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Linkage of Bipolar Disorder to Chromosome 18q and the Validity of Bipolar II Disorder
Francis J. McMahon, MD;
Sylvia G. Simpson, MD;
Melvin G. McInnis, MD;
Judith A. Badner, MD;
Dean F. MacKinnon, MD;
J. Raymond DePaulo, MD
Arch Gen Psychiatry. 2001;58:1025-1031.
ABSTRACT
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Background An analysis of the relationship between clinical features and allele
sharing could clarify the issue of genetic linkage between bipolar affective
disorder (BPAD) and chromosome 18q, contributing to the definition of genetically
valid clinical subtypes.
Methods Relatives ascertained through a proband who had bipolar I disorder (BPI)
were interviewed by a psychiatrist, assigned an all-sources diagnosis, and
genotyped with 32 markers on 18q21-23. Exploratory findings from the first
28 families (n = 247) were tested prospectively in an additional 30 families
(n = 259), and the effect of confirmed findings on the linkage evidence was
assessed.
Results In exploratory analyses, paternal allele sharing on 18q21 was significantly
(P = .03) associated with a diagnostic subtype, and
was greatest in pairs where both siblings had bipolar II disorder (BPII).
Prospective analysis confirmed the finding that BPII-BPII sibling pairs showed
significantly (P = .016) greater paternal allele
sharing. Paternal allele sharing across 18q21-23 was also significantly greater
in families with at least one BPII-BPII sibling pair. In these families, multipoint
affected sibling-pair linkage analysis produced a peak paternal lod score
of 4.67 (1-lod confidence interval, 12 centimorgans [cM]) vs 1.53 (1-lod confidence
interval, 44 cM) in all families.
Conclusions Affected sibling pairs with BPII discriminated between families who
showed evidence of linkage to 18q, and families who did not. Families with
a BPII sibling pair produced an increased lod score and improved linkage resolution.
These findings, limited by the small number of BPII-BPII sibling pairs, strengthen
the evidence of genetic linkage between BPAD and chromosome 18q, and provide
preliminary support for BPII as a genetically valid subtype of BPAD.
INTRODUCTION
ONE OF the great challenges of research in psychiatry lies in the heterogeneity
of the clinical entities.1 When clinical heterogeneity
reflects a diversity of causes at the genetic level, the power to detect susceptibility
loci by genetic linkage analysis is greatly reduced. As yet, there is no valid
and reliable means of dividing clinical entities such as bipolar affective
disorder (BPAD) into genetically simpler subtypes.
In this article, we develop and apply to this problem an approach that
defines groups of sibling pairs based on linkage to a putative susceptibility
locus, then compares clinical features in the linked and unlinked groups.
We hypothesized that differences in clinical features reflect genetic differences,
and that linked pairs differ clinically from unlinked pairs. Such an analysis
might help to verify and extend the initial linkage finding by defining a
clinical subtype that is more clearly linked to the region of interest, and
by improving the resolution of the linkage signal.
We applied this approach to the putative linkage between BPAD and markers
on chromosome 18q. Linkage to this chromosome was first suggested by Berrettini
et al2 in 1994, with results at the "suggestive"
level of genome-wide significance.3 In an independent
sample of 28 pedigrees, Stine et al4 found
evidence of linkage to some of the same markers, but also detected linkage
to chromosome 18q21-22, approximately 50 centimorgans (cM) distant. The putative
18q locus was subject to a parent-of-origin effect. The greatest allele sharing
was observed for paternally transmitted marker alleles in families with an
apparently paternal pattern of illness transmission.
Subsequently, several linkage studies of chromosome 18 markers have
been published, each based on different samples, genetic marker maps, and
statistical methods. These studies can be interpreted as supporting a pericentromeric
locus,5, 6 an 18q21-22 locus,7, 8 both loci,9, 10
other chromosome 18 loci,11, 12, 13
or no compelling chromosome 18 linkage at all.14, 15, 16, 17
Thus, while linkage of BPAD to chromosome 18 seems likely, the evidence in
individual samples is modest, and the linkage signals are not well localized,
particularly across samples. This is the expected situation with genes of
small effect, when significant genetic heterogeneity is present, or when at
least some of the results represent false positives.18, 19
We investigated whether a systematic analysis of the relationship between
clinical features and allele sharing could clarify the question of genetic
linkage between BPAD and markers on chromosome 18q21-22. We studied the Johns
Hopkins/Dana Foundation Bipolar Disorder Pedigrees, a series of multiplex
families showing evidence of linkage to chromosome 18q21-22 in prior studies.4, 7 The overall goals were to define the
clinical features characteristic of families linked to 18q21-22, verify the
prior linkage findings, and improve their resolution as the basis for future
work aimed at cloning a susceptibility allele.
