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Brain derived neurotrophic factor (BDNF) genetic polymorphism (Val66Met) in suicide A study of 512 cases.

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LETTER TO THE EDITOR
Neuropsychiatric Genetics
Brain Derived Neurotrophic Factor (BDNF) Genetic
Polymorphism (Val66Met) in Suicide: A Study of
512 Cases
F. Zarrilli,1 A. Angiolillo,1 G. Castaldo,2 L. Chiariotti,3 S. Keller,3 S. Sacchetti,3 A. Marusic,4
T. Zagar,4 V. Carli,5 A. Roy,6 and M. Sarchiapone5*
1
Facolta di Scienze MFN, Universita del Molise, Isernia, Italy
2
Dipartimento di Biochimica e Biotecnologie Mediche and Facolta di Scienze Biotecnologiche, Universita ‘‘Federico II’’,
CEINGE-Biotecnologie Avanzate, Naples, Italy
3
Dipartimento di Biologia e Patologia Cellulare e Molecolare, Universita ‘‘Federico II’’, CEINGE-Biotecnologie Avanzate, Naples, Italy
University of Primorska, Primorska, Slovenia
4
5
Department of Health Sciences, University of Molise, Campobasso, Italy
6
Psychiatry Service, Department of Veteran Affairs, Newark, New Jersey
Received 3 June 2008; Accepted 28 July 2008
The neurotrophin brain derived neurotrophic factor (BDNF) is a
mediator involved in neuronal survival and plasticity of dopaminergic, cholinergic, and serotonergic neurons [Berton et al., 2006].
An altered expression of BDNF has been found in postmortem
brain of suicide victims [Dwivedi et al., 2003, 2005] suggesting that
the neurotrophin may play a crucial role in the pathophysiology of
suicide. A pathologic alteration of the neurotrophic factor system
could impair neural plasticity and therefore reduce the individual’s
ability to adapt to crisis situation, also leading to suicidal behavior.
The BDNF gene is located on chromosome 11p13, and a single
nucleotide (G196A) polymorphism (SNP) of this gene has been
shown to produce a valine (Val)-to-methionine (Met) substitution
in the proBDNF protein at codon 66 (Val66Met) [Hashimoto,
2007]. This SNP (SNP ID: rs6265) reduces the trafficking of BDNF
protein in the brain [Hashimoto and Lewis, 2006] and might be
related to reduced BDNF activity in psychiatric disorders. The
BDNF Val66Met polymorphism has been reported to be associated
with anxiety-related personality traits in healthy subjects and with
cognitive performance, both of which have been related to suicidality [Itoh et al., 2004; Rybakowski et al., 2003, 2006].
In a previous study we genotyped 170 Caucasian depressed
patients for the Val66Met BDNF polymorphism and we reported,
among carriers of the A allele (AA þ GA), a significantly higher
rate of suicide attempters (65.3% vs. 50.5%; P ¼ .05). Results of
the study allowed us to conclude on a significant association
between BDNF Val66Met polymorphism and suicidal behavior
[Sarchiapone et al., 2008].
In the present study we extended the analysis to a postmortem
sample of 512 subjects. The study was performed on DNA extracted
from samples of Wernicke area obtained in 262 suicide subjects
and 250 non-suicide control subjects. Cases and controls were
matched for age (mean age: 49.3 17.6 vs. 50.3 18.5; t ¼ .544;
P ¼ .587) and sex (M/F: 167/83 vs. 188/74; c2 ¼ .224; P ¼ .250).
2008 Wiley-Liss, Inc.
How to Cite this Article:
Zarrilli F, Angiolillo A, Castaldo G, Chiariotti
L, Keller S, Sacchetti S, Marusic A, Zagar T,
Carli V, Roy A, Sarchiapone M. 2009. Brain
Derived Neurotrophic Factor (BDNF)
Genetic Polymorphism (Val66Met) in
Suicide: A Study of 512 Cases.
Am J Med Genet Part B 150B:599–600.
Samples were extracted within 24 hours of subject’s death in a
period of time comprised between 1999 and 2005. All study subjects
were Slovenian and Caucasian ethnicity. Of the 262 suicide completers, 47.5% committed suicide by hanging, 14.4% by shooting
with firearms, 14.4% by self-poisoning, 7.2% by drowning, 9.1% by
jumping from high places, 4.9% by jumping under vehicles, 2.3% by
cutting.
BDNF G196A (Val66Met) genotyping was performed by polymerase chain reaction followed by PmlI restriction enzyme digestion (details available upon request).
