American Journal of Medical Genetics (Neuropsychiatric Genetics) 88:411–415 (1999)
Lithium Responsive Bipolar Disorder, Unilineality,
and Chromosome 18: A Linkage Study
G. Turecki,1* P. Grof,2 P. Cavazzoni,2 A. Duffy,2 E. Grof,2 R. Martin,3 R. Joober,1 G.A. Rouleau,1 and
M. Alda2
1
Centre for Research in Neuroscience, The Montreal General Hospital, McGill University, Montreal, Canada
Department of Psychiatry, University of Ottawa, Ottawa, Canada
3
Virginia Institute for Psychiatric and Behavioral Genetics, Medical College of Virginia, Richmond, Virginia
2
Over the last three years several studies
have investigated the hypothesis of linkage
between bipolar disorder and markers on
chromosome 18. Although independent
groups have reported positive results, it is
still not clear how these should be interpreted, as linkage spans a considerably
large segment of the chromosome. In this
study we have investigated linkage with
chromosome 18 markers in 19 families of
lithium-responsive bipolar patients, as a
way to select a more homogeneous population. In addition, we have investigated
whether there is evidence of a parent-oforigin effect as suggested by previous studies. Eleven markers spanning the whole
chromosome were typed and linkage analysis was carried out using parametric and
nonparametric methods. Analysis of the
whole sample provided nonsignificant linkage results. However, when the sample included only unilineal families, and was further stratified according to parental origin,
two chromosomal regions provided modestly positive lod scores. Maximum lod
scores of 1.04 (P = 0.001) at D18S53 and 0.87
(P = 0.045) at D18S61 were observed for maternal and paternal pedigrees, respectively.
Nonparametric analysis yielded similar results. In conclusion, our results are congruent with previous reports that suggest an
advantage of unilineal pedigrees in linkage
analysis of bipolar disorder and cannot rule
out a parent-of-origin effect in this genomic
region. Am. J. Med. Genet. (Neuropsychiatr.
Genet.) 88:411–415, 1999. © 1999 Wiley-Liss, Inc.
*Correspondence to: Gustavo Turecki, M.D., Centre for Research in Neuroscience, McGill University, The Montreal General
Hospital, Rm. L7-120, 1650 Cedar Ave., Montreal, Qc H3G 1A4,
Canada. E-mail: gustavo@bagel.epi.mcgill.ca
Received 19 February 1998; Accepted 5 October 1998
© 1999 Wiley-Liss, Inc.
KEY WORDS: bipolar disorder; unilineal
pedigrees; lithium; chromosome 18
INTRODUCTION
Bipolar disorder (BD) is a major psychiatric condition that affects up to 1% of the general population.
Genetic epidemiologic studies have consistently shown
that genetic factors play an important role in the etiology of BD. However, loci predisposing individuals to
this disorder have not been convincingly identified.
Several studies have investigated the presence of susceptibility loci for BD on chromosome 18. In 1994, Berrettini et al. initially reported linkage to markers on
chromosome 18p. A number of different groups have
since failed to replicate this finding [Maier et al., 1995;
Pauls et al., 1995; Claes et al., 1997; Detera-Wadleigh
et al., 1997]. Other reports have found positive linkage
results with markers located in the same [Stine et al.,
1995] or, notably, in different regions of chromosome 18
[Stine et al., 1995; Coon et al., 1996; DeBruyn et al.,
1996; Freimer et al., 1996;]. In addition, some studies
have reported that the evidence for linkage is stronger
in those pedigrees with paternal transmission of the
phenotype [Stine et al., 1995; Gershon et al., 1996;] [for
a complete review, see the report on the chromosome
18 workshop of the 1997 WCPG, Van Broeckhoven et
al., 1998].
Lack of replication of positive findings has clearly
been a major problem in linkage studies of psychiatric
disorders [Risch and Botstein, 1996; Turecki et al.,
1996]. Although the principles defining what should be
considered a replication in linkage studies of complex
traits are still under intense debate [Lander and Kruglyak, 1995; Curtis, 1996; Witte et al., 1996], the observation of positive results spanning large chromosomal
segments—which do not necessarily overlap—makes it
premature to conclude that a susceptibility locus for
BD lies on chromosome 18. Apart from lack of power of
individual negative studies to detect loci that account
for a small relative risk, difficulty in phenotype definition and genetic heterogeneity are two other important, and probably related issues, which may be re-
412
Turecki et al.
sponsible for part of the apparent inconsistency observed in these studies. Defining more objective and
genetically meaningful phenotypes may help overcome
part of the complexity and thus generate more reliable
findings [Tsuang et al., 1993]. We have been studying
bipolar patients with excellent response to lithium as a
method to reduce heterogeneity.
