Am. J. Hum. Genet.
57:682-689, 1995
Intermediate Inheritance of Tourette Syndrome, Assuming
Assortative Mating
Sandra J. Hasstedt,' Mark Leppert,' Francis Filloux,2,3 Ben J. M.
William M. McMahon4'5
Departments of 'Human Genetics, 'Neurology, 3Pediatrics, and 4Psychiatry, University of Utah, and 5Primary Children's Hospital, Salt Lake City; and
6Department of Psychiatry, University Hospital Rotterdam, Rotterdam
Summary
Segregation analysis incorporating assortative mating
was used to test for major locus inheritance of Tourette
syndrome in a single large pedigree containing 182 mem-
bers. The analysis provided evidence of a major locus
with an intermediate inheritance pattern for which the
penetrance was estimated from the data as 28% in het-
erozygotes and 98%-99% in homozygotes. A signifi-
cant assortative mating correlation was estimated from
the data as 70%-79%. In contrast, when assortative
mating was not included in the model, intermediate in-
heritance was not inferred. If, in addition, constancy of
the allele frequencies across generations was not as-
sumed, Mendelian transmission was rejected. Each sub-
ject, affected or unaffected, was assigned a score re-
flecting the presence and severity of symptoms. Higher
mean scores in affected homozygotes than in affected
heterozygotes suggested greater severity in homozy-
gotes: genotype information was obtained from geno-
type probabilities computed assuming intermediate in-
heritance.
Introduction
Tourette syndrome (TS) is a movement disorder charac-
terized by motor and vocal tics (Robertson 1989; Su-
chowersky 1994). Onset usually occurs between the ages
of 2 and 15 years, with age 7 years the most common;
many cases improve or remit by adulthood. Community
surveys estimated the prevalence of TS in Monroe
County, New York as 3/10,000 (Caine et al. 1988), in
North Dakota as 5/10,000 in juveniles (Burd et al.
1986b), 0.5/10,000 in adults (Burd et al. 1986a), in
Israel as 4/10,000 in adolescents (Apter et al. 1992), and
in New Zealand as 0.7/10,000 in juveniles (Robertson
et al. 1994). In contrast, school-based surveys have esti-
Received January 31, 1995; accepted for publication May 25, 1995.
Address for correspondence and reprints: Dr. Sandra J. Hasstedt,
Department of Human Genetics, University of Utah, 2100 Eccles Insti-
tute of Human Genetics, Salt Lake City, Utah 84112.
K 1995 by The American Society of Human Genetics. All rights reserved.
0002-9297/95/5703-0019$02.00
682
van de Wetering,6 and
mated much higher prevalences (Comings et al. 1990;
Kurlan et al. 1994).
Dominant inheritance with incomplete penetrance is
widely, but not universally, accepted as the mode of
inheritance of TS (Pauls 1992b). The alternative pro-
posal comprises "semidominant inheritance," with
higher penetrance in affected homozygotes than in het-
erozygotes (Comings et al. 1984, 1989; Devor 1984).
The different conclusions may reflect disagreement over
which other diagnoses reflect alternate expressions of
the TS gene. Obsessive-compulsive disorder (OCD) and
chronic tics are accepted as alternate expressions (Pauls
et al. 1991; Pauls 1992a); many other disorders have
also been proposed (Comings 1987) and supported
(Pauls et al. 1993) or disputed (Pauls et al. 1994). Link-
age studies assuming dominant inheritance of either TS
and/or chronic tics have failed to localize the TS gene;
approximately 80% of the genome has been excluded
(van de Wetering and Heutink 1993).
Here we report the reanalysis of one large TS pedigree
for which previous segregation analysis rejected Mende-
lian transmission (McMahon et al. 1992). The frequency
of TS in spouses of descendants of the pedigree founder
greatly exceeds the frequency of TS in the population.
