Evidence of association between Val66Met polymorphism at BDNF gene and anxiety disorders in a community sample of children and adolescents.

Abstract

Different lines of evidence support BDNF as a candidate gene in mood and anxiety modulation. More recently, the Met allele of the BDNF Val66Met polymorphism has been implicated in anxiety in animal models and anxiety-traits in humans. The aim of this study is to evaluate the a priori hypothesis that the association between anxiety disorders and Val66Met polymorphism at the BDNF gene would be replicated in a community sample of children and adolescents. 240 subjects from a total sample of 2457 children and adolescents aged 10-17 years from the public schools in the catchment area of the primary care unit of a university hospital participated in this case-control study and were assessed for psychopathology using the K-SADS-PL. A sample of saliva was collected for DNA analysis of Val66Met polymorphism. BDNF was the single gene evaluated in this sample. We found a significant association between carrying one copy of the Met allele and higher chance of anxiety disorders in children and adolescents. The association remained positive even after the adjustment for potential confounders (228 subjects; OR=3.53 (CI95% 1.77-7.06; p<0.001)). Our results support the a priori hypothesis of an association between anxiety and the polymorphism Val66Met. To our knowledge, this is the first study documenting a potential role of this polymorphism in a community sample of anxious children and adolescents.

Full text

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Neuroscience
Letters
502 (2011) 197–
200
Contents
lists
available
at ScienceDirect
Neuroscience
Letters
jou
rn al
h om
epage:
www.elsevier.com/locate/neulet
Evidence
anxiety
of
association
between
Val66Met
polymorphism
at
BDNF
gene
and
disorders
in
a
community
sample
of
children
and
adolescents
Andréa
Andressa
Luis
Tocchettoa,
Giovanni
A.
Saluma,d,
Carolina
Blayaa,e,
Stefania
Techea,
Luciano
Isolana,
Bortoluzzia,
Rafael
Rebelo
e
Silvab,
Juliana
A.
Beckerb,
Marino
M.
Bianchinc,f,
Augusto
Rohded,
Sandra
Leistner-Segalb,
Gisele
G.
Manfroa,d,∗
aAnxiety
bMolecular
cDivision
dNational
eMedical
fBasic
Disorders
Program
for
Children
and
Adolescents,
UFRGS/HCPA,
Brazil
Genetics
Laboratory
– Medical
Genetics
Service/HCPA,
Brazil
of
Neurology,
UFRGS/HCPA,
Brazil
Institute
for
Developmental
Psychiatry
for
Childhood
and
Adolescence,
Brazil
Clinical:
Psychiatry,
UFCSPA,
Brazil
Research
and
Advanced
Investigations
in Neurology,
Experimental
Research
Centre,
HCPA,
Brazil
a
r
t
i
c
l
e