Lithium has been used in the prophylaxis and treatment of BD for almost half a century, and still remains
the first-choice prophylactic therapy [Schou, 1997]. Although lithium is considered specific for the treatment
of BD, with no comparable effect in other psychiatric
disorders, its effectiveness varies widely [Gitlin and
Altshuler, 1997]. There is convincing evidence that
lithium may be more effective in purer forms of BD,
with typical symptomatology and without comorbidity.
Typical patients who respond to lithium suffer from
primary affective disorder with a recurrent and episodic illness course, and a positive family history of
bipolar disorder [Grof et al., 1994]. There is also evidence that responders and nonresponders to lithium
treatment may differ in certain neuroendocrine parameters, such as the serotonergic and endorphin systems
[Grof et al., 1984]. In addition, family studies indicate
a higher recurrence risk for bipolar disorder among
relatives of patients who respond well to lithium treatment [Zvolsky et al., 1974; Mendlewicz et al., 1979;
Smeraldi et al., 1984; Grof et al., 1994]. Taken together, these findings suggest that response to lithium
may define a more homogeneous bipolar phenotype
with less genetic heterogeneity.
Here we report a linkage study using 11 dinucleotide
markers spanning the whole chromosome 18 in 19
families ascertained by lithium responsive bipolar patients, who were further grouped according to parental
origin.
MATERIALS AND METHODS
Subjects
Families for this study were ascertained through
probands affected with BD that were considered excellent lithium responders following stringent criteria applied prospectively (see criteria in Fig. 1). Probands
were recruited from the affective disorder clinics of the
Royal Ottawa Hospital and the Hamilton Psychiatric
Hospital, Canada. After obtaining informed consent,
all available relatives were personally interviewed by
two psychiatrists who were blind to the probands’ diagnoses. Overall, 19 families were included, comprising a total of 170 individuals (68 affected) interviewed
and sampled. Best estimate diagnoses were made by a
panel of experienced psychiatrists (other than the interviewers) who reviewed blindly the data from the
Schedule for Affective Disorders and Schizophrenia
(SADS-L) interviews [Endicott and Spitzer, 1978] and
available medical records. Diagnoses were based on the
Research Diagnostic Criteria (RDC) [Spitzer et al.,
1978]. Relatives were considered affected when they
met criteria for bipolar disorder, manic disorder,
schizoaffective disorder, or major recurrent depression
(with the additional criterion of functional incapacitation). Rates of psychopathology other than these disorders were notably low, but similar to the rates observed
in the general population. In addition, almost no comorbidity was observed. For instance, all probands had
exclusively BD diagnosis. Among relatives, only one
schizophrenia diagnosis was made. Panic disorder was
similarly rare. Because the majority of affected relatives were treated in different clinical facilities, where
treatment protocols are not research oriented, lithium
response could not be assessed in these subjects using
the same criteria used for probands. However, an approximate evaluation of the rate of lithium response
among those relatives who are treated with lithium
estimates that over 80% of affected relatives could be
considered responders.
Laboratory
Genomic DNA was extracted by a standard method
[Sambrook et al., 1989] from venous blood samples.
Eleven Généthon dinucleotide markers spanning the
whole chromosome 18 were investigated (see Tables
I–III). Polymerase chain reaction (PCR) was carried
out in a total volume of 12.5 ␮L containing 40 ng genomic DNA; 125 ng of each primer; 200 ␮M each of
dGTP, dCTP, and dTTP; 25 ␮M dATP; 1.5 ␮Ci
[35S]DATP; 0.5 units of Taq DNA polymerase (Bio/Can
Scientific, Ontario); and 2.0 ␮L of 10× buffer (Bio/Can
Scientific) with MgCl2 included in the final concentration of 1.5 mM. Samples were overlaid with mineral oil
and processed throughout 35 cycles of denaturation at
TABLE I. Results From Nonparametric Linkage Analysis.*
Fig. 1. Criteria used to diagnose bipolar patients as excellent lithium
responders.
