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Differential expression and parent-of-origin effect of the 5-HT2A receptor gene C102T polymorphism Analysis of suicidality in schizophrenia and bipolar disorder.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 144B:370 –374 (2007)
Brief Research Communication
Differential Expression and Parent-of-Origin Effect
of the 5-HT2A Receptor Gene C102T Polymorphism:
Analysis of Suicidality in Schizophrenia and Bipolar Disorder
Vincenzo De Luca, Olga Likhodi, James L. Kennedy, and Albert H.C. Wong*
Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
The serotonin 2A (5-HT2A) receptor gene has been
implicated in the pathogenesis of suicidal behavior
by a genetic association between the 5-HT2A C102T
silent polymorphism and suicidality in patients
with major depression. However, a recent metaanalysis failed to confirm this association. We
developed an improved quantitative assay for
the measurement of allele-specific expression of
the 5-HT2A gene, and find that the ratio of C/T allele
expression in the pre-frontal cortex of heterozygous suicide victims (n ¼ 10) was significantly
decreased in comparison with the non-suicide
group (n ¼ 10) (P ¼ 0.049). Because the 5-HT2A gene
is subject to imprinting, the parent-of-origin may
affect the inheritance of suicidal behavior. Thus we
examined the parental origin of specific alleles for
genetic association in a genetic family-based sample of major psychoses in which information on
suicidal behavior was available. No association
between the 5-HT2A C102T polymorphism
and suicidal behavior in major psychoses was
detected with the transmission/disequilibrium test
(TDT). ß 2007 Wiley-Liss, Inc.
KEY WORDS: suicide;
imprinting; allele ratio; postmortem brain
Please cite this article as follows: De Luca V, Likhodi O,
Kennedy JL, Wong AHC. 2007. Differential Expression
and Parent-of-Origin Effect of the 5-HT2A Receptor
Gene T102C Polymorphism: Analysis of Suicidality in
Schizophrenia and Bipolar Disorder. Am J Med Genet
Part B 144B:370–374.
Suicide and suicidal behavior are responsible for considerable morbidity and mortality in schizophrenia (SCZ) and
bipolar disorder (BD). The lifetime suicide risk is between 4%
CIHR Clinician-Scientist Fellow and NARSAD Young Investigator.
Grant sponsor: Canadian Institutes for Health Research
(CIHR); Grant sponsor: National Alliance for Research in
Schizophrenia and Depression (NARSAD).
*Correspondence to: Dr. Albert H.C. Wong, Centre for Addiction and Mental Health, 250 College Street, Room 711, Toronto,
Ont., Canada M5T 1R8.
Received 9 May 2006; Accepted 20 September 2006
DOI 10.1002/ajmg.b.30458
ß 2007 Wiley-Liss, Inc.
and 13% in SCZ [Meltzer, 2005] and 19% in BD [Goodwin and
Jamison, 1990]. Between 25% and 60% of bipolar patients
make at least one suicide attempt during the course of their
illness [Chen and Dilsaver, 1996] and up to 20–50% of
schizophrenic patients attempt suicide [Roy et al., 1984;
Radomsky et al., 1999]. The contribution of genetics to suicidal
behavior is demonstrated by a higher average concordance for
suicidal behavior among monozygotic twins compared to
dizygotic twins or other relatives of suicidal subjects [Baldessarini and Hennen, 2004]. The observation that 10/26 monozygotic co-twins of suicide completers also attempted suicide,
in comparison to 0/9 dizygotic co-twins, reinforces that suicidal
behavior is influenced by genetic factors [Roy et al., 1995].
These data also suggest that a complex inheritance pattern is
present and that epigenetic effects may be relevant.
The serotonin (5-HT) neurotransmitter system regulates
anxiety, impulsivity, and aggression [Mann, 1995], and so
disturbances in the functioning of the 5-HT system have been
hypothesized to influence suicidal behavior. Several studies
have reported altered serotonin system function in people who
die by suicide. For example, low concentrations of the serotonin
metabolite 5-hydroxyl-indole-acetic-acid (5-HIAA) in cerebrospinal fluid (CSF) have been associated with both suicide attempts
[Asberg et al., 1976] and completed suicide [Nordstrom et al.,
1994]. The 5-HT2A receptor (HRT2A gene) is one of many 5-HT
receptor subtypes, and it has been of particular interest in
studies of suicide and major psychoses. The 5-HT2A-receptor
gene is located on chromosome 13q14-q21 in humans, and
consists of three exons separated by two introns, spanning over
20 kb [Chen et al., 1992]. A series of post-mortem studies found
greater 5-HT2A-binding in the prefrontal cortex of suicide
victims in comparison to controls, with similar findings in
platelets of individuals with major depression who attempted
suicide [Mann, 1999].