SUBJECTS AND METHODS
FAMILY ASCERTAINMENT AND EVALUATION
Ascertainment and evaluation methods are detailed elsewhere.7, 20 All families included in this study
were ascertained with the following criteria: a proband with a history of
bipolar I disorder (BPI); at least 1 additional sibling, or 1 sibling and
only 1 parent, with a major affective disorder; and no evidence of major affective
disorder in both parental lineages by family history. (Two families in which
major affective disorder was discovered in both parental lineages after direct
interview, and 3 families whose probands were not felt at final diagnosis
to have typical BPI, were included.) Informed consent was obtained from all
participants.
Subjects were interviewed by a psychiatrist using the Schedule for Affective
Disorders and Schizophrenia-Lifetime Version (SADS-L).21
Two additional psychiatrists reviewed the interview, family informant data,
and any medical records before assigning a best-estimate diagnosis under Research
Diagnostic Criteria.22 The diagnosis of bipolar
II disorder (BPII) required a subject's having recurrent major depression
as well as hypomanias. Using these methods, we have achieved excellent diagnostic
reliability ( values for BPI, BPII, and recurrent major depression
all equalled or exceeded 0.99).
SAMPLES STUDIED
We used a 2-sample design to allow some exploratory data analysis while
minimizing chance findings. In the first sample, family set A, we carried
out exploratory analyses aimed at formulating a hypothesis as to which clinical
features predict allele sharing. Clinical data came from the mania, hypomania,
and depression sections of the SADS-L and from the diagnostic subtype (BPI,
BPII, recurrent major depression, schizoaffective-manic) assigned by the best-estimate
psychiatrists. We subsequently tested the findings from set A in the second
independent set B.
Data for set A were originally reported elsewhere.4
Briefly, it consisted of 286 diagnosed subjects in 28 families. Of these,
59 subjects (21%) had BPI, 49 subjects (17%) had BPII (plus recurrent major
depression), and 28 subjects (10%) had recurrent major depression (RUP). A
best-estimate diagnosis of "phenotype uncertain" was assigned to 69 subjects
(24%), and 81 subjects (28%) were considered unaffected. Based on informativeness
for linkage analysis, 247 subjects were selected for genotyping.
Set B was also originally described elsewhere.7
It consisted of 30 families, and was completed after set A, but before August
1, 1996 (when the data set was "frozen" for analysis upon meeting prior thresholds
for statistical power).7 Of the 300 subjects
to whom a best-estimate diagnosis could be assigned, 59 (20%) had BPI, 40
(13%) had BPII plus recurrent major depression, 42 (14%) had RUP, and 6 (2%)
had schizoaffective manic disorder. Of the remaining subjects, 70 (23%) were
considered unaffected, and 83 (28%) were considered "phenotype uncertain."
The 259 most informative subjects were selected for genotyping.
GENOTYPING
Genotyping was performed as described previously.7
DNA was genotyped by polymerase chain reaction using multiplexed, fluorescent-labeled
primers and electrophoresis on an automated sequencer (Perkin Elmer Applied
Biosystems Inc, Folster City, Calif) with semiautomated allele scoring. For
the exploratory analyses, we used data from the markers D18S41, D18S64, and
D18S38 (the 18q markers most strongly linked to BPAD when we originally analyzed
these data4) typed in 28 families. For the
prospective analyses, we used a dense set of 32 markers spanning the region
between D18S487 and D18S1095 at a mean sex-averaged interval of 2.4 cM. The
first analysis of these data has been reported previously.7
STATISTICAL METHODS
Exploratory Analyses
Set A genotypes were used to score each sibling pair for unambiguous
sharing or nonsharing of marker alleles. The clinical features of sharing
vs nonsharing pairs were then compared. For categorical variables with more
than 2 categories, all discordant pairs were pooled. Paternal and maternal
alleles were analyzed separately, since earlier analyses indicated that on
18q only paternal marker alleles were shared in excess by affected sibling
pairs.4, 7 Continuous variables
were analyzed by the t test; categorical variables,
by a maximum-likelihood  2 test. The  level of significance
was set at .05; multiple comparisons underwent Bonferroni correction. Statistics
were calculated using STATISTICA (Release 4.5, StatSoft Inc, Tulsa, Okla).