Since an excess of affected spouses may indicate assorta-
tive mating, the present analysis adds an assortative mat-
ing correlation to the genetic model. In addition, the
severity of disease in each subject was assessed, and the
resulting TS score was evaluated as a measure of liability
to TS.
Subjects and Methods
Kindred 1591 comprises the descendants of a man
who lived from 1894 to 1954; the pedigree was ascer-
tained through the founder's 10-year-old grandson, who
presented with chronic multiple motor and vocal tics. Of
500-600 living descendants, we studied 182, including
descendants of 5 of the founder's 10 wives. Extensive
review of genealogical records ruled out consanguinity
between spouses. McMahon et al. (1992) described the
pedigree in detail. This study was approved by the Insti-
tutional Review Board of the University of Utah. In-
formed consent was obtained directly from each adult
Hasstedt et al.: Tourette Syndrome Inheritance
Table I
Number of Points Added to the TS Score,
by TS Symptom Observed
TS Symptom
One or more complex tics, by history .....................5...
Vocal tics other than throat clearing or cough, by
history .......... ........................... 5
Need to touch ............. ........................ 5
Echolaliaa ...................... ........................... 5
Echopraxiab ................................................. 5 stedt 1994), and the maxima obtained with NPSOL (Gill
Waxing-and-waning pattern ..................................... 5
Palilaliac ......... ............................ 2
Self-injurious behavior ............................... ...... 3
a
b
Repetition of another's words or phrases.
Imitation of gestures.
c Repetition of one's own words or phrases.
participant. Parents provided consent for children >18
years of age, with additional assent provided by partici-
pants between the ages of 12 and 18 years.
Each subject was assessed by at least one research
physician expert in the diagnosis of TS and associated
conditions; for each child, a parent was also interviewed.
Because of the geographic isolation and large size of the
pedigree, interviewers were not blinded to the subject's
position within the pedigree. Information about symp-
toms of Tourette and other tic disorders was obtained
through a structured interview utilizing modifications of
the Yale Global Tic Severity Scale (Leckman et al. 1989)
and the Shapiro Checklist (Shapiro et al. 1978). Diag-
nostic classification was then assigned according to re-
search criteria based on the Diagnostic and Statistical
Manual of Mental Disorders, III revised (APA 1990)
and developed for TS genetic linkage studies (Tourette
Syndrome Classification Study Group 1993).
Since normal human behavior includes repetitive
movements, which may be difficult to discriminate from
mild single tics, we devised a scoring system to help
categorize cases as "unaffected," "uncertain," or "af-
fected." Symptoms used in the scoring system derived
from the TS literature, particularly from descriptions of
two large TS families in which the authors proposed
characteristics that discriminate affected from unaf-
fected individuals. Kurlan et al. (1986) reported that
only the affected members of a large Mennonite family
expressed three clinical features: coprolalia (obscene or
forbidden speech), echolalia (repeating speech of oth-
ers), and echopraxia (repeating gestures or movements
of others). Robertson and Gourdie (1990) identified ar-
ithmomania (counting), echolalia, echopraxia and self-
injurious behavior as significantly more common in af-
fected than unaffected members of a British family with
122 members. Using these reports, combined with clini-
683
cal judgment, we determined points for individual symp-
toms as listed in tables 1 and 2. For each subject, we
summed the points corresponding to each observed
symptom and added the total to the number of tics,
Points either observed during the examination or reported by
the subject, to obtain a TS score.
To test for major locus inheritance of TS, we applied
segregation analysis, which uses likelihood procedures,
to test for statistical evidence of a gene (Elston and Stew-
art 1971). Likelihoods were computed using PAP (Has-
et al. 1986). We did not correct for ascertainment
through the proband, since the analysis fixed the preva-
lence of TS and therefore the probability of ascertain-
ment by the method of Thompson and Cannings (1980).
Hypothesis testing compared the likelihood of a sub-
model to the likelihood of a more general model. Under
certain conditions, -2 multiplied by the natural loga-
rithm of the ratio of the likelihoods has an asymptotic
X2 distribution.