There have been many genetic association studies of
polymorphic variants in 5-HT system genes and suicidality.
In particular, the HTR2A C102T gene variant has been
analyzed extensively [Du et al., 2000], but a large metaanalysis (including 1,599 suicidal patients) did not find a
significant association between suicide attempts or suicide
completion and the C102T polymorphism [Anguelova et al.,
2003]. Other family-based genetic association studies using
the transmission disequilibrium test have examined suicidal
behavior, but none of these studies focused on the HTR2A
C102T polymorphism [Zalsman et al., 2001; Wasserman et al.,
2005]. The biological function of the HTR2A C102T polymorphism is unclear because it is synonymous and therefore
does not alter amino acid sequence, although it may affect
mRNA secondary structure [Arranz et al., 1995].
Another polymorphism in the HTR2A promoter region
(1438A/G), is in complete linkage disequilibrium with
C102T and could mediate the differential expression of the
HTR2A C102T alleles. However, Sokolov and Polesskaya [2002]
found that this promoter SNP does not affect transcription
Imprinting of 5-HT2A in Suicidality
in vitro. The presence of a cytosine (C) at position 102 and a
guanosine (G) at the position –1,438 creates two additional
CpG islands, which are present in the C102 chromosomes, but
are absent in the 102T chromosomes and these CpG sites may
be methylated in the brain. Furthermore, carriers of the
HRT2A 102T allele had a higher density of 5-HT2A receptors
than carriers of the HRT2A C102 allele, in a post-mortem and
genetic study that replicated the finding of greater 5-HTR2A
binding in subjects who committed suicide [Turecki et al.,
1999]. Analysis of mRNA expression in human post-mortem
brain tissue suggests that the expression of the HTR2A C102
allele in the cortex of heterozygous individuals is significantly
lower than that of the T allele [Polesskaya and Sokolov, 2002].
This group found no evidence of polymorphic imprinting,
suggesting that if imprinting does occur, it must be a rare
In light of these findings, our aim was to investigate the
possibility that genomic imprinting of the HTR2A gene may
play a role in suicidal behavior by examining both HTR2A
C102T DNA variants and allele-specific mRNA expression in
post-mortem brain samples from patients with SCZ or BD.
Genomic imprinting is an epigenetic mechanism in which the
parental origin of the allele can influence the level of gene
expression [Surani et al., 1986]. The existence of genomic
imprinting can be suggested by the presence of parent-of-origin
effect (POE) in transmissions from maternal versus paternal
meiosis to an affected offspring, thus we also investigated the
possibility of genomic imprinting in suicidality by analyzing
the C102T polymorphism in nuclear families of psychotic
patients with suicidal behavior.
The goals of the current study are: (1) to investigate the
presence of genomic imprinting in suicidal behavior through
POE analysis; (2) to document frequencies of biallelic and
monoallelic expression in post-mortem brains from victims of
suicide and matched controls; (3) to investigate the ratio of
expression of the C102T SNP alleles in completed suicide.
mRNA levels were quantified in samples donated by the
Stanley Medical Research Institute [Torrey et al., 2000]. The
Stanley Array Collection consists of mRNA and genomic DNA
samples extracted from dorsolateral prefrontal cortex
(DLPFC) (Brodmann’s area 46) from 35 individuals in each of
three diagnostic groups: SCZ, BD, and unaffected controls.