Descriptive summary statistics for continuous variables are
expressed as mean s.d. and comparisons are performed with
T-test analysis Departure from Hardy–Weinberg expectation, differences in genotype distributions and comparison of allele
*Correspondence to:
M. Sarchiapone, Via De Sanctis, Campobasso 86100, Italy.
E-mail: marco.sarchiapone@gmail.com
Published online 29 August 2008 in Wiley InterScience
(www.interscience.wiley.com)
DOI 10.1002/ajmg.b.30849
599
600
AMERICAN JOURNAL OF MEDICAL GENETICS PART B
TABLE I. BDNF G196A Genotypes in the Whole Sample and Stratified by Suicide and Gender
Genotype
GG
GA
AA
Whole sample (n ¼ 512)
315
176
21
Suicides (n ¼ 262)
160
90
12
frequencies were evaluated by c2 test and two-tailed Fisher’s exact
test. Statistical analyses were carried out using the Statistical
Package of Social Sciences (SPSS, Inc., Chicago, IL) for Windows,
version 13.0.
The studied sample (N ¼ 512), for alpha established at 0.05, at
a predetermined level of power of 0.80 determined a minimal
detectable effect size of 0.124. The genotype distributions among
both suicide and non-suicide control group were within the
Hardy–Weinberg equilibrium. Frequencies for genotypes GG,
GA, and AA in total population (see Table I) were 61.5%,
34.4%, and 4.1% respectively, with no significant statistical differences between control and case group (c2 ¼ .318, P ¼ .853). After
splitting the sample in two groups (AA þ GA/GG) inter-group
differences in suicide victims’ rate were calculated. c2 test was used
to compare suicide rates between groups. Among carriers of the A
allele (AA þ GA) 51.8% of the subjects died by suicide while in the
GG group 50.8% of subjects were suicide victims. Difference
between groups was not statistically significant (c2 ¼ .047;
P ¼ .856).
In total sample, allelic frequencies were 79% and 21% for G and A
allele respectively in concordance with another study on Caucasian
populations and in contrast with another study on Asiatic populations (Naoe et al., 2007).
The present study—although limited by the different ethnicity of
the studied population (i.e., Caucasians and Slovenian)—excludes
a significant association of BDNF Val66Met polymorphism with
suicide, differently from what we observed in a previous study on
suicide attempters. This observation confirms that, even if family
studies showed a shared inheritability of suicidal tendencies between suicide attempters and completers, completed suicide and
attempted suicide seem to be two distinct phenomena and different
molecular genetic components may be involved. It must be underlined that, in addition to Val66Met polymorphism, two other
polymorphisms have been reported in BDNF gene (i.e., 270C > T
T and 281C > A). We analyzed these polymorphisms on a preliminary cohort of cases but their occurrence was <5% (data not
shown). Furthermore, while the previous study comprised psychiatric subjects with homogeneous diagnosis of DSM-IV Major
Depression, in the postmortem sample, data on psychiatric diagnosis of studied subjects was not available. Moreover the Val66Met
polymorphism of the BDNF gene may not be the only one involved
in suicidal behavior. Difference in BDNF expression reported in
suicide completers may be related to other genetic polymorphisms
or to other epigenetic factors such as DNA methylation. The study
of methylation of the BDNF gene and of the mRNA is needed in
Controls (n ¼ 250)
155
86
9
Male (n ¼ 355)
221
118
16
Female (n ¼ 157)
94
58
5
order to increase our knowledge on the role of BDNF in suicidal
behavior.
ACKNOWLEDGMENTS
This study was supported by the grants from Universita del
Molise and Regione Campania to CEINGE are gratefully acknowledged. We thank Prof. G. Oriani that stimulated us to study in this
field.
REFERENCES
Berton O, McClung CA, Dileone RJ, Krinshan V, Renthal W, Russo SJ.
2006. Essential role of BDNF in the mesolimbic dopamine pathway in
social defeat stress. Science 311:864–868.
Dwivedi Y, Mondal AC, Rizavi HS, Conley RR. 2005. Suicide brain is
associated with decreased expression of neurotrophins. Biol Psychiatry
58:315–324.
Dwivedi Y, Rizavi HS, Conley RR, Roberts RC, Tamminga CA, Pandey GN.
2003. Altered gene expression of brain-derived neurotrophic factor and
receptor tyrosine kinase B in postmortem brain of suicide subjects. Arch
Gen Psychiatry 60:804–815.
Hashimoto K. 2007. BDNF variant linked to anxiety-related behaviors.
Bioessays 29(2):116–119.
Hashimoto T, Lewis DA. 2006. BDNF Val66Met polymorphism and
GAD67 mRNA expression in the prefrontal cortex of subjects with
schizophrenia. Am J Psychiatry 163:534–537.
Itoh K, Hashimoto K, Kumakiri C, Shimizu E, Iyo M. 2004. Association
between brain-derived neurotrophic factor 196 G/A polymorphism and
personality traits in healthy subjects. Am J Med Genet Part B 124B:61–63.
Naoe Y, