Behavioural Brain Research 274 (2014) 137142

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Research report
BDNF val66met genotype and schizotypal personality traits interact
to inuence probabilistic association learning
Ashley Jayne Skilleter
a,b,c
, Cynthia Shannon Weickert
a,b,c
, Ahmed Abdelhalim Moustafa
d
,
Rasha Gendy
e
, Mico Chan
e
, Nur Arin
e
, Philip Bowden Mitchell
a,f
,
Thomas Wesley Weickert
a,b,c,
a
School of Psychiatry, University of New South Wales, Randwick, NSW, Australia
b
Schizophrenia Research Institute, Darlinghurst, NSW, Australia
c
Neuroscience Research Australia, Randwick, NSW, Australia
d
School of Social Sciences and Psychology, Marcs Institute for Brain and Behaviour, University of Western Sydney, Penrith, NSW, Australia
e
School of Medicine, University of New South Wales, Randwick, NSW, Australia
f
Black Dog Institute, Randwick, NSW, Australia
h i g h l i g h t s

BDNF val66met interacts with schizotypal personality traits to inuence learning.

BDNF met-carriers displaying few schizotypal personality traits performed best.

BDNF met-carriers displaying high schizotypal personality traits performed worst.

Fronto-striatal related probabilistic learning decits may be intrinsic to schizophrenia.

a r t i c l e i n f o
Article history:
Received 17 March 2014
Received in revised form24 July 2014
Accepted 27 July 2014
Available online 11 August 2014
Keywords:
Brain derived neurotrophic factor val66met
polymorphism
Probabilistic association learning
Schizotypal personality
a b s t r a c t
The brain derived neurotrophic factor (BDNF) val66met polymorphism rs6265 inuences learning and
may represent a risk factor for schizophrenia. Healthy people with high schizotypal personality traits
display cognitive decits that are similar to but not as severe as those observed in schizophrenia and
they can be studied without confounds of antipsychotics or chronic illness. How genetic variation in
BDNF may impact learning in individuals falling along the schizophrenia spectrum is unknown. We
predicted that schizotypal personality traits would inuence learning and that schizotypal personality-
based differences in learning would vary depending on the BDNF val66met genotype. Eighty-nine healthy
adults completed the Schizotypal Personality Questionnaire (SPQ) and a probabilistic association learning
test. Blood samples were genotyped for the BDNF val66met polymorphism. An ANOVA was performed
with BDNF genotype (val homozygotes and met-carriers) and SPQ score (high/low) as grouping variables
and probabilistic association learning as the dependent variable. Participants with low SPQ scores (fewer
schizotypal personality traits) showed signicantly better learning than those with high SPQ scores. BDNF
met-carriers displaying few schizotypal personality traits performed best, whereas BDNF met-carriers
displaying high schizotypal personality traits performed worst. Thus, the BDNF val66met polymorphism
appears to inuence probabilistic association learning differently depending on the extent of schizotypal
personality traits displayed.
Crown Copyright 2014 Published by Elsevier B.V. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

Corresponding author at: School of Psychiatry, University of New South Wales,

Neuroscience Research Australia, Barker Street, Randwick, NSW2031, Australia.
Tel.: +61 2 9399 1730; fax: +61 2 9399 1034.
E-mail address: t.weickert@unsw.edu.au (T.W. Weickert).
1. Introduction
Brain-derivedneurotrophic factor (BDNF) is awidelydistributed
neurotrophin in the central nervous system and is important for
synaptic plasticity, neuronal differentiation, and survival [14].
A single nucleotide polymorphism (SNP) in the human BDNF
http://dx.doi.org/10.1016/j.bbr.2014.07.041
0166-4328/Crown Copyright 2014 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/3.0/).
138 A.J. Skilleter et al. / Behavioural Brain Research 274 (2014) 137142
gene exists which produces a valine to methionine substitution
in the protein prodomain that can impact intracellular traf-
cking, packaging and regulated secretion of BDNF [5]. The
presence of a met allele may attenuate episodic memory and
hippocampal function in healthy adult humans [57]. However,
some studies examining the val66met polymorphism (rs6265)
of the BDNF gene in patients with schizophrenia report a sig-
nicant over-transmission of the val allele [8,9], in the face of
worse episodic memory performance overall in schizophrenia
[10]. Thus, this discrepancy in the literature may suggest that
the advantageous versus deleterious effects of the BDNF val66met
genotype may vary on the basis of context, e.g., health versus
illness.
While the effect of the BDNF genotype on episodic mem-
ory and hippocampal function has been studied, little is known
regarding the role of the BDNF genotype in probabilistic associa-
tion learning, which requires a gradual learning of cue-outcome
associations that is dependent on normal frontalstriatal activ-
ity [1113]. The relationship between BDNF and probabilistic
association learning is of interest as peripheral blood BDNF lev-
els correlate with brain activity during probabilistic association
learning in healthy adults [14] and the BDNF val66met polymor-
phismalso inuences prefrontal cortex function in healthy people
and those at high genetic risk for schizophrenia [1518]. Proba-
bilistic association learning is impaired in schizophrenia [1922]
and is associated with abnormal fronto-striatal activity [23]. Sib-
lings of people with schizophrenia who may share risk genes
are also more likely to show probabilistic association learning
decits [21].
Schizotypal personality traits, such as magical ideation, per-
ceptual aberration, inappropriate affect, and social anxiety, closely
resemble symptoms characterising schizophrenia but are less
orid and debilitating [24,25]. While schizotypal personality
disorder is a formal diagnosis [26], examining those with a
high expression of schizotypal personality traits (i.e., schizo-
typy) in an otherwise healthy sample is important as this
population may reveal clues to neurobiological routes that
predispose a person to schizophrenia [27] and allows the exam-
ination of behavioural and cognitive processes associated with
schizophrenia without the potential confounds of antipsychotic
treatment and a history of chronic illness. Schizotypal personality
traits are displayed along a spectrum in which some individuals
may display attenuated traits without debilitating effects. Some
genetic polymorphisms, such as in Dysbindin, have been shown
to act as a moderating factor on both schizotypal personality traits
and cognition [28]. Schizotypal personality traits may be related
to BDNF genotype, given that healthy met carriers show more
stress-induced paranoid thoughts than val homozygotes [29], and
schizophrenia-like traits are more often observed in relatives of
people with schizophrenia who may share genes associated with
schizophrenia [3033].
The aim of the present study was to determine the extent
to which schizotypal personality traits inuence frontalstriatal
dependent probabilistic association learning in the context of
BDNF val66met genotype in a sample of healthy young adults.
Given that BDNF in the striatum is derived largely by antero-
grade transport from cortical afferents [34], alterations in the
BDNF genotype may also affect frontalstriatal circuitry and
in turn probabilistic association learning as assayed by per-
formance on the weather prediction test, a reliable assay of
frontalstriatal function [11,13,23]. We predicted that schizo-
typal personality traits would negatively inuence probabilistic
association learning in otherwise healthy young adults and that
schizotypal personality-based differences in learning would vary
depending on the BDNF val66met genotype allelic combination
displayed.
2. Materials and methods
2.1. Participants
Eighty-nine healthy young adults without a history of mental
illness were recruited from the local university and the commu-
nity. All participants were screened for the following exclusion
factors: a personal or family history of psychiatric disorder, history
of alcohol or substance abuse/dependence withinpast 5years, head
injury with loss of consciousness, seizures, central nervous system
infection, developmental disorder, and uncontrolled diabetes or
hypertension. A four subtest version of the Wechsler Adult Intel-
ligence Scale, 3rd Edition (WAIS-III) [35] was administered to all
participants to obtain estimates of current IQ. The Depression, Anx-
iety, and Stress Scales [36] and the SF36v2 Health Survey [37] were
administered to assess negative emotional states and health status,
respectively (see Supplemental Table 1 for demographic character-
istics of the entire sample). Writteninformedconsent was obtained
fromall participants before beginning the study and all procedures
were approvedby the University of NewSouthWales andthe South
Eastern Sydney and Illawarra Area Health Service Human Research
Ethic Committees.
