Obsessive-Compulsive Symptom Dimensions in Affected Sibling Pairs Diagnosed With Gilles de la Tourette Syndrome
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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 116B:60 –68 (2003)
Obsessive-Compulsive Symptom Dimensions in
Affected Sibling Pairs Diagnosed With Gilles de la
Tourette Syndrome
James F. Leckman,1* David L. Pauls,2 Heping Zhang,1,3 Maria C. Rosario-Campos,1 Liliya Katsovich,1
Kenneth K. Kidd,4 Andrew J. Pakstis,4 John P. Alsobrook,5 Mary M. Robertson,6
William M. McMahon,7 John T. Walkup,8 Ben J.M. van de Wetering,9 Robert A. King,1
Donald J. Cohen,1 and the Tourette Syndrome Association International Consortium for Genetics
1
Yale Child Study Center, Yale University School of Medicine, New Haven, Connecticut
2
Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
3
Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut
4
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut
5
CuraGen Corporation, Branford, Connecticut
6
Department of Psychiatry and Behavioral Sciences, University College and the National Hospital for Neurology
and Neurosurgery, Queen Square, London
7
Departments of Human Genetics and Psychiatry, University of Utah School of Medicine, Salt Lake City, Utah
8
Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland
9
Department of Psychiatry, Erasmus University, Rotterdam, The Netherlands
Obsessive-compulsive disorder (OCD) is an Genetics Affected Sibling Pair Study, the
etiologically heterogeneous disorder. Recent authors selected all available GTS sib pairs
factor analyses have consistently identified and their parents for which these OC symp-
several symptom dimensions, two of which tom dimensions (factor scores) could be
are associated with increased familial risk generated. This group included 128 full sibs
for OCD; aggressive, sexual, and religious and their mothers (54) and fathers (54). Four
obsessions and checking compulsions (FAC- OC symptom dimension scores were com-
TOR 1) and symmetry and ordering obses- puted for each family member using an
sions and compulsions (FACTOR 2). Both algorithm derived from item endorsements
of these symptom dimensions are also fre- from the Yale-Brown Obsessive-Compulsive
quently seen in association with Gilles de Scale (Y-BOCS) symptom checklist. In ad-
la Tourette syndrome (GTS). The purpose of dition to a series of univariate analyses,
this study was to determine whether these complex segregation analyses were also com-
obsessive-compulsive (OC) symptom dimen- pleted using these quantitative OC symptom
sions are correlated within families (between dimension scores. FACTOR 1 and FACTOR 2
sibs and between parent-child pairs). Using scores were significantly correlated in sib
data collected by the Tourette Syndrome pairs concordant for GTS. The mother–child
Association International Consortium for correlations, but not father–child correla-
tions, were also significant for these two
factors. Segregation analyses were consis-
tent with dominant major gene effects for
both FACTOR 1 and FACTOR 2. We conclude
A complete list of the consortium members involved in the that familial factors contribute significantly
collection of the data reported is presented in the Acknowl- to OC symptom dimension phenotypes in
edgments section. GTS families. This familial contribution
Grant sponsor: National Heart, Lung and Blood Institute; could be genetic or environmental.
Grant sponsor: National Institutes of Health; Grant numbers:
ß 2003 Wiley-Liss, Inc.
NS-40024-01, MH-493515, NS-16648, MH-00508, MH-30929,
RR-00044, RR-00125, NS-07338, DA-12468, AA-12044.
KEY WORDS: Gilles de la Tourette synd-
*Correspondence to: James F. Leckman, M.D., Child Study rome; obsessive-compulsive
Center, Yale University School of Medicine, 230 South Frontage
Road, New Haven, CT 06520. E-mail: james.leckman@yale.edu disorder; quantitative traits;
Received 14 January 2002; Accepted 12 June 2002
segregation analyses
DOI 10.1002/ajmg.b.10001
ß 2003 Wiley-Liss, Inc.OC Traits Among Tourette Family Members 61
INTRODUCTION titative traits that are familial provides a more powerful
approach than analyses using categorical diagnostic
Substantial recent advances in molecular genetics (qualitative) outcomes [Zhang and Risch, 1996; Alcais
have greatly increased the capacity to localize disease and Abel, 1999; Elston et al., 2000].