It was not possible to score allele sharing by all sibling pairs using
the single-marker genotype data, so we reanalyzed allele sharing by diagnostic
subtype using multipoint haplotypes that take genotypes at adjacent markers
into account, and reduce the effect of variable marker informativeness. Multipoint
haplotype analyses were performed on both sets A and B using data from the
set of 32 markers. Haplotypes were assembled with GENEHUNTER,23
and sibling pairs were scored based on unambiguous sharing or nonsharing of
phased alleles at each marker. Again, paternal and maternal chromosomes were
analyzed separately. Haplotypes were also used to edit out probable genotype
errors prior to linkage analysis, as detailed elsewhere.7
Linkage Analysis
Linkage analysis was performed using the sib_ibd and sib_phase programs
in ASPEX.24 Based on the results of the prior
analyses, we partitioned the 58-pedigree sample into those families that had
at least 1 BPII-BPII sibling pair (n = 16 nuclear families; 1 pedigree was
split into 2 nuclear families) and those that did not (n = 43 nuclear families).
Sex-specific maps were generated using the sib_map program in ASPEX24; marker order was determined genetically as described
previously,7 but it cannot be considered definitive
for such densely placed markers. Bipolar I disorder and BPII were considered
affected phenotypes, and paternal and maternal allele sharing was estimated
for all possible affected sibling pairs under an additive genetic model.
The effect of BPII-BPII allele sharing on linkage resolution was assessed
by comparing linkage results in the total set of 59 nuclear families with
those of the 16 nuclear families with at least 1 BPII-BPII sibling pair. For
purposes of comparison, resolution was based on 1-lod confidence intervals.
Linkage was tested under the same affection status model (BPI and BPII) in
both analyses.
The significance of lod score changes was assessed by generating 5000
samples of 16 nuclear pedigrees randomly selected from the total set, and
subjecting each sample to multipoint linkage analysis as described above.
A more conservative assessment was based on those random samples with at least
48 sibling pairs, since our actual selection strategy implicitly required
at least 48 sibling pairs (16 nuclear families x [2 BPII siblings +
1 BPI proband per family]), and larger samples have more power to detect linkage.
Data Management
Data management was achieved using a relational database system based
on PARADOX (versions 5 and 8, Corel Corporation, Ottawa, Ontario), as described
elsewhere.25 The data in this system have undergone
rigorous cleaning and editing procedures, with a residual error rate estimated
at less than 6 per 10 000 data items.
RESULTS
EXPLORATORY ANALYSES
Thirty-one variables were analyzed (Table 1). Nominally significant differences (P<.05) were observed between sharing and nonsharing pairs in occurrence
of mania immediately before or after major depression, and in occurrence of
mood-congruent psychotic features during major depression. Neither result
remained significant after Bonferroni correction. In contrast, a highly significant
difference (overall 25 = 20.89, P<.001) between sharing and nonsharing pairs was observed for diagnostic
subtype, which remained significant (P = .03) after
Bonferroni correction. No significant differences were detected for the other
28 variables.
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Table 1. Clinical Variables Analyzed*
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The significant effect of diagnostic subtype was examined further by
direct comparison of allele sharing in sibling pairs grouped into all 6 possible
combinations of diagnostic subtype: BPI-BPI, BPI-BPII, BPI-RUP, BPII-BPII,
BPII-RUP, and RUP-RUP. Sibling pairs in which both siblings were diagnosed
with BPII disorder were most likely to share an excess of paternal alleles.
Fifteen of 15 BPII-BPII pairs (100%) shared paternal alleles identical by
descent (IBD), compared with 22 of 30 pairs (73%) for BPI-BPII sibling pairs
and IBD proportions close to the expected 50% for each of the 4 other types
of affected sibling pairs. This result was confirmed by multipoint haplotype
analysis. Again, paternal allele sharing was significantly associated with
a diagnostic subtype (overall 25 = 16.16, P = .007) and was greatest in BPII-BPII sibling pairs (Figure 1A).