2.2. Schizotypal personality traits
The self-report Schizotypal Personality Questionnaire (SPQ) is
a psychometric and multidimensional questionnaire for assessing
schizotypal traits developed fromthe DSM-III-R criteria for schizo-
typal personality disorder [38]. Participants completed the SPQ,
which contains subscales for nine schizotypal traits (ideas of ref-
erence, excessive social anxiety, odd beliefs or magical thinking,
unusual perceptual experiences, odd or eccentric behaviour, no
close friends, odd speech, constricted affect, suspiciousness) [39].
The questionnaire comprises 74 items with each being scored 1 for
a yes and 0 for a no response.
2.3. Probabilistic association learning assessment
Participants were tested on the probabilistic association learn-
ing weather prediction test described in detail elsewhere
[1922,40]. In this test, participants learn the relationship between
two equally occurring outcomes (rain or shine) and combinations
of four cue cards composed of simple geometric shapes. Partici-
pants were instructed to predict an outcome of rain or shine on
the basis of four cue cards presented individually or in combina-
tions of up to 3 cards. They were told that they should guess at rst
but they would gradually improve at determining which cue card
combinations predicted each outcome. The relationships between
cue card combinations and their outcomes (rain or shine)
were predetermined on a probabilistic basis (see Supplemental
Table 2). Card combinations were presented pseudo-randomly
with the constraint that identical cue combinations would not
appear consecutively and identical outcomes were limited to ve
consecutive occurrences. The experimental paradigm consisted
of 15 blocks of weather prediction trials (with 10 trials/block),
yielding 150 weather prediction trials in total. Testing was
administered individually in a quiet room by a trained research
assistant.
2.4. Genetic assay
Blood samples were collected in 9ml EDTA tubes and DNA was
isolated fromthe buffy coat and genotyped for the BDNF val66met
polymorphism (rs6265) using Applied Biosystems TaqMan SNP
assays with our ABI Prism 7900HT Fast Real Time quantitative
PCR system and standard procedures. Genomic DNA (gDNA) from
A.J. Skilleter et al. / Behavioural Brain Research 274 (2014) 137142 139
Table 1
Demographics of the sample, broken down by high/lowSPQ group and BDNF genotype group.
High schizotypy N=39 Lowschizotypy N=50 F value
2
df P
Valval
N=25
Met carrier
N=14
Valval
N=25
Met carrier
N=25
Age 23.1 (0.9) 21.7 (1.2) 21.2 (0.9) 22.8 (0.9) 2.24 1,85 0.14
Years of
education
14.2 (0.4) 14.5 (0.5) 14.4 (0.4) 14.9 (0.4) 0.07 1,85 0.79
Gender, M/F 8/17 7/7 15/10 10/15 4.37 3 0.22
Ethnicity Cau-
casian/Asian
10/15 2/12 16/9 9/16 9.81 3 0.02
WAIS-III FS IQ 111.6 (2.2) 115.6 (2.9) 116.6 (2.2) 114.8 (2.2) 1.46 1,85 0.23
SPQ Total score 25.4 (1.3) 24.7 (1.8) 6.3 (1.3) 6.8 (1.3) 0.17 1,85 0.67
Note: Means with standard deviations in parentheses. WAIS-III FSIQ: Wechsler Adult Intelligence Scale, 3rd Edition Full Scale IQ estimate; SPQ: Schizotypal Personality
Questionnaire.
each case in the cohort was prepared at a dilution of 10g/l. A
PCR solution consisting of 2.5l of 2 Universal mastermix with
ROX, 0.125l genotyping probe, and0.375l ddH
2
Owas prepared,
added into a 384-well plate containing 1l of gDNA from each
sample, and pipetted up and down to ensure the gDNA and PCR
solution were sufciently mixed. The plate was optically sealed,
spun, and set into the Prism 7900 instrument for PCR genotyping.
An Allelic Discrimination (AD) programme was used to determine
BDNF genotype with ABIs SDS version 2.3 software and uorescent
detector markers (VIC and FAM). A Chi-square analysis conrmed
that the allele and genotype frequencies were in HardyWeinberg
equilibrium.