i
n
f
o
Article
Received
Received
Accepted
history:
11 May
2011
in revised
form
17
July
2011
26 July
2011
Keywords:
Anxiety
Child
BDNF
Genetic
Polymorphism
Genetic
disorders
psychiatry
association
studies
a
b
s
t
r
a
c
t
Different
recently,
models
association
in
and
of
using
was
copy
remained
1.77–7.06;
the
this
lines
of
evidence
support
BDNF
as
a
candidate
gene
in
mood
and
anxiety
modulation.
More
the
Met
allele
of the
BDNF
Val66Met
polymorphism
has
been
implicated
in anxiety
in
animal
and
anxiety-traits
in
humans.
The
aim
of this
study
is
to
evaluate
the
a
priori
hypothesis
that
the
between
anxiety
disorders
and
Val66Met
polymorphism
at
the
BDNF
gene
would
be
replicated
a
community
sample
of
children
and
adolescents.
240
subjects
from
a
total
sample
of
2457
children
adolescents
aged
10–17
years
from
the
public
schools
in
the
catchment
area
of the
primary
care
unit
a
university
hospital
participated
in
this
case-control
study
and
were
assessed
for
psychopathology
the
K-SADS-PL.
A
sample
of
saliva
was
collected
for
DNA
analysis
of
Val66Met
polymorphism.
BDNF
the
single
gene
evaluated
in
this
sample.
We
found
a
significant
association
between
carrying
one
of the
Met
allele
and
higher
chance
of
anxiety
disorders
in
children
and
adolescents.
The
association
positive
even
after
the
adjustment
for
potential
confounders
(228
subjects;
OR
=
3.53
(CI95%
p
<
0.001)).
Our
results
support
the
a
priori
hypothesis
of
an
association
between
anxiety
and
polymorphism
Val66Met.
To
our
knowledge,
this
is
the
first
study
documenting
a
potential
role
of
polymorphism
in
a
community
sample
of
anxious
children
© 2011 Elsevier Ireland Ltd. All rights reserved.
and
adolescents.
Anxiety
are
functioning,
ogy
risk
ing
Brain
role
as
[37].
ing
prodomain
disorders
are
prevalent
in childhood
and
adolescence
and
associated
with
impairments
in academic,
social
and
family
as
well
as
related
to the
persistence
of
psychopathol-
in adulthood
[2].
Family
history
is
one
of
the
best-established
factors
for
anxiety
disorders,
with
heritability
estimates
rang-
from
20 to 40%
[12].
derived
neurotrophic
factor
(BDNF)
plays
an
important
in
neuronal
differentiation
during
brain
development,
as
well
in synaptic
plasticity
and
neuronal
survival
in the
adult
brain
A common
variant
of
the
BDNF
gene
in humans,
consist-
of
a single
nucleotide
polymorphism
(SNP,
rs 6265)
in the
region,
which
produces
a valine-to-methionine
sub-
∗Corresponding
los
fax:
E-mail
(G.G.
author
at:
Hospital
de
Clínicas
de
Porto
Alegre,
Av.
Ramiro
Barce-
2350/room
400
N.
Porto
Alegre,
Brazil.
Tel.:
+55
51
3359
8294;
+55
51
3359
8294.
addresses:
gmanfro@hcpa.ufrgs.br, gmanfro@portoweb.com.br
Manfro).
stitution
promising
Animal
is
behaviors
or not
Some
genotype
functional
had
the
and
The
role
and
that
this
ing
adolescents
at
codon
66
(Val66Met),
has
been
explored
with
some
results
in association
to neuropsychiatric
disorders
[21].
models
showed
that
the
Met
allele
of
the
BDNF
genotype
associated
with
a
reduced
BDNF
secretion
and
higher
anxious
[5]. If the
Met
allele
is
associated
with
anxiety
disorders
is a
matter
of
intense
discussion
in literature
[13,17,35,40].
studies
have
also
implicated
the
Val
allele
of
the
BDNF
in vulnerability
for
anxiety
[10,17]. A
recent
study
with
neuroimaging
in adolescents
showed
that
Met-carriers
greater
neural
responses
for
emotional
faces,
suggesting
that
Met
allele
might
affect
important
neural
correlates
for
anxiety
depression
[19].
primary
objective
of
this
investigation
was
to examine
the
of
Val66Met
polymorphism
in anxiety
disorders
in childhood
adolescence.
Our
a priori
hypothesis
was
that
the
Met
allele
of
BDNF
genotype
would
be
a risk
factor
for
anxiety
disorders
in
group.
To our
knowledge
this
is the
first
investigation
examin-
the
impact
of
Val66Met
in a
community
sample
of children
and
evaluated
with
stringent
criteria
for
anxiety
disorders.
0304-3940/$
doi:10.1016/j.neulet.2011.07.044
– see
front
matter ©