The model used in this analysis assumed that the ex-
pression of TS reflects a high value on an unmeasured
quantitative liability scale. Liability, in turn, resulted
from the independent effects of a major locus with a
large effect, additive polygenes each with a small effect,
and random environmental factors. The population
prevalence determined the liability threshold above
which TS is expressed. The major locus had two alleles
and three genotypes, where genotype 1 designates ho-
mozygotes lacking the TS allele, genotype 2 designates
heterozygotes, and genotype 3 designates homozygotes
for the TS allele. The polygenic and random environ-
mental components distributed normally. We assumed
that phenotypic assortative mating produced a correla-
tion between the unmeasured quantitative liabilities of
spouse pairs. This correlation was assumed to be con-
stant across the range of the liability scale, consistent
with spouse pairs mating assortatively by phenotype
rather than by genotype; that is, spouses showed similar
liabilities, which does not imply the same major locus
Table 2
Number of Points Added to the TS Score,
by Obsessive-Compulsive Symptoms Observed
Obsessive-Compulsive Symptom Points
Counting........................................................................ 5
Spelling .......... ............................. 5
Other positive screen for obsessive-compulsive disorder 3
YBOCS' score >10 .................... ................... 8
Observed obsessive-compulsive symptoms denied by
patient .......... ............................. 5
a Yale-Brown Obsessive Compulsive Scales (Goodman et al. 1989).
684 Am. J. Hum. Genet. 57:682-689, 1995

Table 3
Counts of Pedigree Members, by TS Score and Diagnostic Category

TS SCOREb
DIAGNOSTIC
CATEGORYa 0 1-5 6-10 11-15 16-20 21-30 31-40 41-50 51-60 61+

A-1 ........... 0 0 0 5 6 15 12 10 7 2
A-2 ........... 0 0 1 0 2 5 1 1 1 0
B-1 ........... 0 4 6 2 2 2 0 0 0 0
B-2 ........... 0 3 1 4 3 0 0 0 0 0
C-1 ........... 0 6 0 0 1 0 0 0 0 0
C-2 ........... 0 3 3 1 0 0 0 0 0 0
D-2 ........... 0 0 1 0 0 0 0 0 0 0
E-1 ........... 0 1 0 1 1 0 0 0 0 0
E-2 ........... 0 4 1 0 1 0 0 0 0 0
F ...... ..... 0 2 2 0 0 0 0 0 0 0
Uncertain .......... 1 9 6 0 0 0 0 0 0 0
Unaffected ......... 32 11 0 0 0 0 0 0 0 0
a A-1 = definite Tourette; A-2 = Tourette by history; B-1 = definite multiple chronic motor tics (CMT) or chronic phonic tics (CPT); B-2
= multiple CMT or CPT by history; C-1 = definite single CMT or CPT; C-2 = single CMT or CPT by history; D-2 = transient tic disorder
by history; E-1 = definite nonspecific tic disorder; E-2 = nonspecific tic disorder by history; F = definite tic disorder, diagnosis deferred.
bSee text for definition.

genotype but may result from disparate contributions
of polygenes and random environmental factors to dif-
ferent major locus genotypes. We also assumed that as-
sortative mating had remained constant sufficiently long
to allow the population frequencies to have reached
equilibrium. Consequently, the genotype and mating fre-
quencies reflected the level of assortative mating. Posi-
tive assortative mating increases the frequency of homo-
zygotes at the expense of heterozygotes (Hasstedt 1995).