2.5. Data analysis
Statistica version 7 was used for statistical analyses. The mean
total SPQ score was calculated for the whole sample and partic-
ipants were then categorised using a mean split as either being
higher or lower relative to the mean SPQTotal score. Supplemental
Fig. 1 shows the distribution of the SPQ scores as well as the loca-
tion of the mean score split. Percent correct after every 10 trials
was used to determine acquisition rate (improvement over time)
andthe meancumulative percentage correct at the endof 150 trials
was used as a measure of overall performance.
Due to the expected low frequency of participants in the met
homozygote group, we collapsed the val/met group with the met
homozygotes to form a met carrier group. Two-way ANOVAs and
Chi-square analyses were performed to compare the four groups
(high/low SPQ score by 2 BDNF genotypes) on demographic vari-
ables. The main two-way ANOVA consisted of BDNF genotype
(val homozygotes and met-carriers) and SPQ (high/low) as group-
ing variables and probabilistic association learning percent correct
after 150 trials as the dependent variable. Follow-up Least Sig-
nicant Difference (LSD) tests were used to determine signicant
differences amonggroups for anymaineffects andinteractions. The
alpha level for statistical signicance was set at p0.05. Given that
schizotypal personality traits may be conceptualised as being on a
continuum, wealsoperformedaforwardstepwiselinear regression
analysis with years of age, years of education, WAIS-III IQ esti-
mate, and SPQ total scores as predictor variables and probabilistic
association learning percent correct at trial 150 as the dependent
variable in each BDNF val66met genotype group (valval and met
carriers) independently. To determine the extent to which the
BDNF val66met allele produces an allele-dose effect, an additional
supplementary ANOVA was performed in which the sample was
divided into 3 genotype groupings: val/val, val/met and met/met.
Previous work suggests that different strategies employed dur-
ing probabilistic association learning might inuence performance
[41] and thus, the present study also used a strategy cluster-
ing analysis [42] to categorise each participant into one of three
strategies. Probabilistic association learning data were classied
into the following three strategies: the multi-cue strategy in
which participants respond on the basis of associations of all four
cues witheachoutcome (the optimal strategy); the one-cue strat-
egy in which participants respond on the basis of the presence
or absence of a single cue card while disregarding the other cue
cards; and the singleton strategy in which participants only learn
to associate the four card patterns that have only one cue present
and all the others are absent. A one-way ANOVA with strategy use
as a grouping factor was used to determine any effect of strategy
on probabilistic association learning. We examined the frequency
withwhichthehighandlowSPQscoregroups usedthethreestrate-
gies by a Chi-square analysis to determine any group differences in
strategy use.
3. Results
The demographics for the participant sample, broken down by
high/lowschizotypal personality score and the two BDNF val66met
genotype groups are showninTable 1. Aseries of two-way ANOVAs
based on two BDNF val66met genotype groups and high/low SPQ
groups revealed a signicant main effect of SPQgroup for total SPQ
score as expected and no signicant interactions on the basis of
age, years of education, WAIS-III full-scale IQ scores, and total SPQ
scores. The results of separate ANOVAs to test for differences inSPQ
factor scores on the basis of high-low SPQ classication and BDNF
valmet genotype groupings revealed a signicant main effect of
SPQhigh-lowclassication(as expected), no signicant maineffect
of BDNF genotype, and no signicant interaction for each of the
three separate ANOVAs (see Supplemental Table 3). Separate Chi-
square analyses revealed no signicant differences among BDNF
genotype groupings on the basis of gender but signicant differ-
ences among ethnic groups such that there was a larger proportion
of Asians compared to Caucasians, across most of the genotype
groups.
A two-way ANOVA, grouping the BDNF genotypes into val
homozygotes or met-carriers versus high/lowSPQgroups, revealed
a signicant main effect of high/lowschizotypal personality group
such that participants with low SPQ scores showed signicantly
better probabilistic association learning than those with high SPQ
scores, F(1, 85) =7.37, P=0.008 (see Fig. 1). There was no signif-
icant main effect of BNDF genotype on probabilistic association
learning F(1, 85) =0.41, P=0.52. There was a signicant interac-
tion between schizotypal personality group and BDNF genotype
on probabilistic association learning, F(1, 85) =7.35, P=0.008 (see
Fig. 2). Follow-up LSD tests revealed that BDNF met-carriers
with low schizotypal personality trait scores performed sig-
nicantly better during probabilistic association learning than
BDNF met-carriers with high schizotypal personality trait scores,
P=0.0006. BDNF val homozygotes who displayed high schizotypal
140 A.J. Skilleter et al. / Behavioural Brain Research 274 (2014) 137142
Table 2
Results of forward, stepwise linear regression analysis with years of age, years of education, WAIS-III IQ, and SPQtotal score as predictor variables and probabilistic association
learning percent correct at trial 150 as the dependent variable in BDNF val66met genotype groups (valval and met carriers) separately.