2011 Elsevier Ireland Ltd. All rights reserved.

Page 2

198
A.
Tocchetto
et al.
/ Neuroscience
Letters
502 (2011) 197–
200
Cases
and
controls
were
selected
from
a larger
community
sample
ipated
(cases
the
markers
almost
by
tus
of
consent
with
and
The
nia
semi-structured
was
view
determined
impairment
try
disorders).
Children
anxiety
according
out
as controls.
history
any
or
excluded
group,
Additionally,
traits
self-report
perament
been
dency
stimuli
Behavioral
assess
bic
DNA
DNA
cation
of
2457
children
and
adolescents
(10–17
years)
that
partic-
in a cross-sectional
anxiety
disorder
study
[32].
All
subjects
and
controls)
came
from
the
same
community
sample
in
south
of
Brazil.
A recent
study
with
48
ancestry
informative
showed
that
individuals
from
southern
Brazil
present
an
exclusively
European
ancestry
[33]. Skin
color
was
assessed
observation
during
the
clinical
interview.
Socio-economic
sta-
was
evaluated
using
an
official
index
of the
Brazilian
Institute
Geography
and
Statistics.
All
parents
provided
written
informed
for
participating
in the
study.
This
study
is in compliance
the
Declaration
of
Helsinki
and
was
approved
by the
Research
Ethics
Committee
of
HCPA
(07-595).
K-SADS-PL
(Schedule
for
Affective
Disorder
and
Schizophre-
for
School-Age
Children
– Present
and
Lifetime
Version)
is a
interview
based
on
the
DSM-IV
criteria
that
[14]
administered
to the
mother/father
followed
by
a direct
inter-
with
all
the
child/adolescent.
Best-estimate
diagnoses
were
after
reviewing
generated
diagnoses,
symptoms
and
level
by
clinicians
with
experience
in Child
Psychia-
(total
number
of
interviewers
=
6,
kappa
=
0.93
across
anxiety
diagnosed
with
social
anxiety
disorder,
generalized
disorder,
separation
anxiety
disorder
or panic
disorder
–
to the
K-SADS-PL
– were
selected
as
cases.
Subjects
with-
any
anxiety
disorder
except
for
specific
phobia
were
selected
Individuals
with:
(1)
significant
organic
illness;
(2)
of
bipolar
disorder,
pervasive
developmental
disorder
or
psychotic
disorder;
(3)
history
of
alcohol
or drugs
dependence
abuse;
and
(4)
clinical
suspicious
of
mental
retardation
were
from
this
study.
Table
1 outlines
the
rates
of
disorders
by
comorbid
conditions
and
gender.
subjects
were
evaluated
for
the
anxiety-related
harm-avoidance
(HA)
and
behavior
inhibition
(BI)
using
instruments.
HA was
assessed
with
the
Cloninger’s
Tem-
and
Character
Inventory
[6].
This
instrument
has
already
used
in adolescents
[20]. HA is described
as
a
heritable
ten-
to inhibit
or
stop
behaviors
in response
to signals
of
aversive
in order
to avoid
punishment.
The
Self-Report
Scale
of
Inhibition
– Retrospective
Version
[30]
was
used
to
childhood
BI,
a temperamental
risk
factor
for
panic
and
pho-
anxiety
disorders
[36].
was
extracted
from
biological
samples
of
saliva
using
the
2006
Oragene®Kit
(Laboratory
Protocol
for
Manual
Purifi-
of
DNA
