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Differential methylation of the X-chromosome is a possible source of discordance for bipolar disorder female monozygotic twins.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 147B:459 –462 (2008)
Differential Methylation of the X-Chromosome is a
Possible Source of Discordance for Bipolar Disorder
Female Monozygotic Twins
Araceli Rosa,1,2 Marco M. Picchioni,1 Sridevi Kalidindi,1 Caroline S. Loat,2 Joanne Knight,2
Timothea Toulopoulou,1 Ronald Vonk,3 Astrid C. van der Schot,4 Willem Nolen,5 René S. Kahn,4 Peter McGuffin,2
Robin M. Murray,1 and Ian W. Craig2*
1
Division of Psychological Medicine, Institute of Psychiatry, King’s College London, London, UK
MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College London, London, UK
3
Reinier van Arkel groep, DZ’s-Hertogenbosch, The Netherlands
4
Department of Psychiatry, University Medical Centre Utrecht, Utrecht, The Netherlands
5
University Medical Center Groningen, Groningen, The Netherlands
2
Monozygotic (MZ) twins may be subject to epigenetic modifications that could result in different
patterns of gene expression. Several lines of evidence suggest that epigenetic factors may underlie mental disorders such as bipolar disorder (BD)
and schizophrenia (SZ). One important epigenetic
modification, of relevance to female MZ twins,
is X-chromosome inactivation. Some MZ female
twin pairs are discordant for monogenic X linked
disorders because of differential X inactivation.
We postulated that similar mechanisms may
also occur in disorders with more complex inheritance including BD and SZ. Examination
of X-chromosome inactivation patterns in DNA
samples from blood and/or buccal swabs in a series
of 63 female MZ twin pairs concordant or discordant for BD or SZ and healthy MZ controls
suggests a potential contribution from X-linked
loci to discordance within twin pairs for BD but is
inconclusive for SZ. Discordant female bipolar
twins showed greater differences in the methylation of the maternal and paternal X alleles than
concordant twin pairs and suggest that differential skewing of X-chromosome inactivation may
contribute to the discordance observed for bipolar disorder in female MZ twin pairs and
the potential involvement of X-linked loci in the
disorder.
ß 2007 Wiley-Liss, Inc.
KEY WORDS:
X-linkage; bipolar disorder; Xchromosome inactivation; twins;
psychosis
Please cite this article as follows: Rosa A, Picchioni MM,
Kalidindi S, Loat CS, Knight J, Toulopoulou T, Vonk R,
van der Schot AC, Nolen W, Kahn RS, McGuffin P,
Murray RM, Craig IW. 2008. Differential Methylation of
the X-Chromosome is a Possible Source of Discordance
*Correspondence to: Ian W. Craig, SGDP Centre, King’s College
London, Institute of Psychiatry, PO82, De Crespigny Park,
London SE5 8AF, United Kingdom.
E-mail: ian.craig@iop.kcl.ac.uk
Received 19 April 2007; Accepted 3 August 2007
DOI 10.1002/ajmg.b.30616
ß 2007 Wiley-Liss, Inc.
for Bipolar Disorder Female Monozygotic Twins. Am
J Med Genet Part B 147B:459–462.
INTRODUCTION
Bipolar disorder (BD) and schizophrenia (SZ) are debilitating mental disorders of largely unknown etiology. Evidence
from twin, family, and adoption studies indicates a strong
genetic predisposition to both. While the mode of transmission
is poorly characterized, genetic epidemiology suggests that
the two conditions share certain susceptibility genes because
of their familial co-aggregation [Bramon and Sham, 2001;
Cardno et al., 2002].
Comparable concordance rates among monozygotic (MZ)
twins of between 41% and 65% have been reported in recent
twin studies of both SZ and BD [Cardno and Gottesman, 2000;
Cardno et al., 2002]. Since MZ twins share identical maternal
and paternal chromosomes, the traditional explanation for
phenotypic discordance within MZ twins is the influence of
non-shared environmental factors. Recently, however, several
authors have suggested the possible involvement of epigenetic
mechanisms such as methylation of cytosines and histone
modification in this phenomenon [e.g., Singh et al., 2002;
Hardy, 2006]. Several lines of evidence suggest that such
epigenetic factors, may influence susceptibility to BD and SZ
[Petronis, 2001, 2006; Peedicayil, 2003]. Some empirical work
has been performed on the genomes of MZ twins discordant for
SZ which has identified epigenetic differences reflected in
different DNA methylation patterns [e.g., Tsujita et al., 1998;
Petronis, 2003].