Criterion/dependent variables with their signicant predictors P Partial eta-squared Observed power (=0.05)
BDNF valval
Probabilistic association learning percent correct at trial 150
WAIS-III IQ estimate 0.38 0.006 0.15 0.80
BDNF met carriers
Probabilistic association learning percent correct at trial 150
SPQ Total score 0.46 0.003 0.21 0.87
Note: WAIS-III =Wechsler Adult Intelligence Scale, 3rd Edition; SPQ=Schizotypal Personality Questionnaire; BDNF =brain derived neurotrophic factor.
Fig. 1. Schizotypal personality traits inuence probabilistic association learning.
Participants with low SPQ scores showed signicantly better probabilistic asso-
ciation learning than those with high SPQ scores (P=0.008). Error bars represent
standard errors.
Fig. 2. BDNF valmet genotype inuences probabilistic association learning in the
context of schizotypal personality traits. ***BDNF met-carriers with lowschizotypal
personality trait scores performed signicantly better during probabilistic asso-
ciation learning than met-carriers with high schizotypal personality trait scores
(P=0.0006). *BDNF val homozygotes with high schizotypal personality trait scores
and val homozygotes with lowschizotypal personality trait scores both performed
signicantly better than met-carriers with high schizotypal personality trait scores
(P =0.03).
personality trait scores performed signicantly better than met-
carriers with high schizotypal personality trait scores, P=0.03.
BDNF met-carriers with high schizotypal personality trait scores
performed signicantly worse than val homozygotes with low
schizotypal personality trait scores, P=0.03. Although val homozy-
gotes who displayed low schizotypal personality trait scores
appearedto performnumerically worse thanmet-carriers who dis-
played low schizotypal personality trait scores, the difference was
not signicant, P=0.11. SeeSupplemental Fig. 2for similar results in
the three genotype group analysis. Results of the regression anal-
ysis using age, education, IQ, and SPQ total scores as predictors
of probabilistic association learning percent correct at trial 150 in
each of the BDNF genotype groups (val homozygotes and met carri-
ers) independently revealed that only IQ predicted percent correct
at trial 150 in the BDNF val homozygotes; whereas, only SPQ total
score predictedpercent correct at trial 150 inthe BDNF met carriers
(see Table 2).
A one-way ANOVA revealed a signicant effect of strategy, such
that the multi-cue strategy results in the best performance and the
one-cue strategy results in the worst performance, F(2, 96) =26.08,
P<0.0001. Given the low number of participants (<5) in the high
and low SPQ score groups using the one-cue strategy, our Chi-
square analysis to detect group differences in strategy use was
performed using only data for the multi-cue and singleton strate-
gies. Results of this Chi-square analysis revealed that there was
a signicant difference in the number of people in the high/low
SPQgroups whousedmulti-cueor singletonstrategies,
2
(1) =5.46,
P=0.02. A signicantly greater number of people displaying fewer
schizotypal personality traits used the multi-cue strategy (see Sup-
plemental Table 4).
4. Discussion
We found that schizotypal personality traits inuence prob-
abilistic association learning, such that participants with low
SPQ scores showed signicantly better learning than those with
high SPQ scores. Thus, like people with schizophrenia, peo-
ple with a higher expression of schizotypal traits are impaired
in frontalstriatal dependent probabilistic association learning.
However, in this sample it can be concluded that this impair-
ment is not secondary to an effect of antipsychotic medication,
chronic illness, or education/IQ differences between the groups.