The parameters of the model include allele frequency,
q, dominance, d, displacement, t, polygenic heritability,
h2, assortative mating correlation, a2, and transmission
probabilities, T1, T2, and T3. Dominance d = (J2 - 1)/
(J3 - gi), where gi represents the mean for genotype i;
t = (p3 - gl)/a, where a2represents the within-genotype
variance; h2 represents the proportion of (2 attributed
to polygenes; and a2 represents the correlation between
spouses in liability due to assortative mating (Hasstedt
1995). Transmission probability xi represents the proba-
bility a parent of genotype i transmitting the non-TS
allele; to assume allele frequency equilibrium, we let T2
= (P - fIT1 - f3t3)/f2 where p = 1 - q and f, represents
the equilibrium frequency of genotype i; the allele fre-
quency equilibrium assumption restricts the general
model to values of the transmission probabilities which
maintain a constant allele frequency through the genera-
tions. For h2 > 0, the likelihoods were approximated
(Hasstedt 1993).
We inferred major locus inheritance, by rejecting
polygenic inheritance and not rejecting Mendelian trans-
mission. We tested polygenic inheritance (q = 0; d = 0;
t = 0; T1 = 1; '2 = 1/2; 3 = 0) by comparing its likelihood
to the likelihood of Mendelian transmission (t1 = 1; T2
= 1/2; T3 = 0). We tested Mendelian transmission
= 1; T2 = '/2; 3 = 0) by comparing its likelihood with the
(t1
likelihood of the general model (T1, T2, and r3 estimated).
Other hypotheses tested included dominant inheritance
(d = 1), recessive inheritance (d = 0), no polygenic com-
ponent (h2 = 0), and no assortative mating correlation
(a2 = 0), each of which compared the likelihood of the
specified model with the likelihood of Mendelian trans-
mission, while fixing 1 = 1, T2 = 1/2, and t3 = 0.
To estimate the effect of the TS major locus on TS
score, we used genotypic probability estimators (GPEs)
(Hasstedt and Moll 1989). The genotypic probability pi
equals the likelihood conditioned on individual i car-
rying genotype j divided by the unconditional likelihood,
each computed with the parameters fixed at their maxi-
mum likelihood estimates. The GPE of the mean for
genotype j equals I-= V 1 P# y Jij, where yi represents
the TS score of person i, and Ay = V_1 Pi
Results
We examined 168 descendants of the pedigree
founder and 14 spouses of the descendants. TS Scores
ranged from 0 to 69. In table 3, TS scores are compared
with diagnostic categories (Tourette Syndrome Classifi-
cation Study Group 1993) for subjects in the study. Only
six individuals assigned a TS diagnosis (A-1 or A-2)
scored <16; ten individuals assigned tic diagnoses (B-
1, B-2, C-1, E-1, and E-2) scored >16, because of the
additional presence of obsessive-compulsive symptoms.
In table 4, pedigree members are tallied by TS score.
Hasstedt et al.: Tourette Syndrome Inheritance 685
Table 4 Table 6
Counts of Juvenile and Adult Descendants and of Spouses Parameter Estimates for the Inferred Genetic Model
of Descendants, by TS Score
PREVALENCE OF TS
Juvenile Adult Spouses of
TS Scorea Descendantsb Descendantsc Descendants PARAMETERa 5/1,000 .5/1,000
0 ............... 22 8 3 q ....... 8.959 X 10-3 9.016 X 10-4
1-5 ........... 18 21 4 [2 ................ 8.109 x 10-3 9.872 X 10-4
6-10 ......... 10 10 1 f3 ................ 4.905 X 10-3 4.080 X 10-4
11-15 ....... 8 4 1 a ....... .792 .699
16-20 ....... 7 8 1 Pi............... 0 0
21-30 ....... 13 8 1 P2 ............... 28 28
31-40 ....... 7 4 2 P3 ............... 99 98
41-50 .......5 1
51-60 ....... 7 1 0
a
q = allele frequency; [2 = equilibrium frequency of genotype 2;
61+ . .......... 1 1 0 f3 = equilibrium frequency of genotype 3; a2 = assortative mating
correlation; Pi = penetrance of genotype i.
a TS score > 16 signifies affected status; TS score s 15 signifies unaf-
fected status.
bAge s19 years.
c Age
(d = 1) inheritance, implicating an intermediate form
>20 years.
