BDNF Val66Met polymorphism is associated with aggressive behavior in
G. Spallettaa, D.W. Morrisb, F. Angeluccia,*, I.A. Rubinoc, I. Spoletinia, P. Briad, G. Martinottid,
A. Siracusanoc, G. Bonavirie, S. Bernardinif, C. Caltagironea, P. Bossu `a, G. Donohoeb, M. Gillb,
aIRCCS Santa Lucia Foundation, Department of Clinical and Behavioural Neurology, Via Ardetina, 306, 00179 Rome, Italy
bNeuropsychiatric Genetics Research Group, Dept of Psychiatry, Trinity College Dublin, Dublin 2, Ireland
cDepartment of Neuroscience, Tor Vergata University, Rome, Italy
dInstitute of Psychiatry, Catholic University, Rome, Italy
eSapienza University, Department of Neurology, Rome, Italy
fDepartment of Internal Medicine, Tor Vergata University, Rome, Italy
Brain-derived neurotrophic factor (BDNF), a member of the
nerve growth factor family, is widely expressed in the adult
mammalian brain and plays a crucial role in the development,
survival and functional maintenance of neurons. BDNF is a potent
modulator of synaptic transmission and plasticity in the central
nervous system and has been implicated in cognitive processes
such as memory and learning .
Recent studies in laboratory animals suggested that BDNF gene
changes might be associated with aggressive behaviour. Interest-
ingly, BDNF mutant mice were found to be dramatically hyperac-
tive during the light and dark cycles and hyperaggressive [4,12].
These behavioural changes were associated with abnormalities in
serotonergic system. Particularly, forebrain 5-HT levels and fiber
density in BDNF(?) mice were normal at an early age but underwent
premature age-associated decrements. Another study has found that
local knockdown of BDNF in the mesolimbic dopamine pathway
abolishes the development of long-lasting social aversion in mice
experiencing repeated aggression . Additional findings in humans
have shown an association between BDNF gene polymorphisms and
attention deficithyperactivity disorder(ADHD),aheritablechildhood
behavioural disorder characterized by exaggerated levels of hyper-
activity, impulsivity, and inattentiveness [7,20].
A possible role of BDNF in pathogenesis of brain disorders
characterized by aggressive behaviour has been postulated,
especially in the context of schizophrenia . However, human
studies, aimed to demonstrate a direct involvement of BDNF in
[5,17] or in the periphery [15,18]. One of the potentially
confounding factors is the presence of several polymorphisms of
the BDNF gene, the most intensively investigated being Val66Met
(G196A) polymorphism . This is a single nucleotide polymor-
phism in the BDNF gene, leading to a valine (Val) to methionine
(Met) substitution at codon 66 in the prodomain (BDNFMet). The
Met (A) allele of Val66Met has been associated with abnormal
episodic memory in humans [6,8].
The role of BDNF Val66Met polymorphism in schizophrenia is
not well known. Two studies reported no evidence of association
European Psychiatry 25 (2010) 311–313
A R T I C L E I N F O
Received 18 September 2009
Received in revised form 20 October 2009
Accepted 25 October 2009
Available online 28 April 2010
A B S T R A C T
Brain-derived neurotrophic factor (BDNF) gene variants may potentially influence behaviour. In order to
test this hypothesis, we investigated the relationship between BDNF Val66Met polymorphism and
aggressive behaviour in a population of schizophrenic patients. Our results showed that increased
number of BDNF Met alleles was associated with increased aggressive behaviour.
? 2009 Elsevier Masson SAS. All rights reserved.
* Corresponding author. Tel.: +39 06 51501550; fax: +39 06 51501552.
E-mail address: email@example.com (F. Angelucci).
0924-9338/$ – see front matter ? 2009 Elsevier Masson SAS. All rights reserved.
between Val66Met BDNF gene polymorphism and schizophrenia
[13,16] while the Val allele showed a significant association with
schizophrenia in a Scottish population .
Altogether, these observations indicate that BDNF gene
alteration may potentially affect behaviour probably by altering
serotonergic neurotransmission and potentially be associated with
aggressive behavior. To test this hypothesis, and in order to further
elucidate the role of BDNF gene in schizophrenia, in this study, we
investigated the relationship between BDNF Val66Met polymor-
phism and aggressive behaviour in an Italian population of chronic
2. Subjects and methods
One hundred and eighteen outpatients with a diagnosis of
schizophrenia according to DSM-IV were assessed at the IRCCS
Santa Lucia Foundation, Rome. All patients gave written informed
consent to participate in the study after all procedures had been
fully explained. Approval for the study had been obtained from the
local ethic committee. All diagnoses were made by one senior
clinical psychiatrist (G.S.) using the structured clinical interview
for DSM-IV (SCID-P). Exclusion criteria were:
? substance abuse or dependence during the past year;
? a history of traumatic brain injury or any other neurological
? any past or present major medical illness that may affect brain
structures such as diabetes, cerebrovascular disease, etc;
? any brain pathology identified on T2-weighted or FLAIR-MRI
? mental retardation.