These specimens were collected, with informed consent from
next-of-kin, by participating medical examiners between
January 1995 and June 2002. The specimens were all collected,
processed, and stored in a standardized way. Exclusion criteria
for all specimens included: (a) significant structural brain
pathology on post-mortem examination by a qualified neuropathologist, or by pre-mortem imaging, (b) a history of
significant focal neurological signs pre-mortem, (c) a history
of central nervous system disease that could be expected to
alter gene expression in a persistent way, (d) documented
IQ < 70, and (e) poor RNA quality (vide infra). Additional
exclusion criteria for unaffected controls included: (a) age less
than 30 (thus, still in the period of maximum risk), and (b)
substance abuse within 1 year of death or evidence of
significant alcohol-related changes in the liver. Diagnoses
were made by two senior psychiatrists, using DSM-IV criteria,
based on medical records, and when necessary, telephone
interviews with family members. Diagnoses of unaffected
controls were based on structured interviews by a senior
psychiatrist with family member(s) to rule out Axis I
diagnoses. Information about lifetime alcohol and drug abuse
was recorded using a non-parametric scale ranging from
0 ¼ absent to 5 ¼ heavy at time of death. Of the 105 samples
in total, there were 10 individuals who died by suicide, who
were also heterozygous at the HTR2A T102C locus.
We matched these suicide cases for genotype, diagnosis, age
of death and sex to 10 controls who died from other causes.
The control group consisted of seven bipolar and three
schizophrenia subjects (four male and six female) with a mean
age of 43.6 11.04 (Table I). We have no information about
whether the suicide attempts were violent or not but we do
have information about medication treatment (Table II). The
number of BD subjects with psychotic features was four in both
Genomic DNA was analyzed from the same samples and the
single nucleotide polymorphism of the 5-HT2A receptor gene at
position 102 was genotyped with TaqMan1 probes (ABI:
Applied Biosystems Inc., Foster City, CA) to identify heterozygous subjects. HTR2A mRNA levels were measured with
quantitative PCR (Q-PCR; ABI PRISM1 7000 Sequence
Detection System) using TaqMan1 Assays-by-Design (ABI).
The forward primer sequence was 50 -GACACCAGGCTCTACAGTAATGAC-30 and the reverse primer was 50 -CGACTGT
CCAGTTAAATGCATCAGA-30 . Differential allelic expression
and analysis was carried out on the ABI PRISM1 7000 with the
following allele-specific, fluorescent-labeled probes: VIC- 50 CTTCTCCGGAGTTAAA-30 and 6FAM-50 - CTTCTCCAGAG
TTAAA-30 .
All reactions were performed in quadruplicate, and the
investigators performing the PCR (V.D.L. and O.L.) were blind
to the diagnosis of the tissue donors until after the data were
analyzed. Differential allele expression was calculated by
subtracting real-time PCR threshold cycle (Ct) values for the
‘‘C’’ and ‘‘T’’ alleles (DCt). However, assays based on allelespecific probes may generate heterozygote ratios that deviate
from 1 as a result of differential binding efficiencies of the
probes rather than differences in expression [Hoogendoorn
et al., 2000; Bray et al., 2003]. To correct for this potential bias,
the average DCt of the genomic DNA sample was subtracted
from the DCt of the respective cDNA sample (DDCt). Relative
levels of ‘‘C’’ to ‘‘T’’ were calculated as 2DDCt . Total 5-HT2A
mRNA levels were calculated by combining the measured values of both alleles: ‘‘C’’ and ‘‘T’’.
Relative mRNA levels in tissue are commonly expressed as a
ratio between the gene of interest and a control or housekeeping gene. This procedure controls for differences in the
amount of tissue from which the RNA is extracted, the amount
of RNA in each sample, and the efficiency of reverse transcription to cDNA, since any distortion of these variables should
affect the target gene and the control gene equally. In our
study, we were interested in quantitative differences in mRNA
specific to each allele of the HTR2A C102T SNP, and thus these
factors are controlled for because both alleles would be affected
TABLE I. Demographic Characteristics of the Subjects From
Stanley Sample
Suicide subjects Control subjects
Sex M/F
Principal Axis I
Diagnosis, No. (%)
Bipolar disorder
Psychotic bipolar
Mean SD
Age of death
Lifetime alcohol abuse*
Lifetime drug abuse*
Time in the hospital (years)
Age of onset (years)
PMI (hours)
Brain pH
1 (10%)
9 (90%)
3 (30%)
7 (70%)
40.4 10.68
2.40 2.01
1.70 1.83
0.200 0.163
26.6 11.2
41.0 17.6
6.45 0.31
43.6 11.04
2.10 2.31
2.10 2.08
0.267 0.269
24.2 6.3
26.9 14.8
6.30 0.22
*Lifetime alcohol and drug abuse were assessed on a semi-quantitative
scale, with the following order: 0¼ little or none; 1 ¼ social; 2 ¼ moderate in
the past; 3 ¼ moderate at time of death; 4 ¼ heavy past in the past; 5 ¼ heavy
at time of death.