One early epigenetic process affecting gene expression, which
has the potential to create phenotypic differences within pairs of
female MZ twins is X inactivation. To achieve dosage compensation, each cell in a female embryo randomly inactivates
one X chromosome which is marked by hyper-methylation
of CpG islands early in development. A tissue sample of a
female therefore typically contains clones of cells that have
inactivated the paternal X and other clones which have
inactivated the maternal X. Although roughly equal proportions
of cell types may be expected from this essentially random
process, stochastic mechanisms operating on small numbers of
cells may result in skewed X-chromosome inactivation patterns
between the members of female monozygotic twin pairs (FMZ).
This may allow them to express phenotypic discordance for
traits that are influenced by polymorphic X-linked genes. This
has already been demonstrated in FMZ twin pairs discordant for
X-linked single gene disorders including Duchenne muscular
dystrophy, X-linked immunodeficiencies, Lesch-Nyham disease
and Haemophilia [see, Craig et al., 2004].
460
Rosa et al.
More recently, the potential contribution of X-linked
quantitative trait loci (QTLs) to complex behaviors has been
investigated by comparing correlations between female
MZ twin pairs (FMZ) and male MZ twin pairs (MMZ). If
polymorphic X-linked loci are implicated, FMZ should be more
discordant than MMZ as a result of skewed X inactivation [Loat
et al., 2004]. In their recent study, significant differences were
observed for several behaviors including those relating to the
development of early social skills.
The suggestion of X-linkage for BD dates back to at least the
1930s and follows from evidence demonstrating an excess of
females and a deficiency of male transmission for the disorder,
further supported by evidence for linkage between BD and
color blindness [Baron, 1977; Mendlewicz et al., 1979]. In SZ, a
subgroup of familial cases could be due to a genetic defect on the
X chromosome, a hypothesis supported by the observation of an
excess of X-chromosome aneuploidies (XXX and XXY) among
some patients with psychosis [DeLisi et al., 1994] and because
of a number of differences between the sexes in rates and
developmental courses of illness.
Given the potential genetic overlap between BD and SZ
together with the possible involvement of X-linked genes
for both disorders, the main aim of our study was to explore
whether, or not, differential X-chromosome inactivation
among FMZ pairs might underlie the phenotypic discordance
between such pairs for BD and SZ.
MATERIALS AND METHODS
Sample
The study group consisted of monozygotic female twins from
the Maudsley Twin Study of SZ and BD and the Dutch Twin
study on BD. English patients were referred by their treating
psychiatrist and performed structured clinical interviews
using the Schedule for Affective Disorders and SZ-Lifetime
version [Endicott and Spitzer, 1978], augmented with further
clinical information, from which DSM IV [American Psychiatric Association, 1994] diagnoses were made. Control subjects
were recruited from the Institute of Psychiatry Volunteer Twin
Register and by advertisement in the national media. The
Dutch Bipolar Twin pairs (n ¼ 14) were recruited via the Dutch
Patient’s Association for Manic Depressives and Relatives
(n ¼ 4), the ‘‘Lithium-Plus Working Group,’’ a collaborating
group of psychiatrists in The Netherlands with a special
interest in BD (n ¼ 2), by psychiatrists working in several
Dutch psychiatric institutes (n ¼ 3) and by articles or advertisements in national and regional newspapers (n ¼ 5). Clinical
diagnosis for axis I psychiatric disorders were confirmed via
the structured clinical interview for DSM-IV (SCID) and also
via available medical records. Diagnosis for BD in the two
centers was based on similar criteria to achieve DSM-IV
compatibility and included both bipolars I and II. The co-twins
of the index twin for those pairs classified as discordant BD
varied from having no symptoms through depression (NOS)
and one case each of unipolar depression and SZ, paranoid
type. None of the discordant co-twins reached the criteria for
clinically diagnosed BD and as there was no simple quantitative means for scoring the differences in symptoms they were
considered together as a discordant group.