genes on the human genome. These methods are now We addressed the question of familial factors under-
being applied to complex disorders, including Gilles de la lying the OC symptom dimensions commonly seen in
Tourette syndrome (GTS) [Tourette Syndrome Interna- GTS by examining affected sib pairs and their parents
tional Consortium for Genetics, 1999]. One of the major ascertained in the Tourette Syndrome Association
difficulties in the application of these approaches is the International Consortium for Genetics Affected Sibling
likely etiologic heterogeneity of GTS and related pheno- Pair Study [Tourette Syndrome International Consor-
types. Heterogeneity reduces the power of gene-locali- tium for Genetics, 1999]. The purpose of the current
zation methods, such as linkage analysis [Zhang and study was to test the hypothesis that pairs of GTS
Risch, 1996; Gu et al., 1998; Alcais and Abel, 1999]. relatives resemble one another for each of the four
Etiologic heterogeneity may be reflected in phenotypic quantitative OC symptom dimensions at greater
variability, thus it would be highly desirable to dissect than chance expectations. To investigate the possible
the syndrome, at the level of the phenotype, into valid transmission of these quantitative OC symptom dimen-
quantitative heritable components. sions, complex segregation analyses were also carried
Obsessive-compulsive (OC) symptomatology is ob- out.
served frequently in patients with GTS [Pauls and
Leckman, 1986; Pauls et al., 1991; Swerdlow et al., 1999; MATERIALS AND METHODS
Robertson, 2000]. Factor analytic studies of OCD
patients have identified at least four OC symptom Sample
dimensions [Baer, 1994; Leckman et al., 1997, 2001; All families consisted of at least two sibs affected
Mataix-Cols et al., 1999; Summerfeldt et al., 1999; with GTS. Families were not included in the analyses
Cavallini et al., 2002]. One dimension (FACTOR 1) is reported here if both parents were affected with GTS or if
characterized by aggressive, sexual, and religious ob- one parent had GTS, chronic motor or vocal tic disorder
sessions and checking compulsions. FACTOR 2 is (CT), OCD, or subclinical OCD and the other parent also
characterized by symmetry and ordering obsessions received a diagnosis of CT, OCD, or subclinical OCD.
and compulsions. FACTOR 3 includes contamination All diagnoses were made using DSM-III-R criteria. The
obsessions and cleaning/washing compulsions, and the criteria for subclinical OCD were the same as those used
fourth factor (FACTOR 4) includes hoarding obses- to make a diagnosis of OCD, except that the individual
sions and compulsions. Preliminary data supporting the did not perform the compulsions or obsessions for at
validity of these dimensions come from longitudinal least an hour, or did not experience them as ego dystonic,
studies [Mataix-Cols et al., 2002] as well as functional or did not report any impairment. These were the same
brain imaging [Rauch et al., 1998; Phillips et al., 2000] criteria used in the family study of OCD reported by
and treatment studies [Black et al., 1998; Mataix-Cols Pauls et al. [1995]. Written informed consent was
et al., 1999]. Preliminary studies also provide evidence obtained for all participants after the procedures had
for the orderly emergence of similar compulsive traits in been fully explained. Children were also asked to assent
normally developing children [Evans et al., 1997; Zohar to participate in the study in the presence of their
and Felz, 2001]. parents after the purpose of the study, the nature of the
Although these studies suggest that these dimensions interviews, and the blood collection procedures were
are stable over time and may have biological validity, described in age-appropriate language.
there has been little examination of their familial or
genetic nature. At the present time, we are aware of only
Phenotypic Evaluation
one study that has examined the relationship of these
factors to familial risk [Alsobrook et al., 1999]. In that When a family entered the study, information con-
study, the relatives of OCD probands who had high cerning both affected sibs and their parents was col-
scores on FACTOR 1 or FACTOR 2 were at greater risk lected in a two-stage process. The initial stage consisted
for OCD than were relatives of probands who had low of the collection of information concerning symptoms
scores on those factors. To date there have been no associated with GTS and OCD using a self-and-family
published studies done that examine whether the OC report based on the tic inventory and ordinal severity
symptom dimensions are themselves familial. scales of the Yale Global Tic Severity Scale [Leckman
Families of affected sib pairs diagnosed with GTS et al., 1989] and the symptom checklist and ordinal
are ideally suited for efforts to identify the genetic loci scales of the Yale-Brown Obsessive-Compulsive Scale
responsible for these quantitative OC phenotypes. First, [Y-BOCS, Goodman et al., 1989]. Earlier versions of
the early-onset OCD observed in these families is likely these instruments have been used in prior studies of
to be etiologically more homogenous [Pauls et al., 1995; individuals with GTS and OCD and have been shown to
Nestadt et al., 2000]. Second, the two symptom dimen- have good agreement with expert clinician ratings of tic
sions associated with higher familial risk of OCD and OC symptom severity [Leckman et al., 1993, 1994;
(FACTORS 1 and 2) are also frequently observed in Swerdlow et al., 1999]. In a second stage, an experienced
patients with GTS [Leckman et al., 1997; Swerdlow clinician reviewed these symptom ratings with each
et al., 1999; Robertson, 2000]. Third, the use of quan- family member to insure their accuracy and validity.62 Leckman et al.