De Luca et al.
TABLE II. Medications of the Subjects From Stanley Sample
Stanley ID
Mood stabilizers
Fluoxetine, Trazodone, Doxepin
Quetiapine, Olanzapine
Valproate, Gabapentin
Lithium, Valproate
Carbamazepine, Gabapentin
Trazodone, Sertraline
Amitriptyline, Venlafaxine
Fluoxetine, Venlafaxine
Paroxetine, Trazodone
*This subject was on benztropine.
equally. The differential expression ratio for each diagnostic
group was described as a mean standard deviation (Fig. 1).
Group differences were evaluated using independent and
paired t-tests. Agonal status is one of the major limitations of
post-mortem brain studies [Iwamoto and Kato, 2006], and thus
we examined the effect of brain pH and post-mortem interval
(PMI) on the allelic ratio. The correlation between mRNA
expression and confounding factors was calculated by the
Pearson coefficient (PMI and pH) and where appropriate
(alcohol and illicit drug abuse) by non-parametric Spearman
correlations. All test P values were two-tailed.
The family-based DNA sample consisted of 102 nuclear
families in which probands had a DSM-IV diagnosis of major
psychoses (52 Bipolar I; 21 Bipolar II; 9 Schizoaffactive;
20 Schizophrenia) and who had attempted suicide. The
patients were recruited from several hospitals in Toronto
and across central Canada. Genomic DNA was extracted
using standard high salt methods from white blood cells. A sexspecific parent analysis of the transmission of the common
alleles was conducted using the ETDT package [Sham and
Curtis, 1995]. This analysis allows us to detect a POE.
In heterozygous individuals, the ‘‘C’’ and ‘‘T’’ alleles are
expressed in the same cell. The most commonly used approach
for quantifying the C/T ratio is the use of PCR amplification
Fig. 1. Mean and SD of the C/T allele ratio for suicide and control groups.
followed by HpaII digestion that distinguishes the C102T site
[Polesskaya and Sokolov, 2002], but this method is biased by
the efficiency of restriction endonuclease digestion. Another
approach is to measure the relative expression of each allele,
comparing the peak height ratio of each allele-specific extension product derived from SnaPshot analysis, giving a
measurement of relative allele quantity [Bray et al., 2004].
We used instead a Taqman genotyping method, which allows
us to circumvent the problem of incomplete digestion. The
method employs PCR-amplification of cDNA and separate
measurements of the amount of each allele through the use of
sequence-specific oligonucleotide probes labeled with different
fluorescent markers.
Examining the raw Ct value for the ‘‘C’’ and ‘‘T’’ alleles (not
normalized by subtraction from the average genomic DNA
sample), confirmed lower levels of the ‘‘C’’ allele cDNA in
overall sample (n ¼ 20). The average Ct was 31.63 1.76 for the
‘‘C’’ allele and 30.98 1.83 for the ‘‘T’’ allele (t ¼ 13.188; 19 df;
P < 0.001). The average Ct in the genomic DNA was
29.10 1.53 for the ‘‘C’’ allele and 28.09 1.27 for the ‘‘T’’
allele (t ¼ 7.415; 18 df; P < 0.001). However, comparisons of
the raw measurements of Ct for the two alleles should be
treated with caution since differences in PCR amplification
efficiency could affect this parameter. On the other hand, the
fact that the same trend was seen in another study using a
different technique [Polesskaya and Sokolov, 2002] suggests
that C < T allele expression may indeed reflect differences in
the amount of the two versions of the cDNA.
The clinical and demographic variables for both suicide and
non-suicide groups are shown in Table I. The groups were quite
similar for all clinical and tissue variables, with only PMI
showing a trend towards longer PMI in the suicide group
(t ¼ 1.937; 19 df; P ¼ 0.069). However, PMI did not have an
effect on the C/T ratio (r ¼ 0.274; P ¼ 0.242). The DCt in the
genomic DNA was 1.05 0.65.