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Figure 1. Paternal haplotype sharing across
D18S38 (58 families) in affected sibling pairs, grouped by pair type. Data
for families from set A are given in the top half of the figure, and those
from set B are provided in the bottom half. The total number of scored pairs
([n*{n-1}]/2) is indicated under each pair type on the x-axis. BPI indicates
bipolar I disorder; BPII, bipolar II disorder; and RUP, recurrent unipolar
depression.
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PROSPECTIVE ANALYSIS
Based on these results, we formulated the hypothesis that BPII-BPII
sibling pairs share paternal alleles on 18q21 more often than the other types
of sibling pairs. Subsequently, this hypothesis was tested in an independent
set of 30 families using multipoint data (Figure 1B). This indicated that BPII-BPII sibling pairs shared 9
of 11 paternal marker alleles (82% IBD), which was significantly more than
the 71 of 129 (55% IBD) proportion of allele sharing observed in the other
types of affected sibling pairs taken together (Fisher exact test = 0.016).
An apparent decrease in paternal allele sharing by RUP-RUP pairs was based
on only 8 pairings and was not significant.
EFFECT ON LINKAGE EVIDENCE
Inspection of allele sharing in each family revealed that BPI siblings
shared paternal alleles with BPII-BPII sibling pairs in the same family. We
therefore hypothesized that entire families with 1 or more BPII-BPII sibling
pairs would show genetic linkage to 18q, while other families would not. The
results are presented in Table 2.
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Table 2. Point-Wise Identical by Descent Sharing at 18q Marker Loci*
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The BPII sibling pair families demonstrated linkage to several 18q markers.
In these families, there was highly significant (P .005)
linkage to paternal alleles at five 18q21 markers, near the markers tested
in the initial clinical analyses, and to 4 more distal markers. The evidence
for linkage peaked at D18S346 in 18q21 (86.0% IBD; 21 = 22.35, P = .000002) and again distally
at D18S1106 in 18q22-23 (80.8% IBD; 21 = 19.69, P = .000009).
Families of BPII sibling pairs accounted for essentially all of the
evidence of linkage to 18q previously observed in this pedigree sample. No
evidence of linkage was detected in the 43 families with no BPII-BPII sibling
pairs, even though these families had a larger total number of affected sibling
pairs and would display more evidence of linkage if it existed. When paternal
allele sharing in the 2 sets of families was directly compared (Table 2), there was significantly (P.01)
increased sharing at 12 markers in BPII sibling pair families; the most significant
difference (80.8% vs 47.2% IBD; 21 = 20.19, P<.001) was observed at D18S1106. Little evidence of
linkage to maternal alleles was seen in either group of families. These data
are consistent with one or more 18q loci linked to BPAD in BPII sibling pair
families.
EFFECT ON LINKAGE RESOLUTION
The linkage resolution was substantially improved in families with a
BPII-BPII pair (Figure 2). In these
families, the 1-lod confidence interval for linkage spanned approximately
12 cM (sex averaged), compared with a confidence interval of more than 44
cM (sex averaged) for all 58 families. This approximately 3-fold improvement
in linkage resolution is consistent with published simulations,19
and it implies a substantial decrease in genetic heterogeneity. Also consistent
with a decrease in heterogeneity was an increase in the peak paternal lod
score, from 1.53 in the total sample to 4.67 in the 16 BPII sibling pair families.
This occured despite a reduction in sample size from 164 to 81 affected sibling
pairs.
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Figure 2. Genetic linkage results for 32
markers on chromosome 18q21-23. The analysis was performed in the total set
of 59 nuclear families, and in the 16 nuclear families with at least 1 BPII-BPII
(bipolar II disorder) sibling pair. For both analyses, BPI (bipolar I disorder)
and BPII subjects were considered affected. The sex-averaged genetic distance
is shown on the x-axis, and the multipoint maximum-likelihood paternal lod
score is shown on the y-axis. CM indicates centimorgan.
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The observed increase in lod score was highly significant by asymptotic
theory (21 = 18.79, P<.001)
and by simulation. A paternal lod score greater than 4.67 was observed 22
times in 5000 simulations — equivalent to an empirical P value of .004. The empirical P value remained
significant (P = .01) when the estimate was restricted
to random samples containing at least 48 sibling pairs (see the "Subjects
and Methods" section).