Locus
Wzobs
P
NPL
P
D18S59
D18S476
D18S63
D18S62
D18S53
D18S56
D18S57
D18S487
D18S64
D18S61
D18S70
34.13
27.39
40.03
35.01
36.92
34.69
37.17
31.21
42.65
42.65
51.35
0.92
0.58
0.34
0.19
0.23
0.41
0.10
0.79
0.77
0.19
0.30
−0.90
−0.55
−0.30
−0.40
1.17
−0.25
0.11
−0.23
1.42
1.51
1.52
0.82
0.70
0.61
0.65
0.11
0.58
0.43
0.58
0.08
0.06
0.06
*WZobs: Weighted Z statistic from SimIBD. The weight used was 1/sqrt q).
NPL: GENEHUNTER’s nonparametric statistic.
Bipolar Disorder and Chromosome 18
413
TABLE II. Unilineal Pedigrees Subdivided According to Parental Origin.*
Paternal (n ⳱ 4)
Locus
Zmax
P
D18S59
D18S476
D18S63
D18S62
D18S53
D18S56
D18S57
D18S487
D18S64
D18S61
D18S70
0.35
0
0
0.67
0.81
0.36
0.70
0
0.17
0.87
0.66
0.01
Maternal (n ⳱ 4)
Model
Zmax
1
0
0.22
0
0
1.04
0
0.29
0
0.73
0.16
0
0.02
0.002**
0.11
0.02
1
1
3
1
0.19
0.045**
0.01
3
3
3
P
0.13
Total (n ⳱ 8)
Model
1,2
0.001**
3
0.16
1
0.03
0.18
2
2
Zmax
P
Model
0.26
0.19
0
0.11
1.35
0
0.99
0
0.52
0.64
0.10
0.14
0.19
1
1
0.26
0.01**
1
1
0.05
1
0.07
0.06
0.29
2
2
3
*Zmax, maximum lod score. Models: 1, dominant; 2, intermediate; 3, recessive. P value obtained empirically by simulating a nonlinked marker in 100 replicates.
**1,000 replicates were conducted.
94°C, annealing at the optimal temperature for the
specific marker, and elongation at 72°C, followed by a
final elongation period of 72°C. PCR products were
analyzed on a 6% denaturating polyacrylamide gel (38:
2 acrylamide:bisacrylamide). Samples were run for a
variable period in a vertical electrophoresis gel apparatus (Life Technologies, Inc., MD). Gels were dried
and exposed to X-ray films for 24 to 72 hr at room
temperature. All marker determinations were made
blind to clinical diagnoses.
Genetic Analysis
Power Calculation. To estimate the power of our
families to detect linkage, we have carried out simulations using the SLINK program [Ott, 1989; Weeks et
al., 1990]. The parameters assumed were dominant
mode of inheritance; disease allele frequency of 0.012;
sex-specific liability classes with penetrances of 0.4 and
0.7 for males and females, respectively; and no sporadic
cases. Linkage heterogeneity with 60 and 80% of the
families linked was also simulated. One thousand replicates were carried out with a five-allele linked
marker. The average maximum lod score observed in
the analysis of all families was 3.39 ± 1.60 (␪ ⳱ 0.05),
with 78.2 and 49% of the lod scores greater than 2.0 for
␣ ⳱ 0.8 and ␣ ⳱ 0.6, respectively. Empirical P values
were obtained using the SIMULATE program [Ott and
Terwilliger, 1992] and analyzing the replicates using
TABLE III. Nonparametric Linkage Analysis in Pedigrees
Grouped According to Parental Origin.
Paternal
Locus
D18S59
D18S476
D18S63
D18S62
D18S53
D18S56
D18S57
D18S487
D18S64
D18S61
D18S70
Maternal
Total
WZobs
P
WZobs
P
WZobs
P
12.35
9.11
13.62
15.34
12.99
13.94
9.34
10.7
13.02
16.12
18.80
0.59
0.45
0.42
0.04
0.17
0.17
0.58
0.65
0.32
0.09
0.34
7.05
5.08
6.56
4.56
7.68
5.09
5.91
4.24
6.98
6.13
6.56
0.43
0.33
0.62
0.78
0.003*
0.85
0.25
0.69
0.33
0.68
0.55
19.41
14.20
22.33
19.90
20.67
19.04
14.94
14.20
20.00
22.26
25.36
0.55
0.42
0.23
0.07
0.039*
0.32
0.81
0.41
0.21
0.32
0.29
*Empirical P values were estimated with 1,000 simulations.
the MSIM program [Ott, 1989; Weeks et al., 1990]. One
hundred or 1,000 replicates were carried out (see Table
II), using the corresponding genetic model and marker
information from linkage computations.