These instruments are currently being used in family and relative pairs for quantitative traits was examined
studies of both GTS and OCD. by standard parametric analyses of association and
Factor scores were computed using an algorithm analyses of covariance. Because this analysis contain-
derived from an earlier study of 292 individuals with ed non-independent sib pairs from sibships containing
OCD and based on item endorsements from the Y-BOCS three or more affected individuals, we repeated all
Symptom Checklist. This factor analysis is described analyses, using just the two oldest sibs from sibships
more fully in Leckman et al. [1997]. Briefly, a principal with three or more affected members. Age was included
components factor analysis with a Varimax rotation was as a covariate in the univariate models.
carried out on symptom counts from the 13 a priori Complex segregation analyses were carried out to
categories in the Y-BOCS symptom checklist in two examine the hypothesis that there is transmission of
independent groups of patients with OCD (N ¼ 208 and OCD within families and if that transmission is con-
N ¼ 98) [Leckman et al., 1993, 1994, 1995; Pauls et al., sistent with genetic modes of inheritance. Analyses were
1995]. The two data sets yielded nearly identical results. carried out using the unified model as implemented in
Four factors, obsessions and checking, symmetry and the computer program POINTER [Lalouel et al., 1983].
ordering, cleanliness and washing, and hoarding, The unified model allows for the possible contributions
emerged in each data set, in total accounting for more of both major genetic and polygenic loci (the so-called
than 60% of the variance. The algorithm used to mixed model). Specific genetic models are hierarchical
generate the factor scores in this study was based on and were examined by comparing the maximum like-
the category-specific coefficients, derived from the total lihood estimates using a w2 test. In these analyses four
sample of OCD subjects, and reported in Table II of that parameters were estimated: 1) Q, the frequency of the
earlier study [Leckman et al., 1997]. Specifically, the putative major susceptibility allele; 2) D, the degree of
number of items endorsed for each of the 13 symptom dominance of that allele; 3) H, the heritability of the
categories by each participant in this study was multi- polygenic component contributing to the expression of
plied by the respective category-specific coefficients OCD; and 4) T, the effect of the major susceptibility
from the earlier study to generate the four factor scores. allele in the population. In addition, V, stands for
the variance of the quantitative trait and, U, the mean
Best-Estimate Diagnoses value of the quantitative trait given the phenotype. For
the factor scores the variance should be 1.0 and the mean
All diagnoses were made using the best-estimate
should be 0.0. No ascertainment correction was em-
approach [Leckman et al., 1982]. The best-estimate
ployed for these analyses because the ascertainment
procedure used in the present study followed a standard
was based on the presence of GTS and not the value of
protocol. Before the initial diagnostic estimate was
these factors.
made, separate files for each individual were prepared.
By taking twice the difference between the maximum
These files contained all available information about the
log likelihood estimates for each model we compared
individual, including the completed interview packet
competing genetic models. This difference in log like-
and medical records, when available. Three clinicians
lihoods is distributed as a w2 statistic with degrees of
(Bv dW, Rotterdam site; WM, Utah site; and RAK, Yale
freedom equal to the difference in the number of esti-
site) reviewed all available information and indepen-
mated parameters in the two models. For example, four
dently made diagnostic assessments. All three diagnos-
parameters are estimated when fitting the Mendelian
ticians were blind to the prior diagnosis of the individual
mixed model and only one is estimated when fitting the
and to his/her relationship to the proband. Two raters
polygenic model. Twice the difference between the log
evaluated each interview. If they judged DSM-IV
likelihoods for the mixed and polygenic model is distri-
criteria to be satisfied, then they rated that diagnosis
buted as a w2 with 3 degrees of freedom.
as ‘‘definite.’’ If they judged DSM-IV criteria to be sati-
First, we compared the model of ‘‘No Transmission’’
sfied save one criterion, then they rated that diag-
with the mixed model assessed evidence for transmis-
nosis as ‘‘probable.’’ The best estimates of the two
sion. If twice the difference in log likelihoods did not
diagnosticians were then compared. When there was
yield a significant w2 statistic, we concluded that there
disagreement between the two raters, the third diag-
was no evidence for vertical transmission and no further
nostician reviewed the individual files and a final
comparisons were made. If the difference in log like-
consensus diagnosis was assigned. These consensus
lihood yielded a significant w2 statistic, it is taken as
diagnoses were then compared to the diagnosis assign-
evidence for possible vertical transmission and further
ed by the clinician at the site where the family was
comparisons were made. The next two comparisons
recruited. If there were differences, the clinical materi-
examined: 1) if models of a major gene alone (no poly-
als were reviewed via a conference call and consensus
genic background) were sufficient to account for the
was reached if possible. If there was still disagreement,
presumed vertical transmission; and 2) if models of
more data were requested to help resolve the differ-
polygenic inheritance (no major locus) were consistent
ences. If there was still disagreement, the family was
with the pattern of transmission.
removed from the sample.