The C/T allele cDNA level ratio in the 10 heterozygous
suicide victims was 1.25 0.15, after the correction for the
calibrator (genomic DNA DCt). The DCt in suicide victims
cDNA was 0.73 0.17, significantly lower than the expected
DCt of 1.05 (t ¼ 5.734; 9 df; P < 0.001). The DCt was <1.05 in
cDNA from all 10 heterozygous suicide victims. The relative
expression of the ‘‘C’’ to ‘‘T’’ allele in heterozygous non-suicide
Imprinting of 5-HT2A in Suicidality
controls was 1.42 0.21 after the correction. Also this group
DCt (0.55 0.23) was significantly lower than the expected 1.05
(t ¼ 6.748; 9 df; P < 0.001). The mean ratios for the suicide and
non-suicide groups were significantly different (t ¼ 2.107;
18 df; P ¼ 0.049), with the ‘‘C’’ allele showing lower cDNA levels
in the suicide group in comparison to the control subjects. The
allele ratio is not associated with demographic variables such
as gender (t ¼ 1.216; 18 df; P ¼ 0.240), age at death (r ¼ 0.20;
P ¼ 0.984), PMI (r ¼ 0.272; P ¼ 0.242), or brain pH
(r ¼ 0.259; P ¼ 0.270). Furthermore, the C/T ratio was not
influenced by the clinical variables of diagnosis (schizophrenia
vs. bipolar: t ¼ 1.222; 18 df; P ¼ 0.238), lifetime alcohol abuse
(r ¼ 0.107; P ¼ 0.653), lifetime drug abuse (r ¼ 0.039;
P ¼ 0.870), age of onset of illness (r ¼ 0.118; P ¼ 0.621) or
time spent in hospital (r ¼ 0.071; P ¼ 0.774).
The total levels of the 5-HT2A receptor mRNA were
2.14 0.08 in the non-suicide controls, and 2.06 0.06 in the
suicide victims, and this difference is statistically significant
(t ¼ 2.406; 18 df; P ¼ 0.027). Comparison of the total level of
5-HT2A receptor mRNA between heterozygous suicide victims
and non-suicide controls confirmed lower levels of the ‘‘C’’ allele
in suicide subjects.
The analysis of the C102T SNP did not reveal preferential
transmission for either allele overall (35 vs. 29; Chisquare ¼ 0.563; 1 df; P ¼ 0.452). The separate analysis of
individual alleles from maternal meiosis showed a trend
(Chi-square ¼ 2.164; 1 df; P ¼ 0.141); the allele C was maternally transmitted only eight times while not transmitted
15 times. The C allele was paternally transmitted 13 times
while not transmitted 12 times (Chi-square ¼ 0.040; 1 df;
P ¼ 0.841).
This particular data sample of post-mortem brain was not
previously analyzed using this differential allelic expression
technique. Our main findings are that decreased levels of the
HTR2A C102 allele mRNA may be associated with suicide in
major psychoses, and that suicide victims have a lower C102/
102T allele expression ratio than controls. Few studies have
explored the HTR2A C102T SNP in combination with other
HTR2A gene sequence variants in the context of suicide.
Previous studies have shown lower levels of the C102 allele, but
did not account for the possible confounder of diagnosis
[Polesskaya and Sokolov, 2002].
The molecular mechanism causing the HTR2A C102 allele
mRNA to be decreased versus the 102T allele is unclear. One
possibility is that epigenetic mechanisms may be involved,
specifically differential methylation of this gene in suicide
victims in comparison to non-suicide control subjects. Sokolov
and Polesskaya [2002] found that only 50% of the C102 sites are
methylated in brain tissue; thus, lower HTR2A C102 allele
mRNA expression in suicide victims could be the result of
greater methylation. Furthermore, the HTR2A promoter
polymorphism (1438G) that is linked to the C102T SNP
may not directly affect transcription [Sokolov and Polesskaya,
We did not find evidence of genomic imprinting (complete
inactivation of one allele in some individuals) in our sample of
10 heterozygous suicide victims and 10 heterozygous nonsuicide controls. This is in contrast with findings of complete
imprinting of one allele in the analysis of 18 human adult
brains, with four individuals showing monoallelic expression
while others had biallelic expression [Bunzel et al., 1998]. It is
possible that complete polymorphic imprinting of the 5-HTR2A
gene may be a rare event. Consistent with this lack of
imprinting at RNA level in suicide victims, the ETDT did not
show a POE in suicide attempters, even though the 102T allele
was transmitted more frequently from the mother.