of inheritance for TS. In addition, correlation due to
assortative mating was significant (hypothesis a2 = 0
rejected), but polygenic inheritance was not significant
Only 30 descendants and three spouses of descendants (hypothesis h2 = 0 not rejected).
received a score of 0, signifying the absence of any symp- Table 6 presents the parameter estimates of the in-
tom. Considering a TS score of > 16 points as TS, 67 ferred genetic model for each assumed prevalence rate;
descendants and 5 spouses of descendants were thereby only the allele and genotype frequency estimates depend
diagnosed with TS. Of the 72 individuals diagnosed with substantially on the assumed prevalence rate. The geno-
TS, 38 were male and 34 were female; age ranged from type frequency estimates differ from Hardy-Weinberg
7 to 66 years. equilibrium because of the assortative mating. The pene-
In the likelihood analysis, studied individuals were trances are essentially the same for the two prevalence
classified only as affected (TS score : 16) or unaffected rates, with no sporadic cases, low penetrance in hetero-
(0 TS score 15). We constrained the parameters of
- -
zygotes, and almost complete penetrance in homozy-
the model to conform to the population prevalence of gotes. The estimates in table 6 predict that only 32%-
TS; because of uncertainty about the prevalence, we per- 41% of TS cases in the population are heterozygotes.
formed the analysis twice, assuming population preva- Despite the significance of the assortative mating cor-
lence rates of 5/1,000 and 0.5/1,000. For both preva- relation, we repeated the analysis, assuming random
lence rates, we inferred major locus inheritance of TS mating in order to explore the impact of including as-
(table 5) by rejecting purely polygenic inheritance (q sortative mating in the analysis. We again inferred major
= 0) and not rejecting Mendelian transmission (X1 1; = locus inheritance (table 7) by rejecting purely polygenic
X3 = 0). We rejected both recessive (d = 0) and dominant
Table 7
Table 5 Chi-square Statistics for the Tested Hypotheses,
Assuming Random Mating
Chi-square Statistics for the Tested Hypotheses
PREVALENCE OF TS
PREVALENCE OF TS
HYPOTHESIS df 5/1,000 .5/1,000
HYPOTHESIS df 5/1,000 .5/1,000
q =0 ......................... ...... 3 16.25a
34.03a
q =0 .................... 3 65.76a 107.33a T1 1; T3 = 0 ....................... .28 2.00
T1= 1;T3 = 0 ............ 2 .12 .76 Tl= 1; -r2 = 1/2, T3 = 0 .............. 3 17.29a43.45a
d = 0............... 1 35.87a 44.63a d =0 .......... ............. 1 0.00 17.16a
d =1 ....... ....... 1 23.SOa 20.10a d = 1 ....................... ....... 1 3.068.18a
h2= 0 .................... 1 3.04 1.02 = 0 .......................... .... 1 1.224.35b
a2 = .................... 1 49.50a 73.30a
P < .005.
ap < .005. bp< .05.
686
Table 8
Mean' TS Score, by Genotype
TS
PREVALENCE OF TS DIAGNOSIS
5/1,000 .............. Unaffected
Affected
.5/1,000 ............. Unaffected
Affected
NOTE.-Numbers in parentheses represent numbers of individuals.
a Computed as genotypic probability estimators.
inheritance (hypothesis q = 0 rejected) and not rejecting
Mendelian transmission (X1 = 1; T3 = 0). However, in
contrast to the inference of intermediate inheritance in
the presence of assortative mating, we inferred recessive
inheritance for a prevalence rate of 5/1,000 and inferred
dominant inheritance for a prevalence rate of 0.5/1,000.
The inferred recessive model for a prevalence rate of 5/
1,000 combined a high allele frequency (31%), a low
penetrance (5%), and a large polygenic component
(100%). These unreasonable parameter estimates sug-
gest the inability of the proposed model to fit the data
rather than recessive inheritance of TS. When not assum-
ing allele frequency equilibrium, we rejected Mendelian
transmission (X1 = 1; X2 = 1/2; X3 = 0).