Evidence for a major locus component in transmission
was assessed by comparing the likelihood of this model
Statistical Analyses
to that of the likelihood of the mixed model. If the dif-
Because the original factor scores were normally ference in twice the log likelihood was not significant,
distributed [Leckman et al., 1997], resemblance in sib the major locus hypothesis was not rejected. If at theOC Traits Among Tourette Family Members 63
TABLE I. Gilles de la Tourette Syndrome Sibships Studied for FACTOR 1 and FACTOR 2 scores (Table III). We repe-
Obsessive-Compulsive Symptoms ated this analysis after removing non-independent
Number Number of Number Number of Number sib pairs. The results were similar, with a significant
of siblings sibships of siblings mothers of fathers correspondence between sib pairs with respect to
with GTS (n ¼ 54) n ¼ 128 n ¼ 54 n ¼ 54 FACTOR 1 and FACTOR 2 (Table III). Partial correla-
tions were also significant such that sib 1’s FACTOR 1
Two 38 76 38 38
Three 12 36 12 12
score was significantly related to sib 2’s FACTOR 1 score
Four 4 16 4 4 even after controlling for the effects of sib 1’s and sib 2’s
FACTOR 2 scores (data not shown). Similarly, the
partial correlations for FACTOR 2 were also significant
same time, then similar comparison between the poly- even after controlling for the effects of sib 1’s and sib 2’s
genic hypothesis and the mixed model hypothesis could FACTOR 1 scores (data not shown).
be rejected, then a mode of inheritance that includes a The mothers, but not fathers, resembled their affect-
major locus with no polygenic background would be the ed children with respect to FACTOR 1 and FACTOR 2
most parsimonious. If both major locus and polygenic scores (Table III). When we repeated this analysis
hypotheses can be rejected, then a mode of transmission after removing non-independent sib pairs, the results
with both a major locus and polygenic background (i.e., were similar, with a significant mother–child corre-
the mixed model) would be the most parsimonious. spondence with respect to just FACTOR 1 and FACTOR
2 (Table III). Partial correlations were also significant
RESULTS such that both sib 1’s and sib 2’s FACTOR 1 scores were
Sample significantly related to the mother’s FACTOR 1 score
even after controlling for the effects of sib 1’s or sib 2’s
The 236 subjects came from 54 families (Table I). and the mothers’ FACTOR 2 scores (data not shown).
Thirty-eight of the families contained two sibs affected Similarly, the partial correlations for FACTOR 2 were
with GTS. Twelve families contained three sibs affected also significant even after controlling for the effects of
with GTS. Four families had four affected sibs. One either sib’s and the mother’s FACTOR 1 scores (data not
hundred and sixty-two subjects (68.6%) were judged to shown).
have probable or definite GTS. Ninety-seven subjects Because the mother served as the primary informant
(41%) were judged to have probable or definite OCD. for the prepubertal subjects, these correlations were
Table II presents the clinical characteristics of GTS- computed again using only the data from 17 sibs pairs
affected sib pairs and their parents. where both were above the age of 15 years. The sib–sib
correlations for FACTOR 1 and FACTOR 2 scores were
Sib and Parental Resemblance for Obsessive
in same range as for the entire set of sib pairs (0.38 and
Compulsive Symptom Dimensions
0.39, respectively, P < 0.10). Interestingly, the FACTOR
We were able to compute four OC symptom dimen- 4 scores also approached significance (0.42, P ¼ 0.09).
sions (FACTORS 1–4) for all 236 subjects. The sibs The mother–child correlations for these older sibs were
resembled each other significantly with respect to also comparable to those found in the entire set of
TABLE II. Clinical Characteristics of Gilles de la Tourette Syndrome Affected Sibling Pairs and
Their Parents
Eldest sibling 2nd Eldest Mother Father
(N ¼ 54) sibling (N ¼ 54) (N ¼ 54) (N ¼ 54)
Male, n (%) 38 (70) 42 (78) 0 (0) 54 (100)
Mean age, years (SD) 14.8 (7.1) 13.6 (7.7) 42.8 (7.5) 44.3 (7.6)
GTS diagnosis: n (%)
Definite 43 (80) 46 (85) 14 (26) 11 (20)
Probable 11 (20) 8 (15) 3 (7) 6 (3)
Age of tic onset, years (SD) 5.7 (2.3) 5.6 (2.6) 7.6 (3.3) 7.6 (2.0)
OCD diagnosis: n (%)
Definite 23 (43) 22 (41) 14 (26) 4 (7)
Probable 8 (15) 7 (13) 4 (7) 3 (6)
OCD age of onset, years (SD) 6.7 (3.5) 6.7 (3.4) 10.3 (3.6) 11.5 (9.6)
SSRI medication history: n (%)
Ever 19 (35) 21 (39) 17 (31) 13 (24)
Current 13 (24) 15 (28) 10 (19) 8 (15)
YGTSS-total tic score
Current (SD) 16.2 (10.7)a 16.2 (10.0)b
Y-BOCS-total score
Current (SD) 17.6 (7.9)c 17.4 (5.9)d
a
n ¼ 41.
b
n ¼ 40.
c
n ¼ 22.
d
n ¼ 18.64 Leckman et al.