Other studies have shown probabilistic association learning and/or
frontalstriatal dysfunction in rst episode psychosis patients [43],
people displaying prodromal symptoms [44], people at high risk
to develop psychosis [45], and in unaffected siblings of people
with schizophrenia [21,46]. This supports our hypothesis that even
within a healthy population, schizotypal traits do impact learn-
ing and that studying healthy adults with schizotypal personality
traits may provide further insight into cognitive dysfunction in
schizophrenia. However, it is important to note that although
our high schizotypal group displays some schizotypal personality
traits, these schizotypal traits are on a continuum; thus, our high
schizotypal group would not meet criteria for diagnosis of schizo-
typal personality disorder but may still be useful to examine the
effects of schizotypal personality traits.
Noguchi et al. [47] examined the association between schizoty-
pal traits in healthy adults and cognitive function and found that
A.J. Skilleter et al. / Behavioural Brain Research 274 (2014) 137142 141
SPQ scores showed a signicant inverse correlation with verbal IQ
and the information, comprehension and similarities subtests from
the Wechsler Adult Intelligence Scale-Revised. McClure et al. [48]
showedthat a cognitive composite score was signicantlyimpaired
in schizotypal personality disorder relative to healthy controls and
avoidant personality disorder. The results of the current study fur-
ther suggest that a relatively high expression of schizotypal traits
in healthy adults are associated with learning decits, suggesting
that schizotypal traits themselves, even at a non-clinical level, may
interfere with cognition and co-occur with some cognitive decits.
To our knowledge, the impact of the BDNF polymorphism on
frontalstriatal learninginhumans has not previouslybeendemon-
strated. We found that BDNF met homozygotes displaying few
schizotypal personality traits performed best and those BDNF met
homozygotes displaying a high degree of schizotypal personality
traits performed worst on probabilistic association learning. Thus,
a high load of schizotypal personality traits appears to predict
poorer learning, which may be accentuated by the BDNF met allele.
Consistent with previous studies of healthy adults, the presence of
the BDNF val allele appears to provide a protective effect on learn-
ing, but only in the context of high schizotypal personality traits.
This suggests that there may be a deleterious impact of the BDNF
met allele for learning requiring frontalstriatal circuitry and sup-
ports the negative effect of the BDNF met allele on memory shown
in previous studies of healthy adults [57] but only in the con-
text of a high load of schizotypal personality traits. However, the
possibleassociationof themet alleletobetter frontalstriatal learn-
ing performance in low schizotypal personality trait individuals
suggests that genotype effects can vary depending on personal-
ity characteristics that are likely inuenced by variation in other
genes.
Eisenberg et al. [49] found that the met allele was associated
with signicantly less hippocampal regional cerebral blood ow
(rCBF) in people with schizophrenia during a working-memory
task. However, the opposite effect of BDNF genotype was seen in
healthy controls, such that the met-carriers showed increased hip-
pocampal rCBF, suggesting that variation in the BDNF val66met
polymorphism interacts differentially with aspects of hippocam-
pal and frontotemporal function in schizophrenia and healthy
adults. The SPQ highlow group by BDNF genotype interaction in
the present study showing signicantly impaired learning in met
homozygotes with high schizotypal personality scores and signif-
icantly better learning in met homozygotes with low schizotypal
personality scores supports the Eisenberg et al. [49] nding of a
differential effect for the BDNF met genotype on brain physiology
(rCBF) that is dependent on diagnostic status (schizophrenia versus
healthy control) and shows that this differential genotype effect
may not be simply secondary to antipsychotic effects or to other
confounds of having a chronic debilitating mental illness.
Egan et al. [5] demonstrated that when the BDNF met allele
is transfected into rat hippocampal neurons, it results in blunted
BDNF trafcking, activity-dependent secretion, and less BDNF
protein release. The current study found that within the high
schizotypy group, val homozygotes perform signicantly better
than met homozygotes, which suggests that when there is more
releasable BDNF protein (e.g., in vals), there is better learning in
those with more schizotypal traits relative to met homozygotes
with more schizotypal traits. This is supported by previous stud-
ies demonstrating that the met allele is detrimental for learning
and memory [5,6] as well as IQ [50] in healthy adults. However,
in the current study the exact opposite effect was found in those
individuals with lowSPQ scores, where the met allele appeared to
be benecial (althoughnot signicantly greater) for frontalstriatal
learning relative to BDNF val homozygotes. This suggests that ear-
lier studies may have recruited individuals on the high end of the
SPQ spectrumand that the BDNF val/met polymorphismhas quite
different effects depending on the extent of schizotypal personality
traits expressed.