We assigned TS scores, rather than simply a TS diag-
nosis, in the hope that the TS scores would reflect liabil-
ity to TS. Table 8 gives mean TS score by genotype for
the intermediate model inferred, on allowing for assorta-
tive mating. For affected subjects (TS score > 16), ho-
mozygotes for the TS allele have a higher mean TS score
than do heterozygotes. In contrast, TS scores in unaf-
fected subjects (TS score 15) fail to distinguish hetero-
-
zygotes from homozygotes lacking the TS allele.
Discussion
Herein, we inferred a gene for TS in a single large
pedigree, Kindred 1591. The gene showed intermediate
inheritance with high penetrance in homozygotes for
the TS allele, low penetrance in heterozygotes, and zero
penetrance in non-gene-carriers. Polygenic heritability
was nonsignificant. The inferred genetic model included
a large assortative mating correlation. Compared with
random mating, positive assortative mating increases the
frequency of homozygotes at the expense of heterozy-
gotes. Consequently, we inferred a low allele frequency
but estimated that only 32%-41% of TS cases occur in
heterozygotes, in contrast to the high allele frequency
and predominance of heterozygotes predicted previously
for intermediate inheritance (Comings et al. 1989). All
Am. J. Hum. Genet. 57:682-689, 1995
GENOTYPE
1 2 3
4.38 (21) 3.94 (85) 4.91 (4)
... 26.72 (5) 33.59 (67)
4.18 (26) 3.97 (80) 5.10 (4)
... 28.85 (11) 33.89 (61)
conclusions held, regardless of the assumed population
prevalance.
In contrast to the inference of intermediate inheritance
in this study, many other investigators have inferred
dominant inheritance of TS (Pauls 1992b). One possible
explanation is that, in the families analyzed previously,
all TS cases were heterozygotes; although we estimated
that less than half of TS occurs in heterozygotes, the
proportion would be higher in a population with a lower
level of assortative mating. Alternatively, dominant in-
heritance may have been inferred erroneously in other
studies because of the failure to account for assortative
mating. In fact, we inferred dominant inheritance for
this pedigree when assuming random mating and the
rarer prevalence. On the other hand, Comings et al.
(1984) and Devor (1984) inferred intermediate inheri-
tance despite assuming random mating. Nevertheless,
when we assumed random mating, we rejected Mende-
lian transmission, as we did in a previous analysis of this
pedigree (McMahon et al. 1992) and other investigators
have in the analysis of other pedigrees (Curtis et al.
1992).
As stated above, the assumption of random mating
lead to the inference of a different genetic model than
did the assumption of assortative mating. On the other
hand, random mating probably obtains for most traits,
and, even in the presence of significant assortative mat-
ing, the assumption of random mating does not neces-
sarily lead to the incorrect inference (Hasstedt 1995).
Therefore, one should consider accounting for assorta-
tive mating in the segregation analysis of physical or
psychological traits, but the standard assumption of ran-
dom mating may suffice, unless the estimated assortative
mating correlation is high.
Assortative mating comprises only one possible expla-
nation of the occurrence of affected spouse pairs. First,
a high disease prevalence offers an alternative explana-
tion; however, an extremely high prevalence would be
required to account for TS occurring in 36% of the
spouses marrying into Kindred 1591. Second, ascertain-
Hasstedt et al.: Tourette Syndrome Inheritance
ment through severe TS cases who are homozygotes,
making both parents heterozygotes and sometimes af-
fected, provides a plausible explanation for bilineality
(both parents affected) in nuclear families (Comings et
al. 1989) but an inadequate explanation for an excess
of affected spouses marrying into a large pedigree such
as Kindred 1591. Finally, causative environmental fac-
tors that are shared by spouses could produce an excess
of affected spouse pairs. However, this explanation
would not apply to TS, for which onset occurs long
before age of marriage. Assortative mating remains the
only defensible explanation of the high rate at which
affected spouses marry into Kindred 1591 and concurs
with the assortative mating reported for many psycho-
logical traits and psychiatric disorders (Merikangas
1982; Parnas 1985, 1988).