TABLE III. Pearson Correlations Between Obsessive-Compulsive Symptom Factor Scores{
OC factora Sib1–Sib2 Sib1-mother Sib1-father Sib2-mother Sib2-father
Factor 1 0.41*, 0.41* 0.64*, 0.46* 0.13, 0.11 0.36*, 0.24 0.01, 0.15
Factor 2 0.38*, 0.33*** 0.41*, 0.25**** 0.00, 0.20 0.31**, 0.35** 0.01, 0.03
Factor 3 0.11, 0.08 0.26***, 0.08 0.04, 0.09 0.26***, 0.25**** 0.11, 0.22
Factor 4 0.16, 0.15 0.12, 0.06 0.05, 0.08 0.18, 012 0.06, 0.15
{
In each cell the first coefficient is for all sib-pairs and all parent-sib pairs. The second coefficient is for the oldest two sibs and their parent-sib correlations.
OC, obsessive-compulsive.
a
OC Factors scores were generated based on an algorithm developed in a study of 292 patients with OC disorder [Leckman et al., 1997]. Factor 1 includes
aggressive, sexual, religious and somatic obsessions and checking compulsions. Factor 2 includes obsessions of symmetry and exactness and ordering,
counting, doing and redoing compulsions. Factor 3 includes obsessions of cleanliness and washing compulsions. Factor 4 includes obsessions and compulsions
related to hoarding.
*P < 0.0001.
**P < 0.01.
***P < 0.05.
****P < 0.10.
mother–child pairs (FACTOR 1 [mother–sib 1: 0.84, FACTOR 2 scores were the most robust predictors of the
P < 0.0001; mother–sib 2: 0.53, P ¼ 0.03], FACTOR 2 sib’s scores for FACTORS 1 and 2.
[mother–sib 1: 0.63, P < 0.007; mother–sib 2: 0.00, NS]
and FACTOR 4 [mother–sib 1: 0.57, P < 0.02; mother–
Factor Analysis
sib 2: 0.43, P ¼ 0.09]).
In a further effort to examine the relative effect of Using a principal components factor analysis with Vari-
parent-child vs. sib associations a series of univariate max rotation, we examined the results when we specifi-
analyses were carried out in which sib 1’s factors scores ed a four-factor model. The four factors that emerged
were related to sib 2’s factor scores as well as the closely resembled the results from the earlier analyses
mother’s and father’s factor scores while simultane- that relied solely on individuals with OCD. This solution
ously controlling for the effects of age. As presented in also accounted for more than 70% of the variance
Table IV, the effects of the mother’s FACTOR 1 and (Table V).
TABLE IV. Analyses of Variance of Sib1 OC Factor 1 and Factor 2 Scores*
Dependent measure Independent variables F (1, 83), P-valuea F (1, 43), P-valueb
S1 Factor 1 Sib1 age 8.71, .004 2.15, NS
Sib2 age 0.128, NS 0.000, NS
Mother’s age 0.618, NS 0.01, NS
Father’s age 3.60, .06 0.39, NS
Sib2 Factor 1 5.44, .02 3.31, .08
Mother Factor 1 35.89, .0001 9.50, .004
Father Factor 1 0.05, NS 0.00, NS
S1 Factor 2 Sib1 age 1.98, NS 2.59, NS
Sib2 age 0.303, NS 0.79, NS
Mother’s age 5.90, .017 0.05, NS
Father’s age 6.91, .01 0.14, NS
Sib2 Factor 2 5.31, .02 2.28, NS
Mother Factor 2 11.32, .001 2.72, .10
Father Factor 2 1.08, NS 2.22, NS
S1 Factor 3 Sib1 age 0.002, NS 0.84, NS
Sib2 age 3.56, .06 0.07, NS
Mother’s age 5.14, .03 0.89, NS
Father’s age 8.78, .004 1.81, NS
Sib2 Factor 3 0.007, NS 0.37, NS
Mother Factor 3 2.12, .15 0.26, NS
Father Factor 3 1.42, NS 1.16, NS
S1 Factor 4 Sib1 age 2.91, .09 4.79, .04
Sib2 age 0.01, NS 0.80, NS
Mother’s age 0.18, NS 0.03, NS
Father’s age 1.42, NS 0.52, NS
Sib2 Factor 4 0.13, NS 016, NS
Mother Factor 4 0.40, NS 0.17, NS
Father Factor 4 0.33, NS 0.22, NS
*ANCOVAs in which we evaluated the effect of the Sib2’s and the parents’ Factor scores on Sib1’s Factor scores
while simultaneously controlling for age.