All subjects gave written informed consent before participating, after the study was approved by the ethical committee
of both Institutions (i.e., Multi Centre Research Ethics
Committee and Medical Ethical Review Board of the UMC
Utrecht).
DNA Extraction and Methylation Study
Mouth swab and/or blood samples from the twins were
collected. DNA was available for 63 twin pairs; these comprised
14 FMZ pairs discordant for BD, 9 FMZ pairs concordant for
BD, 4 FMZ pairs discordant for SZ, 6 FMZ pairs concordant for
SZ, and 30 FMZ pairs of healthy control twins with no personal
or family history of a psychotic, SZ spectrum or mood disorder,
this was ascertained using the Family Interview for Genetic
Studies [Gershon and Guroff, 1984]. From this sample, DNA
from both tissues was available for 3 pairs discordant for BD,
3 pairs concordant for BD, 3 pairs discordant for SZ, 3 pairs
concordant for SZ, and 17 control pairs. The remainder had
DNA available for one or other of the tissues, but for the same
tissue for both members of the twin pair.
DNA from buccal mucosa and from peripheral blood
leukocytes was extracted following standard techniques for
all the samples [Freeman et al., 1997, 2003]. Twin zygosity was
determined using a standardized twin likeness questionnaire
augmented with a multiplex zygosity test protocol based on the
analysis of between 9 and 12 unlinked, highly polymorphic
microsatellite loci to confirm zygosity status.
The activation status of the X-chromosome was determined
by a polymerase chain reaction amplification (PCR) of a region
containing a targeted CpG site and a highly polymorphic
simple sequence repeat (SSR) at the human androgen receptor
locus (AR) [Allen et al., 1992]. This technique is based on
the differential methylation at CpG islands of X-linked housekeeping genes on the active and inactive X-chromosomes. The
cytosine residues of the CpG dinucleotides in such islands
are methylated on the inactive X, which prevents digestion at
CCGG sites recognized by the methylation sensitive restriction
enzyme HpaII. Therefore, only CpG islands at these loci on the
active X chromosome will be digested following exposure to this
enzyme. Heterozygous females, distinguished by copy number
at the SSR, will give PCR products that differ in size from
maternal and paternal X-chromosome templates.
Briefly, genomic DNA was split into three aliquots (150 ng
each). One was incubated with HpaII—digesting unmethylated active DNA (informative digestion). The second aliquot
was incubated similarly but without restriction enzyme
enabling the amplification of both alleles (mock digestion).
The third was incubated with MspI—a methylation insensitive
restriction enzyme, that constitutes a control to verify
there was not an SNP at the CCGG site (control). All the
digests were amplified using primers, which flank the region
comprising both the polymorphic and the restriction site and
one of which was 6-FAM fluorescently-labeled (details on
request). The fluorescently labeled products were analyzed on
an automated DNA sequencer (Applied Biosystems (ABI),
Warrington, Cheshire, UK). The peak heights were measured
using Gene Scan software (Applied Biosystems). The ratio of
the peak heights of the two alleles after the control digestion
was used as a correction factor for any preferential amplification of one allele compared to the other as follows: ratio in mock
digestion (Rm) ¼ Peak 1 height/Peak 2 height; ratio in HpaII
digestion (Rh) ¼ Peak 1 height/Peak 2 height; normalized
ratio (Rn) ¼ Rh/Rm; hence, Percentage of inactivation of allele
1 ¼ (Rn/Rn þ 1) 100 [Monteiro et al., 1998]. Differences
between the inactivation ratios (i.e., differences in the
percentages of inactivation for allele 1—defined as the lower
molecular weight of the two alleles) were taken as measure of
inactivation discordance.
RESULTS
Of 63 MZ female twin pairs analyzed, only two pairs were
homozygous for the repeat polymorphism and hence were
uninformative—one control and one discordant SZ pair.
For those subjects with DNA from both peripheral blood and
buccal mucosa (n ¼ 58), we compared the X-inactivation pattern
between the two tissues. On the whole, a similar pattern of
X-inactivation was observed within both tissues (r ¼ 0.73,
Evidence for X-Linked QTLs in Bipolar Disorder
P < 0.01); however, considering the possible difference between
tissues for X inactivation reported in previous studies, we
decided to analyze the data from both tissues separately.