Sociodemographic and clinical characteristics of patients with
schizophrenia separately for the different BDNF Val66Met alleles
are shown in Table 1.
Positive and negative symptoms and general psychopathology
were measured by a senior psychiatrist (G.S.) using the positive
and negative syndrome scale (PANSS) . PANSS ratings were
based on the totality of available information pertaining to the last
month period, including direct assessment during the diagnostic
interview and reports by primary and psychiatry care staff.
Aggressive behaviour was assessed by using the modified overt
aggression scale (MOAS) . MOAS ratings were based on the
most severe behaviour of the patient during the 12 months before
the assessment and were obtained from the records made by the
or caregivers were given clear explanations as to how to identify
and report patients’ aggressiveness.
All antipsychotic dosages were converted to estimated equiva-
lent dosages of olanzapine by using a standard table. Age at onset
was defined as age of first hospitalization or, where possible, age at
onset of positive or negative symptoms preceding the first
The BDNF Val66Met polymorphism (rs6265) was genotyped
Comparison among patients with different BDNF Val66Met
polymorphisms was performed using the Chi2test on categorical
variables and using factorial analysis of variance (ANOVA)
followed by Fisher’s protected least significant difference (PLSD)
post-hoc test on continuous variables. Clinical and sociodemo-
graphic predictors of the number of Met alleles of the BDNF
polymorphism were assessed by using stepwise multiple regres-
sion analyses, using a forward procedure and an F to enter of 4. The
level of statistical significance was defined as p < 0.05.
As showed in Table 1, the three groups of patients did not differ
significantly for age, level of education and gender. One-way
ANOVAs also showed that there were no significant differences
among patients with different BDNF Val66Met alleles on the
severity of positive symptoms, negative symptoms or general
There was a significant difference among the three groups with
different BDNF alleles on the MOAS total score with an increased
severity in patients with more Met alleles. Post-hoc pairwise
comparisons revealed that patients with the BDNF Met/Val
genotype were more aggressive than patients with Val/Val
genotype (p = 0.025). Furthermore, BDNF Met/Met patients tended
to be more aggressive than Val/Val patients (p = 0.075). No
significant differences were observed between BDNF Met/Met
and Met/Val patients (p = 0.508). Analysis of MOAS subscales
indicated that overt physical aggression mainly contributed to this
result (see Table 1).
With these results in mind and taking into consideration that
sociodemographic variables, such as age, educational level and
Sociodemographic and clinical characteristics of 118 schizophrenic outpatients with different BDNF Val66Met polimorphisms.
Gender male (n, %)
Educational level (years?S.D.)
Olanzapine equivalents (mg/day)
PANSS general psychopathology
MOAS total score
MOAS verbal aggression
MOAS property aggression
MOAS physical aggression
Suicide attempt (n, %)
DSM-IV subtypes (n, %)
BDNF: brain-derived neurotrophic factor; PANSS: positive and negative syndrome scale; MOAS: modified overt aggression scale; S.D.: standard deviation; df: degrees of
aStatistically significant results.
G. Spalletta et al./European Psychiatry 25 (2010) 311–313
gender, neuroleptic dosages and psychiatric symptoms may Download full-text
influence the severity of aggressive behaviour, we performed a
stepwise multiple regression analysis in order to clarify if these
variables were also correlated with the BDNF Val66Met alleles. In
this analysis, the number of BDNF alleles was the dependent
variable and all the sociodemographic and clinical variables here
investigated were the independent variables. Interestingly, the
only statistically significant predictor of the number of Met alleles
in our sample of schizophrenic outpatients was the MOAS total
score. The resulting equation was significant (F = 7.281; df = 1,116;
p = 0.008) and explained 5.9% (R2) of the overall variance of the
number of Met alleles. In particular, higher MOAS total score
predicted the higher number of Met alleles (standard coefficient
Our study indicates that the Val66Met polymorphism of BDNF
gene is associated with a different level of aggressiveness in
schizophrenic patients. In particular, the Met allele was associat-
ed with increased aggression. Our data also support the notion
that Val66Met BDNF polymorphism only correlates to a specific
sub-phenotype inside the whole population of schizophrenic
patients . The association between BDNF genetic variants and
specific schizophrenia subgroups may also explain the contrast-
ing results of BDNF protein levels in the hippocampal region of
the recruitment of patients with different behavioural pheno-
In any case, the mechanism by which a substitution of a single
amino acid in BDNF gene may cause altered behaviour is not
clear. It has been previously demonstrated that Val66Met
polymorphism does not affect mature BDNF protein function
but significantly alters the intracellular trafficking and packaging
of pro-BDNF . In this respect, the Met allele of BDNF
polymorphism displayed impaired activity with possible con-
sequences for neuronal function. BDNF is also an important
trophic factor for serotonergic neurons, and a reduced BDNF
trophic support in 5-HT neurons in human may alter serotonergic
system and lead to behavioral abnormalities, including an
In conclusion, our data revealed an association between the
BDNF gene Val66Met polymorphism and aggression in schizo-
phrenic patients. Future studies in larger cohorts of patients will
confirm whether this BDNF polymorphism is directly involved in
the pathogenesis of aggressive behaviour in schizophrenia.