Whileusingadichotomous model andbreakingschizotypal per-
sonality traits into high and low categories for analysis may not
be most consistent with the continuous nature of the schizotypal
personality trait concept and scale, we obtained similar results in
both an ANOVA using the dichotomous model and our regression
analyses in which SPQ scores were treated as a continuous vari-
able. The regression analyses demonstrated that a change in the
degree of schizotypal personality traits contributed signicantly to
the extent of probabilistic association learning only in BDNF met
carriers. These results show that in this case whether the analysis
is performed based on cut off scores or using SPQ scores as a con-
tinuous variable, the effect in BDNF met carriers is robust enough
to yield signicant effects with either model.
Finally, we conrmedthat themulticuestrategywas theoptimal
strategy, which supports previous ndings on strategy use during
probabilistic association learning [41,51]. We also found that those
with a low expression of schizotypal personality traits used the
more optimal multi-cue strategy which is consistent with display-
ing a signicantly better performance.
There are limitations to the current study. In the original sample
on which the SPQ was developed and normed [38] the mean SPQ
total score was 26.9, as opposed to our study in which the mean
SPQ total score was 14.7. Thus, our sample showed a lesser extent
of schizotypal traits than the original study. In a similar manner,
manyof the people inour highschizotypal personalitygroupwould
not have been classied as deviant, having an SPQ score >42 [52].
Second, we recruited mainly students fromthe local university and
thus a sampling bias may exist such that our sample has a higher
cognitive functioning capacity as reected in the above average
WAIS-III IQscores. Inspiteof theselimitations, inthe39peoplewho
scoredabove14.7, their meantotal SPQscorewas 25.2andwas sub-
stantially different fromthe meanscore of 6.6 inthe lowSPQgroup.
We did not nd a main effect of BDNF valmet polymorphism on
probabilistic association learning. However, our nding of a BDNF
valmet genotype by SPQhighlowgroup interactionsuggests that
a genotype effect on learning may be revealed in the context of
schizotypal personality traits. There was also a higher proportionof
Asians than Caucasians in our study sample, particularly in the met
homozygote groups. However, because they represent the major-
ity in both the high and lowSPQscore met homozygote groups, the
ethnicity is relatively balanced across these schizotypal personal-
ity trait and genotype groups and the proportion is consistent with
previous research showing that the frequency of the met allele is
signicantly higher in Asians [53].
In conclusion, this study helps rene our understanding of the
contributions of the BDNF genotype and illness-associated traits on
dysfunctional frontalstriatal dependant learninginschizophrenia.
These results provide the rst evidence for a specic genetic effect
of the BDNF val66met polymorphisminthe context of a sub-clinical
level of pathology in relation to schizotypal personality traits on
probabilistic association learning. This study contributes to the
growing body of evidence on the role of alterations of BDNF in the
pathophysiology of schizophrenia by showing worse performance
in a group of healthy people who were BDNF met carriers with
increased schizotypal personality traits and an absence of antipsy-
chotics and history of chronic illness, suggesting that probabilistic
associationlearningdecits may be intrinsic tofrontalstriatal dys-
function associated with schizophrenia.
Acknowledgments
This work was supported by the University of New South
Wales School of Psychiatry, and Neuroscience Research Australia.
142 A.J. Skilleter et al. / Behavioural Brain Research 274 (2014) 137142
Cynthia ShannonWeickerts work was supported by Schizophrenia
Research Institute (utilising infrastructure funding from the NSW
Ministry of Health and the Macquarie Group Foundation), the Uni-
versity of NewSouth Wales, and Neuroscience Research Australia.
CSWis a recipient of a National Health and Medical Research Coun-
cil (Australia) Senior Research Fellowship (#1021970). AJS is a
recipient of the Ian Scott Scholarship awarded by Australian Rotary
Health.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bbr.2014.07.041.
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