0.05)*
3.34 (0.19)
1.58
0 (0.50)
0.23 (0.63)
0.13 (0.94)
0.04
0 (0.50)
0.03 (0.86)
0.17 (0.92)
0
Schonell
0.04 (0.42)
1.97 (0.16)
2.33 (0.31)
0.76
0.67 (0.20)
0.01 (0.93)
0.37 (0.83)
0.03
0 (0.50)
1 (0.32)
2.97 (0.23)
0.36
Speed
Inspection time
0 (0.50)
0.27 (0.60)
0.12 (0.94)
0
0.13 (0.36)
0.01 (0.92)
2.81 (0.24)
0
0.09 (0.38)
0.17 (0.68)
8.47 (0.01)
0
Choice RT
0 (0.50)
0.05 (0.81)
2.55 (0.28)
0
1.79 (0.09)
1.29 (0.25)
1.16 (0.56)
0.34
0 (0.50)
2.47 (0.12)
0.78 (0.68)
0.81
The percentage of variance (%Var) in the trait explained by joint allele effects was estimated from Mx. Significant effects indicated in bold.
a2 df test.
*0.054
Association Between CAG Repeats and Cognitive Measures99