Whether the assortative mating inferred herein occurs
in all TS pedigrees remains an open question. Answering
the question requires that all spouses who marry into
TS pedigrees be evaluated for TS directly rather than by
history provided by family informants. Other investiga-
tors have previously recommended that direct interview
of the subject be used to make the diagnosis, since inter-
views of relatives produce fewer positive diagnoses of
neuropsychiatric disorders (Andreason et al. 1977; Or-
vaschel et al. 1982; Pauls et al. 1984). In fact, the cooc-
currence of assortative mating and a low heterozygous
penetrance suggests the prudence of interviewing not
only the spouses but also their relatives.
Blinding interviewers about pedigree membership is
methodologically desirable. This could best be accom-
plished by videotaping diagnostic interviews for later
scoring by raters unaware of pedigree membership. Is-
sues of practicality, expense, and family sensitivity to
intrusion precluded applying this approach to this pedi-
gree.
In this study, as part of the interview of each subject,
a score was assigned in an attempt to quantitate the
severity of the subject's TS symptoms. The scoring sys-
tem necessarily reflects clinical judgment about the rela-
tive importance of disparate symptoms. Therefore, the
numeric value of the score assigned a subject may not
unerringly reflect his or her underlying liability resulting
from genes or environmental factors. One measure of
the success of the scoring system is by comparison with
the liability assumed in the genetic model. The model
predicts that mean liability to TS ranges from lowest to
highest across the four groups: (1) non-gene-carriers,
(2) unaffected heterozygotes, (3) affected heterozygotes,
and (4) homozygotes. In fact, mean TS score does in-
crease from groups (3) to (4), suggesting that greater
severity results from possessing two copies of the TS
allele. Mean TS score also increases from groups (2) to
(3), but by definition, since affection corresponded to a
TS score of 16. The failure of mean TS score to in-
-
687
crease from groups (1) to (2) suggests that nonzero TS
scores at the lower end of the range do not reflect liabil-
ity as reliably as at the upper end of the range, possibly
because chronic tics occur frequently in the absence of
a TS gene (Pauls and Leckman 1986; Price et al. 1988).
Therefore, a TS score only partially reflects liability
to TS.
The wide range of TS scores observed implicates other
genes or environmental factors in the expression of the
TS gene. Although a homozygous penetrance estimated
as 98%-99% suggests that possessing two copies of the
TS allele essentially assures the expression of TS, severity
nevertheless varies within the genotype. Furthermore, a
heterozygous penetrance estimated as 28 % suggests that
a single copy of the TS allele results in the expression
of TS only on interaction with other genes or environ-
mental factors. The observed discordance in monozy-
gotic twins implicates environmental factors (Price et al.
1985), and a lower birth weight in the MZ twin with
the higher tic score (Hyde et al. 1992) suggests that
prenatal environmental factors play a role in TS expres-
sion. Nonetheless, roles for postnatal environmental fac-
tors or for other genes remain possibilities; streptococcal
infection may be an environmental trigger for TS (Kies-
sling et al. 1993; Swedo et al. 1993). In fact, despite
various hypotheses (Comings and Comings 1986;
Lichter et al. 1993; Furtado and Suchowersky 1994),
the genes or environmental factors influencing the devel-
opment of TS remain unknown. In addition, phenocop-
ies are likely in the population; although we estimated
a penetrance of zero in non-gene-carriers, this pedigree
contains little information about this penetrance.