Linkage Analysis. Parametric linkage analysis
was conducted using the MLINK program from the
FASTLINK package [Cottingham et al., 1993; Lathrop
et al., 1984]. Three major genetic models were explored
in order to maximize the evidence for linkage. These
models were (a) dominant [allele frequency (q) 0.012,
male penetrance (fM) 0.4, female penetrance (fF) 0.7,
and normal penetrance 0.005 for males (fM0) and 0.009
for females (fF0)]; (b) intermediate [q ⳱ 0.024, fM ⳱
0.4/0.1, fF ⳱ 0.7/0.175, fM0 ⳱ 0.005, fF0 ⳱ 0.009]; (c)
recessive [q ⳱ 0.11, fM ⳱ 0.35, fF ⳱ 0.65, fM0 ⳱ 0.005,
fF0 ⳱ 0.009]. The parameters for the recessive model
were based on segregation analysis of this sample.
Nonparametric linkage analysis was conducted using the SimIBD [Davis et al., 1996] and GENEHUNTER
[Kruglyak et al., 1996] programs. SimIBD calculates a
simulation-based nonparametric statistic that provides
a powerful test for linkage using identity-by-descent
information in general pedigrees. GENHUNTER
implements, among other things, a nonparametric
linkage test that also uses identity-by-descent information, computing a normalized score that reflects allele
sharing in either pairs or all affected individuals from
a pedigree. The map order and distances employed in
the analysis were taken from the published CEPH/
Généthon chromosome 18 linkage map.
Parental Origin. Due to previous findings suggesting that unilineal pedigrees with paternal transmission of BD provide stronger evidence in favor of
linkage to markers on chromosome 18 [Stine et al.,
1995], we attempted to analyze pedigrees according to
parental origin. Our pedigrees were ascertained regardless of lineality characteristics. Thus, among all
pedigrees, only eight were clearly unilineal. Of these,
four were of paternal origin (when the trait was segregating through the father’s family). Pedigrees were
considered unilineal if the trait segregated exclusively
through one of the proband parent’s family, with no
evidence of affected relatives of at least first and second
degree in the other parent’s family. No clinical differ-
414
Turecki et al.
ence was observed between unilineal and bilineal pedigrees. These pedigrees comprised a total of 77 sampled
individuals (31 affected), with paternal families including 41 sampled subjects (17 affected) and maternal
families, 36 sampled subjects (14 affected).
RESULTS
The probands’ mean age of onset was 24.5 ± 8.1
years. The average number of episodes prior to lithium
treatment was 9.3 ± 6.7 and the patients have been
successfully treated with lithium on monotherapy for
13.9 ± 8.0 years. Two-point lod score results observed
in the parametric linkage analysis were not significant
(results available on request), with a maximum lod
score of 1.12 observed under the intermediate model for
marker D18S61 at ␪ ⳱ 0.10. Lod scores for this marker
under the dominant and recessive models were mostly
negative or just above zero.
Nonparametric results were also not significant. The
weighted Z statistics obtained in the nonparametric
analysis are shown in Table II. The empirical P values
were estimated with 1,000 replicates. Results observed
with GENEHUNTER nonparametric analysis were
similarly not significant.
The analysis of subsamples grouped according to parental origin provided interesting results (see Table II).
Overall, though no formally significant lod scores were
observed, two different regions yielded most positive
results with considerably small empirical P values. A
maximum lod score of 1.35 (P ⳱ 0.01) was observed for
marker D18S53 (18p11) in all unilineal pedigrees, with
a lod score of 0.81 (P ⳱ 0.002) and 1.04 (P ⳱ 0.001) in
paternal and maternal pedigrees, respectively. Other
positive results were observed on 18q, with paternal
pedigrees yielding a maximum lod score of 0.87 (P ⳱
0.045) at D18S61, maternal families at D18S64 (lod
score 0.73, P ⳱ 0.03) and total unilineal pedigrees at
D18S57 (lod score 0.99, P ⳱ 0.05). Nonparametric linkage analysis using unilineal pedigrees classified according to parental origin yielded similar results (see
Table III).