from
4.0
mL
of
Oragene®DNA
saliva).
Genotyping
was
researchers
and
controls.
Data
percentage
individuals,
man
a group.
with
dent’s
confounders
A
(HA
der
was
psychopathology
Tests
ducted
performed
DOS.
allele
than
was
I
From
sectional
saliva
unrelated
cases
tion.
From
Generalized
der,
panic
41
four
(67.9%)
p = 0.035).
Demographic
parisons
genotypic
Caucasian
equilibrium
?2= 1.23;
based
on
the
technique
described
by
Ribasés
et
al.
[31]. The
involved
in genotyping
were
blind
for
the
phenotypes,
identical
procedures
were
used
for
genotyping
all
cases
and
are
presented
as
mean
± standard
deviation,
count
and
(%).
For
the
analysis,
we
excluded
the
four
Met/Met
considering
the
small
sample
size
as
suggested
by Kauf-
et al.
[15]. Analysis
was
carried
on
using
anxiety
disorders
as
Bivariate
analysis
between
cases
and
controls
were
made
Fisher’s
Exact
test,
Pearson’s
Chi-square
and
independent
Stu-
t-test.
We
ran
a
logistic
regression
model
controlling
for
using
anxiety
disorders
group
as
dependent
variable.
linear
regression
model
was
used
to analyze
anxiety-related
traits
and
BI).
All
variables
with
a
p-value
less
than
0.20
plus
age,
gen-
and
skin
color
were
included
in the
model.
Additional
analysis
run
using
as
a control
group
only
those
subjects
without
any
(n = 61).
for
deviation
from
Hardy-Weinberg
equilibrium
were
con-
with
the
?2test
for
goodness
of
fit.
Statistical
analysis
was
using
the
software
SPSS
version
14.0
and
PEPI
v.
4.0
for
The
level
of
significance
used
was
˛ = 0.05.
Considering
a
Met
frequency
of
20%,
we
have
a power
of
84%
to detect
OR
higher
2.5.
It is important
to note
that
no other
polymorphism
or gene
assessed
in
this
sample
thus
minimizing
chances
of
Error
type
due
to multiple
testing.
the
2457
children
that
accepted
to participate
in the
cross-
study,
240
attended
diagnostic
evaluation
and
had
their
collected
for
DNA
extraction
for
this
case–control
study.
Only
children
were
included
in the
analysis
(n = 234).
Three
and
three
controls
were
excluded
due
to mental
retarda-
Hence
the
final
sample
included
131
cases
and
97
controls.
cases
of
anxiety
disorders,
93 (71%)
were
diagnosed
as
having
Anxiety
Disorder,
55 (42%)
with
social
anxiety
disor-
46 (35.1%)
with
separation
anxiety
disorder
and
9 (6.9%)
with
disorder.
Seventy-five
(57.3%)
had
one
anxiety
disorder
only,
(31.3%)
had
two
anxiety
disorders
and
15 (1.5%)
had
three
or
anxiety
disorders.
Family
history
of
anxiety
was
positive
in 57
patients
and
27
(32.1%)
controls
(OR
1.88,
CI95%
1.07–3.31,
data,
psychiatric
comorbidity
and
genotype
com-
between
cases
and
controls
are
depicted
in Table
1.
The
frequencies
observed
are
very
similar
to other
studies
in
populations
[10]. The
sample
was
in Hardy-Weinberg
(Val/Val
156,
Val/Met
68,
Met/Met
4
individuals,
df
= 1; p = 0.26).
Table
Descriptive
1
of
cases
and
controls
in the
total
sample.
Variables