a
This analysis was performed using all available S1 pairs (N ¼ 91).
b
This analysis was performed using just the eldest two siblings (N ¼ 51).OC Traits Among Tourette Family Members 65
TABLE V. Varimax Rot ated Factor Structure for Yale-Brown Obsessive Compulsive Scale
Symptom Checklist Category Scores
Factor loadinga
Obsessions Symmetry Cleanliness
Symptom category and checking and ordering and washing Hoarding
Aggressive obsessions 0.62 0.18 0.49 0.18
Contamination obsessions 0.43 0.27 0.70 0.05
Sexual obsessions 0.83 0.18 0.18 0.11
Hoarding obsessions 0.09 0.19 0.19 0.87
Religious obsessions 0.66 0.22 0.21 0.22
Obsessions of symmetry 0.23 0.76 0.19 0.23
Somatic obsessions 0.58 0.18 0.49 0.15
Cleaning compulsions 0.02 0.08 0.70 0.03
Checking compulsions 0.22 0.45 0.68 0.29
Repeating rituals 0.05 0.33 0.68 0.30
Counting compulsions 0.41 0.56 0.18 0.21
Ordering and arranging 0.12 0.83 0.29 0.13
Hoarding and collecting 0.33 0.23 0.06 0.78
% of variance explained 21.5 16.7 21.3 13.6 Sum ¼ 72.1%
a
Robust loadings (greater than 0.50) are printed in bold.
Segregation Analyses DISCUSSION
Results of segregation analyses using the four factors The findings in this study suggest that at least some
as quantitative phenotypes are presented in Table VI. of the OC symptom dimensions are heritable. First, for
Significant evidence for genetic transmission was ob- FACTORS 1 and 2, there was a significant correlation
tained for all factors. Of interest is that the specific mode both between sib pairs and mother–child pairs. To our
of transmission differed for specific factors. The most knowledge, this is the first report of familial resem-
parsimonious solution for each factor suggests genes of blance for these quantitative phenotypes in patients
major effect. For FACTORS 1 and 2 the transmission with GTS, OCD, and closely related disorders. Second,
was consistent with dominant inheritance whereas for these correlational findings are strengthened by the
FACTORS 3 and 4 the most parsimonious solution was results of segregation analyses that suggest that the
consistent with recessive inheritance. patterns within families are consistent with genetic
TABLE VI. Segregation Analyses of Yale-Brown Obsessive Compulsive Scale Factor Scores*
V U D T Q H 2Ln(L)
a
OC Factor 1
No transmission 0.70 0.07 0.53 0.01 0.00e 0.00e 0.00e 0.00e 283.563
Mixed model 0.94 0.09 0.04 0.10 1.00f 1.57 0.10 0.29 0.08 0.06 0.06 246.950
Single locus model 0.94 0.09 0.04 0.19 1.00f 1.57 0.11 0.29 0.08 0.00e 248.029
Polygenic model 0.67 0.07 0.50 0.02 0.00e 0.00e 0.00e 0.44 0.08 264.975
OC Factor2b
No transmission 0.88 0.08 0.36 0.02 0.00e 0.00e 0.00e 0.00e 308.599
Mixed model 0.84 0.08 0.13 0.10 1.00f 1.49 0.08 0.39 0.07 0.04 0.05 275.565
Single locus model 0.84 0.08 0.14 0.09 1.00f 1.49 0.08 0.39 0.07 0.00e 275.818
Polygenic model 0.90 0.10 0.17 0.10 0.00e 0.00e 0.00e 0.54 0.10 291.243
OC Factor 3c
No transmission 0.39 0.04 0.56 0.07 0.00e 0.00e 0.00e 0.00e 217.381
Mixed model 0.56 0.09 0.37 0.03 0.01 0.07 1.51 0.10 0.50 0.07 0.04 0.04 169.891
Single locus model 0.55 0.08 0.37 0.03 0.03 0.06 1.50 0.10 0.52 0.07 0.00e 170.617
Polygenic model 0.41 0.04 0.52 0.01 0.00e 0.00e 0.00e 0.24 0.05 217.362
OC Factor 4d
No transmission 1.09 0.10 0.37 0.07 0.00e 0.00e 0.00e 0.00e 333.097
Mixed model 0.97 0.18 1.03 0.22 0.00f 1.91 0.07 0.85 0.06 0.01 0.01 287.290
Single locus model 0.97 0.19 1.03 0.23 0.00f 1.91 0.07 0.85 0.07 0.00e 287.294
Polygenic model 1.09 0.10 0.38 0.08 0.00e 0.00e 0.00e 0.08 0.08 332.643
*V, variance of the quantitative trait; U, mean value of the quantitative trait; D, the degree of dominance of that allele; T, the effect of the major susceptibility
allele in the population; Q, the frequency of the putative major susceptibility allele; H, the heritability of the polygenic component; NS, not significant.