DISCUSSION
It has been proposed that a locus for BD can be assigned to chromosome 18 based on positive linkage results found by independent studies [Berrettini et al.,
1997]. There remains, however, some controversy over
this issue [Rice, 1997]. Though much has been thought
about interpreting linkage results in complex traits
such as psychiatric disorders, it is still not clear, in
practice, when linkage should be considered replicated.
Positive results that span long chromosomal segments,
cosegregating regions that often do not overlap between studies, use of different markers, investigation
of different phenotypic and genetic models, and adoption of different levels of statistical stringency, among
several other problems, make it difficult to define clear
guidelines for successful replication. Similar problems
arise when claiming nonreplication if the data do not
clearly exclude linkage, and samples lack sufficient
statistical power to detect a locus of similar effect to
that reported in the positive study. In this context, how
should we interpret our results?
Considering the entire sample, our findings do not
support linkage between BD and any of the markers
tested. Apart from one exception (marker D18S61),
most results are clearly negative. A maximum lod score
of 1.12 (at ␪ ⳱ 0.1; nominal P value: 0.023) was observed for marker D18S61 in the parametric linkage
analysis when maximizing lod scores over different genetic models. This result was not supported by the nonparametric analysis. D18S61 is located on the long arm
of chromosome 18, within the region where positive lod
scores were previously found in linkage studies of bipolar families from Costa Rica, and therefore, the
nominal P value associated with this marker result
could be considered sufficiently low to suggest a confirmation of linkage [Lander and Kruglyak, 1995]. However, this result was isolated and was interpreted as
being the consequence of multiple testing due to maximization of evidence for linkage over different genetic
models.
A parent of origin effect in linkage studies of BD was
first described by Stine et al. (1995). They observed
that unilineal bipolar pedigrees, where the trait was
transmitted through the father, provided evidence for
linkage with markers located on chromosome 18q. In
these pedigrees, there was an excess sharing of paternally transmitted alleles between sib pairs. Whether
this procedure uncovers a more homogeneous subgroup—leading to an increase in the signal for linkage—or whether the observed phenomenon reflects an
underlying biological process, such as imprinting or
meiotic instability of repetitive sequences, remains to
be determined. Subdividing our families according to
unilineal transmission and parental origin, a different
scenario was observed. Maximum lod scores were
found for marker D18S53 (lod score 1.35; P ⳱ 0.01)
when only unilineal families, regardless of parental
origin, were analyzed. This marker is located on the
short arm of chromosome 18 (18p11.21-32), in the region originally reported as linked to BD by Berrettini et
al. [1994] and confirmed by Stine et al. [1995] when
studying unilineal families of both paternal and maternal origin. In paternal pedigrees, marker D18S61 provided the maximum lod score (lod score 0.87; P ⳱
0.045). Though not formally significant, this result is in
agreement with the findings of Stine et al. [1995] who
observed evidence for linkage with markers on a neighboring region of 18q in paternal pedigrees. Taking into
account that stratifying the sample in subgroups leads
to a considerable reduction in statistical power, the
positive results observed were noteworthy, yielding
small empirical P values. However, it should be considered that multiple analyses were carried out in this
study. Therefore, to further confirm these results, we
are currently in the process of sampling additional
families to increase the number of unilineal families.
Although a pattern similar to that found by Stine et
al. [1995] was observed when only unilineal families
were analyzed and stratified according to parental origin, some differences between studies should be
pointed out. We have been systematically collecting
families that were selected according to lithium re-
Bipolar Disorder and Chromosome 18
sponse but not according to unilineal transmission. The
probands included in this study have no comorbidity
and our families segregate almost exclusively affective
disorders, whereas part of the families included in the
study by Stine et al. [1995] were later reported to cosegregate other psychiatric disease such as panic disorder [MacKinnon et al., 1997].
In conclusion, evidence for linkage to chromosome 18
markers was not found when all families were considered together, but support for previously reported positive linkage results was observed when families were
stratified according to parental origin. These results,
however, should be further explored in view of the reduced number of unilineal families included in this
study.
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