Study
groups

Statistics
Controls
(n = 97)

Cases
(n = 131)

Crude
OR
(CI95%)
or SMD
(CI95%)

Test
statistic

p-Value
Gender
Age
Skin
Socio-economic
Psychiatric
Enuresis
Attention
Oppositional
Tics
Depressive
Post-traumatic
Specific
BDNF
Val/Val
Val/Met
(female)

57 (60.6%)
12.5 (SD
69 (73.4%)
52 (65.0%)

93 (75%)

OR
SMD
OR
OR
= 1.94
(1.09–3.48)

0.027
0.14
0.24
0.364
(years)
= 2.41)

13.0 (SD
83
61
= 2.36)
= −0.47
(−1.10
to 0.15)

t = −1.47
(df
= 226)

color
(white)
(65.9%)
= 0.69
(0.38–1.25)

status
(disadvantage)
(58.1%)
= 0.74
(0.41–1.36)

comorbidities

6 (6.2%)
24 (24.7%)
17 (17.5%)
5 (5.2%)
11 (11.3%)
1 (1%)
17 (17.5%)

12
29
16
12
34
(9.2%)

OR
OR
OR
OR
OR
OR
OR
= 1.52
(0.55–4.23)

?2= 0.678
?2= 0.212
?2= 1.270
?2= 1.332
?2= 7.992
?2= 4.580
?2= 24.924
(df
= 1)

0.465
0.751
0.341
0.313
0.007
0.047
<0.001
deficit
hyperactivity
disorder
(22.1%)
= 0.86
(0.46–1.60)
(df
= 1)

defiant
disorder
(12.2%)
= 0.65
(0.31–1.37)
(df
= 1)

(9.2%)
= 1.87
(0.63–5.50)
(df
= 1)

disorder
(26.6%)
9 (6.9%)
65
= 2.82
(1.34–5.92)
(df
= 1)

stress
disorder
= 7.14
(0.88–57.34)
(df
= 1)

phobia
(49.6%)
= 4.63
(2.48–8.66)
(df
=
1)

genotypes

76 (78.4%)
18

80
50
(61.1%)

1
OR
?2= 9.62
(df
= 1)
(18.6%)
(38.2%)
= 2.63
(1.41–4.92)

0.002
Note: There
Abbreviations:
Bold
were
no Asian
or Indian
children
in the
sample.
Data
are
shown
for
psychiatric
comorbidity
more
frequent
than
5%.
OR,
odds
ratio;
CI,
confident
interval;
SMD,
standardized
mean
difference;
?2, chi-square;
df,
degrees
of
freedom.
values
indicate
p < 0.05.

Page 3

A.
Tocchetto
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al.
/ Neuroscience
Letters
502 (2011) 197–
200
199
Table 2
Multivarible
logistic
regression
for
anxiety
disorders
diagnoses.
B
Wald

OR
(CI95%)

p-Value
Gender
Age
Skin
Val/Met
Lifetime
Lifetime
Lifetime
Lifetime

0.215
0.007
−0.481
1.264
1.072
1.628
−1.970
1.357

0.432
0.012
2.244
12.856
5.400
2.076
2.793
15.649

1.24
1.01
0.62
3.54
2.92
5.09
0.139
3.88
(0.65–2.35)

0.511
0.913
0.134
<0.001
0.020
0.150
0.095
<0.001
(0.88–1.15)

color
(0.33–1.16)

genotype
(1.77–7.06)

depression
(1.18–7.21)

PTSD
(0.55–46.62)

conduct
(0.01–1.40)

specific
phobia
(1.98–7.61)