COMMENT
In both exploratory and prospective analyses performed on independent
sets of families, affected sibling pairs with BPII were distinguished between
families who showed evidence of genetic linkage to chromosome 18q and families
who did not. The families with BPII-BPII pairs demonstrated significantly
higher allele sharing at several 18q markers, accounting for essentially all
the evidence of linkage to this region previously observed in this sample.
Furthermore, families with BPII-BPII pairs substantially improved the peak
lod score and the resolution of the multipoint linkage analysis. These results
strengthen the evidence that a gene important in BPAD resides on chromosome
18q and provides preliminary support for BPII as a genetically valid subtype
of BPAD.
This study has several strengths. All subjects were interviewed and
diagnosed by psychiatrists. Perhaps as a result of this, we achieved high
interrater reliability. In particular, the diagnosis of BPII disorder showed
a score of 0.99 at the best-estimate level in this sample. The clinical
data were managed using stringent error prevention, detection, and correction
procedures,25 and the genotype data were derived
from a dense microsatellite marker map. The potential effect of multiple comparisons
on type I error was minimized by a 2-sample design and by assessing the significance
of the lod score change through simulation.
The major weakness of this study is the small number of BPII-BPII sibling
pairs in each set of families. Although to our knowledge this is one of the
largest BPAD family samples studied to date, with 586 subjects in 58 pedigrees,
set A contained only 15 independent BPII-BPII pairs, and set B contained only
11. Our linkage results are based on all 81 affected sibling pairs in the
16 BPII sibling pair families, not just the BPII-BPII pairs; however, even
this sample is not large by current standards. Stratification can be a valuable
strategy when it results—as in this study—in increased allele
sharing26; however, the shrinking of comparison
groups is an inevitable consequence of subdividing the affected phenotype
in an attempt to define more genetically homogeneous groupings. One could
avoid stratification, and perform instead a covariate-based linkage analysis,
a method that is now becoming feasible.27, 28
Such a method should also ideally allow the simultaneous assessment of many
clinical variables with allele-sharing, thus minimizing multiple comparisons.
Another weakness of this study is the reliance on the retrospective self-report
of clinical symptoms by subjects. The effect of any misreporting was minimized
by seeking corroborative data in medical records and in the reports of family
informants.
The more severe forms of a phenotype are traditionally considered easier
to map by linkage analysis. Accordingly, some authorities have recommended
using only BPI cases in linkage studies.14, 29, 30
Our data suggest that this strategy may not be optimal for detecting genetic
linkage to 18q, even in families ascertained through BPI probands. In our
sample, the siblings with BPII contributed substantially to the detection
of linkage, and they clustered in families that had the greatest evidence
of linkage to 18q. Bipolar I disorder may actually represent complications
of a milder, genetically less complex disorder, as we have suggested previously.31
Parent-of-origin effects encompass an important and growing class of
clinical genetic phenomena, wherein the phenotype in the offspring depends
on the sex of the transmitting parent.32 We
have previously reported that the parent of origin influences the linkage
of BPAD to chromosome 18q. In the same 28 families that constitute set A,
Stine et al4 found greater lod scores in families
with apparently transmitting fathers — an effect that was most striking
for 18q21 markers. In the same 30 families that constitute set B, McMahon
et al7 observed the largest IBD scores for
paternally transmitted marker alleles, but the excess allele sharing was not
confined to families with apparently transmitting fathers. Thus, the paternal
parent-of-origin effect seems to be robust when based on observed transmission
of marker alleles, but not when based on apparent transmission of illness.
This may reflect uncertainty in the classification of families by apparent
pattern of illness transmission, hidden bilineality, or other factors.
In order to take the prior findings on 18q into account while avoiding
these uncertainties, we chose to base the present analysis on observed transmission
of marker alleles. We again found robust evidence of linkage to paternal,
but not maternal alleles. Only 4 of the 16 families with BPII sibling pairs
had an apparently transmitting father. This is consistent with our conclusion
that the clustering of BPII-BPII sibling pairs is the key feature of families
linked to18q in this sample. The importance of paternally transmitted marker
alleles remains, and perhaps implicates genomic imprinting or other mechanisms.