We also found decreased total 5-HT2A receptor mRNA in
suicide victims, in contrast with some previous findings, but
our methods were different and we analyzed only heterozygous
5-HT2A T102C subjects. Another issue is the type of brain
tissue studied: we examined only DLPFC, whereas Bray et al.
[2004] found no significant effect of C102T polymorphism on
mRNA expression in RNA from different cortical regions
(frontal, parietal, and temporal). One potential limitation is
that the sample used to analyze the differential allelic
expression is small, but the observed power for this analysis
was 63.7% considering the not so large effect size observed in
this study (
n-2-unequal/index.php). Our results suggest that differential
allele-specific expression of the HTR2A gene, influenced by the
C102T polymorphism may be involved in suicidal behavior in
major psychiatric disorders. Further, work to directly test the
epigenetic regulation of this gene is required to confirm this
In summary, the three main results presented (lower
expression of 5-HT2A mRNA, lower HTR2A 102C vs. T102
allele expression and the absence of imprinting), contradict
some previous findings. Our finding of decreased HTR2A
mRNA in suicide victims is inconsistent with Turecki et al.
[1999], and could be explained by the fact that we analyzed only
subjects heterozygous for the C102T polymorphism. However,
our observation that the C102T polymorphism affects mRNA
levels is concordant with Turecki et al. [1999]. With regards to
the issue of imprinting, our results are consistent with two
previous reports [Polesskaya and Sokolov, 2002; Bray et al.,
2004] that found no imprinting, with one published study
reporting evidence for imprinting [Bunzel et al., 1998]. Our
data show decreased expression of the HTR2A C102 allele,
which is in the same direction as one paper [Polesskaya and
Sokolov, 2002] but not another [Bray et al., 2004]. It is possible
that differences in the brain region studied (Bray’s sample:
temporal and frontal cortex) could be responsible for these
Other limitations of our study include the unavailability of
information on suicide method, previous suicide attempts, and
concomitant personality disorders. Of course these clinical
factors could increase sample heterogeneity, but it is unlikely
that these factors influence the allelic ratio. The suicide and
non-suicide groups are matched overall but not individually
case-matched (there are more bipolar patients in the suicide
group). However, the number of BD subjects with psychotic
features in both groups is four, so the groups are matched on
this feature. Furthermore, major axis I co-morbidity was not
present in either group. Although the male–female and
bipolar-schizophrenia distribution is not the same in the
suicide and non-suicide groups, the C102T allele ratio is not
significantly different between the two diagnostic groups or
between male and female subjects. Another limitation is the
fact that different medication treatment may influence the
HTR2A allelic ratio even though a specific effect of psychotropic drugs on differential allelic expression is not yet
Differences in allele-specific PCR amplification efficiency
could have affected the comparison, even though we have
compared allelic ratios and not the raw measurement Ct
values. It is also possible that the small number of post-mortem
samples analyzed may have skewed our results, and the
limited number of families available for genetic association
analysis prevents firm conclusions from being drawn about the
POE of this polymorphism.
Vincenzo De Luca is supported by a Postdoctoral Research
Fellowship and a Pilot Grant from the American Foundation
for Suicide Prevention. Post-mortem brain tissue mRNA
and DNA was donated by The Stanley Medical Research
Institute Array Collection courtesy of Dr. Michael B. Knable,
De Luca et al.
Dr. E. Fuller Torrey, Dr. Maree J. Webster, Dr. Serge Weis, and
Dr. Robert H. Yolken. The authors would also like to thank
Mawahib Semeralul for her technical assistance.
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expressions, disorder, c102t, origin, parents, effect, polymorphism, differential, analysis, genes, ht2a, suicidality, receptov, bipolar, schizophrenia
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