Abbreviations:
Bold
PTSD,
posttraumatic
stress
disorder;
OR,
odds
ratio.
values
indicate
p < 0.05.
Logistic
allele
childhood
(Table
exclusively
confirms
between
(B
sion
phobia).
individuals
ciation
Out
for
anxiety-related
copy
17.51
(0.31),
In
pendent
adolescence.
mal
reported
[9,11,25].
that
gene
At
First,
fear
including
that
bral
studies
allele
pal
polymorphism
ing
depressed
a known
sion,
et
allele),
tory
replicated
treatment
also
of
In
type
not
bition)
suggested
ety
regression
shows
that
carrying
one
copy
of
the
Met
confers
increased
chance
of
having
an anxiety
disorder
during
and
adolescence,
OR
= 3.53
(CI95%
1.77–7.06;
p < 0.001)
2).
Secondary
analysis
considering
as
the
control
group
subjects
with
no major
psychiatric
disorder
(n = 61)
the
difference
regarding
carrying
the
Met
allele
described
anxious
patients
and
non-anxious
controls,
OR
= 3.73
= 1.32,
Wald
= 9.76,
CI95%
1.63–8.54;
p = 0.002;
logistic
regres-
controlled
for
gender,
age,
skin
color
and
presence
of
specific
Additionally,
we
run
an
analysis
including
the
Met/Met
in a dominant
model
and
we
still
have
a positive
asso-
(cases
51/80
vs.
controls
21/76,
Fisher’s
test,
p = 0.0062).
of
the
final
sample
of
228
subjects,
102
were
evaluated
harm-avoidance
(HA)
and
104
for
behavior
inhibition
(BI).
No
traits
measures
were
associated
with
caring
one
of
Met
allele
(mean
(SD)
for
HA
Val/Val
16.68
(6.20)
vs.
Val/Met
(6.38),
p = 0.521;
for
BI
Val/Val
1.93
(0.32)
vs.
Val/Met
1.93
p = 0.961).
our
study,
we
observed
that
Val/Met
genotype
was
an
inde-
risk
factor
for
anxiety
disorders
during
childhood
and
Our
results
are
in agreement
with
findings
from
ani-
models
[5]
and
association
studies
in adulthood
that
have
an
association
between
BDNF
and
anxiety
modulation
Taken
together
all
these
results
support
the
hypothesis
BDNF
has
neurobiological
features
that
makes
it
a
candidate
in regulation
of
anxiety.
least
two
possible
explanations
might
account
for
our
results.
BDNF
may
be
associated
with
anxiety
by interfering
in
processing
orchestrated
by
mesial
temporal
lobe
structures,
amygdala
and
hippocampus.
Several
evidences
suggest
hippocampus
and
amygdala
play
a major
role
in the
cere-
pathways
linked
to anxiety
[1]. According
with
previous
[3,26,28],
individuals
heterozygous
for
the
66Met
BDNF
have
smaller
hippocampus
volume
and
worse
hippocam-
dependent
memory
functions.
Second,
it is possible
that
BDNF
interfere
in serotonin-mediated
pathways
lead-
to anxiety.
Decreased
BDNF
expression
has
been
described
in
adolescents
exposed
to adverse
events
[4]
– and
there
is
relation
between
traumatic
events,
anxiety
and
depres-
with
some
theoretical
common
causal
pathways.
Kaufman
al.
[15]
showed
an interaction
between
the
BDNF
genotype
(Met
the
gene
of
the
serotonin
transporter
and
maltreatment
his-
in predicting
depression
in a sample
of
children,
which
was
not
by recent
studies
[27]. Moreover,
chronic
antidepressant
with
selective
serotonin
reuptake
inhibitors
(which
are
effective
in the
treatment
of
anxiety)
increases
the
expression
BDNF
and
may
enhance
its
localization
at
synaptic
level
[4].
our
study
we
found
an association
between
Val/Met
geno-
and
between
the
dominant
model
and
anxiety
disorders,
but
with
anxiety-related
traits
(harm-avoidance
and
behavior
inhi-
in children
and
adolescents
as
it was
expected.
It can
be
that
the
association
between
the
Met
allele
and
anxi-
is dependent
on
the
presence
of
symptoms
severe
enough
to
cause
hand,
traits
from
ments
is
due
impairment
and
to reach
the
diagnostic
status.
On
the
other
we
could
have
not
found
an association
between
anxiety
and
the
Val/Met
genotype
because
these
traits,
differently
the
diagnostic
evaluation,
were
assessed
by self-report
instru-
that
could
not
be
completely
understood
by
our
subjects.
It
also
possible
that
we
did
not
have
power
to detect
an
association
to the
We analyzed
nificant
children