One source of variable expressivity of TS, gender, has
recently been questioned. Earlier population surveys re-
ported male-to-female ratios of 9 in juveniles (Burd et
al. 1986b; Caine et al. 1988) and of 3-4 in adults (Burd
et al. 1986a), but a recent survey reported a lower ratio
of 1.6 in adolescents (Apter et al. 1992), similar to recent
family studies (Curtis et al. 1992; Eapen et al.1993).
The decline in the male-to-female ratio follows the inclu-
sion in the TS diagnosis of OCD, which is more common
in women. The inclusion of OCD essentially equalizes
the numbers of affected males and females (Pauls et al.
1991). Kindred 1591 contains approximately equal
numbers of male and female TS cases; the male-to-fe-
male ratio equals 1.1.
The rejection of Mendelian transmission in a segrega-
tion analysis does not rule out major locus inheritance,
since factors such as age trends and inadequate ascer-
tainment correction are alternate causes. The assump-
tion of allele frequency equilibrium (p = f1tl + f2T2
+ ft3) reduces the chances of the alternative causes of
rejection but may be too restrictive. For one thing, for
rare q, the equilibrium constraint restricts t1 to values
close to 1. Possibly as a consequence, the equilibrium
688
assumption allowed the inference of dominant (low
prevalence) or recessive (high prevalence) inheritance of
TS when assuming random mating, despite the rejection
of Mendelian transmission in the absence of the equilib-
rium assumption and the inference of intermediate in-
heritance on assuming assortative mating. Nevertheless,
for assortative mating, allele frequency equilibrium fol-
lows logically from the assumption of genotype fre-
quency equilibrium and from the dependence of the ge-
notype frequencies on both the transmission probabili-
ties and the allele frequencies. Consequently, we tested
Mendelian transmission in the presence of assortative
mating only while assuming allele frequency equilib-
rium, possibly not adequately challenging the genetic
model. In contrast, allele frequency equilibrium was not
assumed in analysis of other traits showing lower levels
of assortative mating (Hasstedt 1995).
If the genetic model inferred herein applies to all in-
herited TS, the failure to localize the TS gene (van de
Wetering and Heutink 1993) could result from the in-
correct assumption of rare dominant inheritance in the
linkage analysis; affected offspring who inherit a TS al-
lele from the parent who marries into the pedigree would
appear to be recombinants with a linked marker, when
rare dominant inheritance is assumed. Repeating the
linkage analysis by assuming other modes of inheritance,
for example recessive inheritance, might allow the dem-
onstration of linkage. Also, eliminating all bilineal nu-
clear families from the linkage study lessens, but, be-
cause of the low heterozygote penetrance, does not elim-
inate, the chance that multiple TS alleles occur in one
pedigree. We estimated that 5-7/9 unaffected spouses
marrying into Kindred 1591 carry a TS allele, although
this high proportion may be an artifact of the assump-
tion of a spouse correlation in liability. Using the model
inferred herein in the linkage analysis would allow the
pedigree to contain multiple copies of a TS allele at a
single locus. On the other hand, single-locus inheritance
was an untested assumption of the analysis; a different
locus may underlie the TS in each affected spouse; if
true, in Kindred 1591 and possibly other large pedigrees
(Kurlan et al. 1986; Robertson and Gourdie 1990) dif-
ferent TS cases could result from TS alleles at different
loci, producing locus heterogeneity within a single pedi-
gree. As a consequence, association studies (Nothen et
al. 1994) or affected-sib-pair linkage studies may pro-
vide the only chance of localizing the TS gene(s).
In summary, the assumption of assortative mating al-
lowed us to infer intermediate inheritance of TS in a
single large pedigree. Conclusions differing from those
of other family studies of TS can be attributed to differ-
ences in the analysis; the suggestion that the mode of
inheritance is not dominant, as previously assumed, may
explain the failure to localize the TS gene, despite exten-
sive effort (van de Wetering and Heutink 1993).
Am. J. Hum. Genet. 57:682-689, 1995
Acknowledgments
This research was supported by NIH grants MH0098 (to
W.M.M.) and HD17463 (to S.J.H.).
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