a
No transmission vs. mixed, w2(4) ¼ 36.613 (P < 0.000001); Mixed vs. single locus, w2(1) ¼ 1.079, NS; Mixed vs. polygenic, w2(3) ¼ 18.025 (P < 0.0005).
b
No transmission vs. mixed, w2(4) ¼ 33.034 (P < 0.000001); Mixed vs. single locus, w2(1) ¼ 0.253, NS; Mixed vs. polygenic, w2(3) ¼ 15.678 (P < 0.002).
c
No transmission vs. mixed, w2(4) ¼ 47.490 (P < 0.000001); Mixed vs. single locus, w2(1) ¼ 0.726, NS; Mixed vs. polygenic, w2(3) ¼ 47.471 (P < 0.000001).
d
No transmission vs. mixed, w2(4) ¼ 45.807 (P < 0.000001); Mixed vs. single locus, w2(1) ¼ 0.004, NS; Mixed vs. polygenic, w2(3) ¼ 45.353 (P < 0.0001).
e
Parameter fixed for the analysis.
f
Parameter converged at the boundary, no standard error estimated.66 Leckman et al.
transmission. The most parsimonious results were con- imprinting) vs. gender-specific effects. It may also be
sistent with the hypothesis that there are genes of major important to use analytic strategies that would permit
effect underlying each of these OC symptom dimensions. the use of data from all sibs and that would also take into
It is important to note that although FACTORS 3 and 4 account the correlation of observations within families
that did not show a significant correlation between sibs [Hudson et al., 2001]. The selection of the oldest two sibs
or parents, their transmission patterns within families in this analysis was not wholly an arbitrary decision,
were consistent with recessive inheritance. For reces- however, because their inclusion should provide the
sive inheritance, the expected correlation between sibs best lifetime data regarding the development of OC
would be 0.25 and between parents and children it would symptoms.
approach zero. Consequently, it is not surprising that The results of the segregation analyses should be
the correlations observed for those factors were small viewed with caution. For example, because FACTORS 1
and, given the size of our current sample, not statisti- and 2 are known to be associated with tic disorders,
cally significant. the ascertainment of the sib pairs was not comple-
tely unbiased with regard to two of these quantitative
phenotypes. In addition, the estimates of allele fre-
Limits
quencies are uniformly high (0.29–0.85) and may re-
Although much of the available data are promising, flect some aspect of the unique ascertainment of this
there are many questions yet unanswered concerning sample. In addition, given that the factor scores for
the value of a dimensional approach in OCD and related FACTORS 1, 2, and 3 were inter-correlated, future
disorders. Principal among these is how best to measure analyses should endeavor to estimate the unique vari-
these dimensional traits in patients and populations. ance for each factor as well as the common variance
Among patient populations the factor structure for these for all four. These residual variances and the common
OC symptom dimensions has been remarkably consis- variance could then be used as quantitative phenotypes
tent across at least six large studies [Leckman et al., in future segregation and linkage analyses using larger
1997, 2001; Mataix-Cols et al., 1999; Summerfeldt et al., data sets.
1999; Cavallini et al., 2002]. The results of the present
study offer additional support for the validity of these
CONCLUSIONS
symptom dimensions. These symptom dimensions ap-
pear to be relatively stable over 2-year intervals in Common disorders with genetic susceptibilities are
adults [Mataix-Cols et al., 2002], but similar studies likely to involve the action of multiple genes interact-
have yet to be carried out in younger OCD patient ing with each other and with environmental factors,
groups. Studies of normal populations have yet to be making it difficult to localize the specific genetic loci
completed although data from normally developing chil- responsible. An important route to the disentangling of
dren are consistent with the orderly emergence of these this complex inheritance may be through the study of
traits [Evans et al., 1997; Zohar and Felz, 2001]. normal variation in quantitative psychological traits.