theory,
life
in
tability
shown
sures
at
ized
anxiety
ering
takes
Besides
because
out
as
Yet our
ple
–
in the
ing.
cannot
study.
genetic
tion
through
and
trolled
not
This
munity
and
Previous
dren
One
and
orders
selection
severe
cases
ing
disorder
treatment.
cept
smaller
sample
size
included
in the
BI
and
HA
measures.
anxiety
disorders
as
a group
based
on
the
sig-
comorbidity
and
overlap
between
anxiety
diagnosis
in
and
adolescents
[16,29].
Considering
the
diathesis-stress
anxiety
may
be expressed
according
to stressors
during
the
course
[22,39]. The
analysis
considering
anxiety
as
a group
is
agreement
to previous
studies
that
have
shown
that
the
heri-
of
anxiety
is not
disorder
specific
[36]. Most
studies
have
moderate
convergence
between
children’s
self-report
mea-
and
anxiety
diagnoses
but
demonstrated
poorer
agreement
the
level
of
specific
anxiety
disorders
[34]. Moreover
random-
clinical
trials
for
anxiety
disorders
in childhood
also
evaluate
disorder
as
a group
[38]. This
approach,
even
not
consid-
the
validity
of
different
diagnosis
of
anxiety
disorders
poor,
into
account
a
common
etiology
and
treatment
response
[18].
this,
we
excluded
specific
phobia
from
the
anxiety
group
of
its
higher
frequency
and
higher
rates
of remission
with-
treatment
[7].
Moreover
it has
a different
factor
of
heritability
compared
to other
anxiety
disorders
[8].
study
presents
some
limitations.
The
moderate
sam-
size
was
due
to the
origin
of the
sample
– community
sample
subjects
were
not
looking
for
treatment,
and
the
participation
study
required
a
hospital
visit
both
time
and
cost
demand-
Additionally,
the
risk
for
biases
related
to ethnic
stratification
be
excluded
and
no genomic
control
was
performed
in
our
Therefore
our
findings
could
have
been
biased
by
hidden
heterogeneity
that
can
be
present
in the
Brazilian
popula-
of
European
ancestry.
This
confounding
factor
was
minimized
the
selection
of
a community
school
sample
– all
the
cases
controls
came
from
exactly
the
same
population
and
we
con-
the
analysis
for
skin
color.
Another
limitation
is that
we
did
have
power
to test
for
gender
and
gene
interaction.
study
is innovative
in combining
three
aspects:
(1)
a
com-
sample,
(2)
a
sample
comprised
by
children
and
adolescents
(3)
a stringent
psychiatric
evaluation
for
anxiety
disorders.
studies
had
investigated
the
effect
of
BDNF
gene
in chil-
and
adolescents,
but
did
not
evaluate
psychiatric
disorder.
evaluated
a
sample
with
“anxious
depression
symptoms”
[24]
the
other
one
characterized
adolescents
with
internalizing
dis-
[23]. Studying
a community
sample
avoids
the
potential
biases
of
clinical
samples,
such
as
the
restriction
to more
cases
of
patients
in treatment.
In our
study,
we
included
as
subjects
that
have
never
been
previously
diagnosed
as
hav-
anxiety
disorders.
Our
cases
included
those
with
less
severe
and
those
whose
parents’
hesitate
looking
for
psychiatric
Consequently,
our
findings
can
represent
a broader
con-
of
anxiety
disorders,
which
is
not
restricted
to severe
cases.

Page 4

200
A.
Tocchetto
et al.
/ Neuroscience
Letters
502 (2011) 197–
200
Besides
tion,
Studying
tunity
possibly
cal
and
add
findings
reinforces
opment
confirm
this,
both
cases
and
controls
came
from
the
same
popula-
with
the
same
epidemiological
background.
psychiatric
symptoms
in children
brings
the
oppor-
of
evaluating
complex
behavior
early
in the
development,
contributing
to the
understanding
of
psychopathologi-
processes.
Our
findings
from
a community
sample
of
children
adolescents
assessed
through
out
a detailed
clinical
evaluation
new
relevant
data
to the
international
literature,
since
genetic
on
this
polymorphism
in childhood
are
scarce.
Our
study
the
hypothesis
that
BDNF
can
be
related
to the
devel-
of
early
onset
of
anxiety
disorders.
Additional
studies
to
our
findings
are
necessary.
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