 Angelucci F, Brene ´ S, Mathe ´ AA. BDNF in schizophrenia, depression and
corresponding animal models. Mol Psychiatry 2005;10:345–52.
 Berton O, McClung CA, Di leone RJ, Krishnan V, Renthal W, Russo SJ, et al.
Essential role of BDNF in the mesolimbic dopamine pathway in social defeat
stress. Science 2006;311:864–8.
 Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N, et al. Characterization
of single-nucleotide polymorphisms in coding regions of human genes. Nat
 ChanJP, UngerTJ,ByrnesJ,RiosM.Examinationof behavioraldeficitstriggered
by targeting BDNF in fetal or postnatal brains of mice. Neuroscience
 Durany N, Michel T, Zochling R, Boissl KW, Cruz-Sanchez FF, Riederer P, et al.
Brain-derived neurotrophic factor and neurotrophin 3 in schizophrenic psy-
choses. Schizophr Res 2001;52:79–86.
 Egan M, Kojima M, Callicot JH, Goldberg TE, Kolachana BS, Bertolino A, et al.
The BDNF val66met polymorphism affects activity-dependent secretion of
BDNF and human memory and hippocampal function. Cell 2003;112:257–69.
 Guerin AA, Beitchman JH, Strauss J, Kennedy JL. Association study of the brain-
derived neurotrophic factor gene and childhood aggression. Psychiatr Genet
 Hariri AR, Goldberg TE, Mattay VS, Kolachana BS, Callicott JH, Egan MF, et al.
Brain-derived neurotrophic factor val66met polymorphism affects human
memory-related hippocampal activity and predicts memory performance. J
 KaySR,FiszbeinA,OplerLA.Thepositive andnegative syndromescale(PANSS)
for schizophrenia. Schizophr Bull 1987;13:261–76.
 Kay SR, Wolkenfeld F, Murrill LM. Profiles of aggression among psychiatric
patients. I. Nature and prevalence. J Nerv Ment Dis 1988;176:539–46.
 Krebs MO, Guillin O, Bourdell MC, Schwartz JC, Olie JP, Poirier MF, et al. Brain
and therapeutic response in schizophrenia. Mol Psychiatry 2000;5:558–62.
 Lyons WE, Mamounas LA, Ricaurte GA, Coppola V, Reid SW, Bora SH, et al.
Brain-derived neurotrophic factor-deficient mice develop aggressiveness and
hyperphagia in conjunction with brain serotonergic abnormalities. Proc Natl
Acad Sci U S A 1999;96:15239–44.
 Nanko S, Kunugi H, Hirasawa H, Kato N, Nabika T, Kobayashi S. Brain-derived
neurotrophic factor gene and schizophrenia: polymorphism screening and
association analysis. Schizophr Res 2003;62:281–3.
 Neves-Pereira M, Cheung JK, Pasdar A, Zhang F, Breen G, Yates P, et al. BDNF
gene is a risk factor for schizophrenia in a Scottish population. Mol Psychiatry
 Shimizu E, Hashimoto K, Watanabe H, Komatsu N, Okamura N, Koike K, et al.
Serum brain-derived neurotrophic factor (BDNF) levels in schizophrenia are
indistinguishable from controls. Neurosci Lett 2003;351:111–4.
 Skibinska M, Hauser J, Czerski PM, Leszczynska-Rodziewicz A, Kosmowska M,
Kapelski P, et al. Association analysis of brain-derived neurotrophic factor
(BDNF) gene Val66Met polymorphism in schizophrenia and bipolar affective
disorder. World J Biol Psychiatry 2004;5:215–20.
 Takahashi M, Shirakawa O, Toyooka K, Kitamura N, Hashimoto T, Maeda K,
et al. Abnormal expression of brain-derived neurotrophic factor and its
receptor in the corticolimbic system of schizophrenic patients. Mol Psychiatry
 Toyooka K, Asama K, Watanabe Y, Muratake T, Takahashi M, Someya T, et al.
Decreased levels of brain-derived neurotrophic factor in serum of chronic
schizophrenic patients. Psychiatr Res 2002;110:249–57.
 Tyler WJ, Alonso M, Bramham CR, Pozzo-Miller LD. From acquisition to
consolidation: on the role of brain-derived neurotrophic factor signaling in
hippocampal-dependent learning. Learn Mem 2002;9:224–37.
 Xu X, Mill J, Zhou K, Brookes K, Chen CK, Asherson P. Family-based association
study between brain-derived neurotrophic factor gene polymorphisms and
attention deficit hyperactivity disorder in UK and Taiwanese samples. Am J
Med Genet B Neuropsychiatr Genet 2007;144:83–6.
G. Spalletta et al./European Psychiatry 25 (2010) 311–313