It is also possible that the observed associations Studies of the symptoms of OCD have led to the identi-
between the sib pairs and the mother-child dyads is fication of at least four such traits. A preliminary study
due in part to a measurement bias in that the mothers of OCD probands has found evidence that at least two
typically served as the primary informant in the study. of these factors may be useful in family aggregation
We believe, however, that this may not be a major factor. studies. This study confirms the promise of these
First, these associations were generally stronger when factors, particularly in patients at high risk for GTS.
the analyses were confined to the older sib pairs. Second, Genome scans are currently underway to utilize these
the observed associations were generally not present for quantitative OC phenotypes in multipoint linkage ana-
FACTOR 3, contamination obsessions and cleaning lyses [Zhang et al., 2002]. Further, if OCD proves to be a
compulsions, traits that would likely be subject to the multidimensional and etiologically heterogeneous con-
same biases. Third, the requirement that an experi- dition, it may be used to develop ‘‘state’’ as well as ‘‘trait’’
enced clinician validate each symptom also insured the assessment instruments based on these symptom
highest standard of accuracy. Finally, the possibility dimensions [Leckman et al., 2000]. Such scales could
that these findings are the result of non-genetic trans- then be used in clinical trials to quantify more precisely
mission cannot be excluded given the design of this the patterns of treatment response. The factors asso-
study. ciated with an unfavorable treatment response remain
Other issues include the accuracy of the four-factor largely unknown. Although global ratings of pretre-
solution with some investigators suggesting that FAC- atment symptom severity appear not to be a useful
TOR 1 is divisible within two separate domains: aggres- predictor of response [Steketee, 1993; Ackerman et al.,
sive obsessions and related checking compulsions vs. 1994], the differential patterns of response for OCD
obsessions with either sexual or religious content patients with hoarding symptoms emphasize the po-
[Mataix-Cols et al., 1999]. tential value of separate severity scales for separate
Future studies using a larger collection of sib pairs symptom dimensions.
will also need to examine gender-specific associations With regard to GTS, these results are consistent
(mother–son, mother–daughter, father–son, father– with the high rate of OC symptoms reported in GTS
daughter) in an effort to replicate these findings as well families [Pauls and Leckman, 1986; Pauls et al., 1991;
as evaluate possible parent-of-origin effects (genetic Leckman et al., 1997; Swerdlow et al., 1999; Robertson,OC Traits Among Tourette Family Members 67
2000] and may aid in the identification of autosomal support to the investigators and without whose help the
genes that predispose individuals to both GTS and study would not have been possible: J. Tanner, K. Lynch,
specific forms of OCD [Pauls and Leckman, 1986; H. Grantz, E. Shepherd, S. Soules, and R. Makuch
Robertson and Gourdie, 1990; Eapen et al., 1993; Gardos (Child Study Center, Yale University School of Medi-
et al., 2001]. cine and Department of Epidemiology, Yale University
These dimensions may also be of heuristic value in School of Public Health); T. Amos and J. Brown
the context of evolutionary perspectives on psycho- (Departments of Psychiatry and Neurology, Johns
pathology and the emergence of related behaviors across Hopkins University School of Medicine, Baltimore);
the OCD spectrum including eating disorders, body C. Mortimore (The National Hospital for Neurology
dysmorphic disorder, autism, and Prader-Willi syn- and Neurosurgery, Queen Square, London); C.M. Casti-
drome as well as during the course of normal develop- glione, Departments of Genetics and Psychiatry, Yale
ment [Evans et al., 1997; Leckman and Mayes, 1998; University School of Medicine); G. Strand (Norwegian
Bienvenu et al., 2000; Zohar and Felz, 2001; Halmi et al., Center for ADHD, Tourette Syndrome and Narcolepsy,
in press]. Oslo); G. Breedveld and L. Testers (Department of
Clinical Genetics, Erasmus University, Rotterdam); and
F. Filloux, H. Coon, and A. Peiffer (Departments of
ACKNOWLEDGMENTS
Psychiatry, Neurology, and Human Genetics, Univer-
This article is dedicated to the memory of Donald sity of Utah School of Medicine, Salt Lake City). This
J. Cohen, MD, and Arnold J. Friedhoff, MD. Both were work was funded by contributions from members of the
lifelong supporters of the Tourette Syndrome Associa- National Tourette Syndrome Association in the United
tion (TSA) and the search for GTS vulnerability genes. States. Additional funding was provided by the Tourette
Members of the TSA International Consortium for Syndrome Foundation of Canada and by grants from the
Genetics includes D.L. Pauls (Consortium Principal National Heart, Lung and Blood Institute (Mammalian
Investigator) Massachusetts General Hospital and Genotyping Service) and the National Institutes
Harvard Medical School, Boston. The other members of Health (NS-40024-01, MH-493515, NS-16648,
listed alphabetically by site are: J.T. Walkup, J. Guliano, MH-00508 [a Research Scientist Award to D.L.P.],
H.S. Singer, and M.A. Riddle, Departments of Psychia- MH-30929, RR-00044, RR-00125, NS-07338, DA-
try and Neurology, Johns Hopkins University School of 12468, and AA-12044).
Medicine, Baltimore; M.M. Robertson, Department of
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