MacKinnon et al33 evaluated the effect
of panic attack comorbidity on linkage of BPAD to 18q. Post hoc analyses of
set A indicated that the linkage evidence was strongest in families where
the proband had panic attacks. This could not be adequately tested in set
B, since only 2 families had a proband with panic attacks. We cannot rule
out that another factor correlated with BPII, and perhaps also with panic
attacks, may account for our findings, and we have not tested the effect of
BPII on linkage elsewhere in the genome. Nevertheless, diagnostic subtype
was the only 1 of 31 variables we analyzed that successfully discriminated
linked and unlinked families in our sample.
The peak paternal lod score of 4.67 that we observed in the BPII sibling
pair families should be viewed with caution. This lod score was obtained after
past analyses of the same data sets that evaluated linkage in a variety of
ways.4, 7, 34, 35
Our simulation studies indicate that the increase in lod score that was observed
in the BPII sibling pair families would rarely be seen by chance alone. Furthermore,
the increase in lod score was not diffuse, but it was focused at a few adjacent
markers, thus increasing the resolution of the linkage signal and fulfilling
one of the chief aims of this study.
Friddle et al34 published a genome-wide
linkage study of BPAD, using 50 of the 58 families included herein. That study
found little evidence of linkage to 18q or any other locus, either by single-locus
nonparametric analyses or by a 2-locus heterogeneity analysis. Several important
differences with the present study may account for the discrepant results.
Friddle et al employed a less dense marker map on 18q21-23 (an approximately
9-cM mean interval, compared with 2.4 cM in the present study), and the marker
data they analyzed were fully informative in only about half as many sibling
pairs.34 Marker density and sample size can
be critical factors in detecting alleles of modest effect.35
In addition, Friddle et al35 did not analyze
their results by parent of origin. Since most of the positive linkages between
BPAD and 18q report a parent of origin effect, this may be an important factor
in detecting linkage to this region. Friddle et al also failed to detect linkage
under their heterogeneity model, which assumed 2 major loci that each accounted
for linkage in at least half of the families.34
This failure would not be surprising if, as we now conclude, the 18q linkage
is primarily confined to BPII sibling pair families, which constitute much
less than half (27%) of this sample.
Our results offer a potential explanation for the apparently inconsistent
results of previous chromosome 18q linkage studies and point to a strategy
for replication. Future studies should take careful account of the families
with BPII-BPII sibling pairs and should analyze linkage separately for paternal
and maternal marker alleles. By decreasing heterogeneity, this approach may
lead to more consistent results that could ultimately clarify the complex
molecular anatomy of BPAD, moving us closer to the identification of susceptibility
alleles.
AUTHOR INFORMATION
Accepted for publication November 27, 2000.
Presented in part at the annual meeting of the American Psychiatric
Association, New York, NY, May 9, 1996; the World Congress of Psychiatric
Genetics, Bonn, Germany, October 9, 1998; and the annual meeting of the American
Psychopathological Association, New York, NY, March 4, 2000.
The ascertainment of families for this study was supported by grant
R01 MH42243 from the National Institutes of Health (Bethesda, Md) and by a
grant from the Charles A. Dana Foundation Consortium on the Genetic Basis
of Manic Depressive Disorder, New York, NY. Dr McMahon's effort was supported
by grant K08 MH01295 from the National Institutes of Health, and by an Independent
Investigator Award from the National Alliance for Research on Schizophrenia
and Depression, Chicago. Additional support was provided by the Ted and Vada
Stanley Foundation, Arlington, Va.
Some genotype data were contributed by Drs Robin Sherrington, Sarah
Shaw and Lon Cardon. We thank Drs Nancy Cox, Deborah Meyers, and Jianfeng
Xu for statistical advice; Drs Susan Folstein, Paul R. McHugh and Elliot S.
Gershon for critical input; and the family volunteers.
From the Departments of Psychiatry, University of Chicago, Chicago,
Ill (Drs McMahon and Badner); and The Johns Hopkins University School of Medicine,
Baltimore, Md (Drs Simpson, McInnis, MacKinnon, and DePaulo).
Corresponding author and reprints: Francis J. McMahon, MD, Department
of Psychiatry, University of Chicago, 924 E 57th St, R012, Chicago, IL 60637
(e-mail: fmcmahon{at}uchicago.edu).
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