To estimate the degree of similarity within FMZ twin
pairs, we calculated the intra-pair difference as the absolute
difference in the percentages of X inactivation between
both members of each pair. Then, we calculated the mean
values and the standard errors of the mean for the intra-pair
differences in each of the five groups studied: BD discordant
(BDD), BD concordant (BDC), SZ discordant (SZD), SZ concordant (SZC), and healthy controls (C) (see Fig. 1A,B).
Based on the information from cheek swabs, the twins
discordant for BD appeared to be the most discordant for the
methylation status of their maternal and paternal X alleles
(intra-pair difference for the percentage of X inactivation
17.3 5.7; see Fig. 1A) especially compared to twins concordant for the same disorder (intra-pair difference for the
percentage of X inactivation 5.1 1.7; see Fig. 1A). In pair wise
analysis, discordant bipolar versus concordant bipolar showed
a significant difference at the 0.05 level (BDD vs. BDC: F ¼ 5.1,
df ¼ 7, P ¼ 0.05) and discordant bipolar versus controls showed
a trend to significant difference: F ¼ 2.4, df ¼ 24, P ¼ 0.1. None
of the other pair-wise comparisons were significant (Table I).
The results for peripheral blood based on higher numbers
(Fig. 1B), supported the conclusion that bipolar discordant
twin pairs are significantly more skewed in inactivation (BDD
vs. BDC: F ¼ 2.3, df ¼ 18, P ¼ 0.03) than concordant twin pairs
and also showed a strong trend to significantly greater skewing
than controls (BDD vs. C: F ¼ 1.9, df ¼ 29, P ¼ 0.06). Again,
none of the other pair-wise comparisons were significant
(Table I).
DISCUSSION
Overall, these preliminary data suggest that as a group,
pairs of twins discordant for BD may be more discordant for X
inactivation patterns than the other pairs of twins we studied,
suggesting that the X-chromosome may be involved in BD. The
discordant BD twin pairs showed a strong trend to significant
difference from controls. At the molecular level, it may suggest
that the expression of X chromosomal genes with alleles
divergent in functions implicated in BD can be quite different
between members of the twin pair, and could contribute to
their phenotypic discordance for this complex behavioral
phenotype. To our knowledge, modern twin studies have not
generally reported sex differences in concordance for func-
461
tional psychosis. Nevertheless, according to the Maudsley
Twin data [see McGuffin et al., 2003] the MZ concordances for
psychosis are slightly higher in males compared to females,
this would support the tentative conclusions of our preliminary
findings.
While the three discordant SZ pairs studied also showed
greater differences than the concordant SZ pairs in the
percentage of X inactivation in buccal mucosa, the discordance
was less marked than for the BDD twins. This may reflect
the limited numbers available to study and a larger sample will
be required to establish if there any evidence for X linked QTLs
in SZ. This possibility remains plausible given the observation
of X-chromosome aneuploidies among psychotic patients
[DeLisi et al., 1994] and the epigenetic control of some regions
on the X-chromosome suggested in relation to psychosis in
previous studies [Giouzeli et al., 2004].
Genomic discordance between members of FMZ twin
pairs can have two possible causes: the random nature of
X-inactivation patterns, and deviation in epigenetic modification such as methylation and or histone modification acting
on both sex chromosomes and autosomes. This epigenetic
regulation may be influenced by environmental and stochastic
factors and is compatible with the epidemiological data on
SZ and BD [Singh et al., 2002]. The detection of epigenetic
difference at genomic sites on both sex chromosomes and
autosomes between members of MZ twins has remained
largely unexplored primarily because of poor understanding
of the phenomenon, the difficulty in obtaining large MZ
samples of patients and limitations in technology.
The X-chromosome has been implicated in a number of
other behavioral traits including: homosexuality, affective
disorders, general cognitive ability, and antisocial behavior,
as well as having a large number of loci assigned that
are associated with mental retardation [Loat et al., 2004;
Bocklandt et al., 2006; Ropers, 2006].
Finally, our findings should be interpreted cautiously in
the light of the methodological limitations. Firstly, because
of restrictions in the availability of alternative material,
X-chromosome inactivation was tested in buccal mucosa, and
peripheral blood, but not directly from brain, the primary
organ affected in BD and SZ. There are fundamental practical
difficulties in studying tissue-specific methylation patterns
in brain tissue; however, from the few studies carried out, it
appears that correlations of inactivation profiles between
different human tissues are reasonably high [see Brown and
Robinson, 2000]. Secondly, a further possible limitation of our
Fig. 1. Mean value of the intra-pair differences for the percentage of X-inactivation in the five groups of monozygotic female twins (FMZ) studied
(SEM)—y-axis: FMZ discordant for schizophrenia (SZD), FMZ concordant for schizophrenia (SZC), FMZ discordant for bipolar disorder (BDD), FMZ
concordant for bipolar disorder (BDC), and FMZ healthy controls. Values obtained in: (A) DNA from cheek swabs, (B) DNA from blood. [Color figure can be
viewed in the online issue, which is available at www.interscience.wiley.com.]
462
Rosa et al.
TABLE I. Values of the Intra-Pair Differences for the Percentage of X-Inactivation in the Five Groups Studied and Statistical
Comparisons With the Control Group
Intra-pair differences
for X-inactivation
DNA from cheek swabs
DNA from blood
Group
SZ discordant
SZ concordant
BD discordant
BD concordant
Controls
SZ discordant
SZ concordant
BD discordant
BD concordant
Controls
n
Mean SE
Statistical comparisons
3
4
4
5
22
3
4
13
7
18
10.1 3.4
8.5 1.9
17.3 5.7
5.1 1.7
9.7 2.3
2.7 1.1
6.7 2.2
13.0 2.6
4.6 2.4
6.4 2.2
SZD vs. C: t ¼ 0.1, df ¼ 23; P ¼ 0.9
SZC vs. C: t ¼ 0.2, df ¼ 24; P ¼ 0.8
BDD vs. C: t ¼ 1.5, df ¼ 24; P ¼ 0.1
BDC vs. C: t ¼ 1.1, df ¼ 25; P ¼ 0.2
—
SZD vs. C: t ¼ 0.7, df ¼ 19; P ¼ 0.5
SZC vs. C: t ¼ 0.1, df ¼ 20; P ¼ 0.9
BDD vs. C: t ¼ 1.9, df ¼ 29; P ¼ 0.06
BDC vs. C: t ¼ 0.5, df ¼ 23; P ¼ 0.6
—
results and interpretations arises from the fact we do not have
information on chorionicity. Whether, or not, female MZ twins
have similar X inactivation is highly dependent on the timing
of twinning event [Monteiro et al., 1998] and chorionicity
can provide evidence of a differential prenatal environment,
in which dichorionic twins may experience more extreme
differences compared to monochorionic twins. This factor
should be taken into account in future studies.
Finally, the study’s power was limited by the small sample
size of the concordant and discordant pairs, especially for
SZ; however, the results for BP are replicated employing
DNA extracted from both buccal cells and blood. Studies of
additional MZ twins with BD and SZ are needed to explore
further the findings reported here. Whether, or not, these
results are replicated, it is clear that the study of MZ twins
continues to provide a unique opportunity to investigate the
etiology of complex disorders and future epigenetic studies
may lead to a better understanding of molecular differences in
genetically identical individuals.
Cardno AG, Rijsdijk FV, Sham PC, Murray RM, McGuffin P. 2002. A
twin-study of genetic relationships between psychotic symptoms. Am
J Psychiatry 159:539–545.
ACKNOWLEDGMENTS
Giouzeli M, Williams NA, Lonie LJ, DeLisi LE, Crow TJ. 2004. ProtocadherinX/Y, a candidate gene-pair for schizophrenia and schizoaffective disorder: A DHPLC investigation of genomic sequence. Am J Med
Genet Part B 129B:1–9.
This work was supported by the Wellcome Trust (MMP
Research Training Fellowship 064971) and the Stanley
Medical Research Institute. We also thank AGAUR (Generalitat de Catalunya) and Fundació Seny (Barcelona) for support
to A. Rosa. We are also very grateful to L. Maguire and B.
Freeman who performed the zygosity tests at the SGDP and
the laboratory staff of the Division of Biomedical Genetics,
UMC, Utrecht.
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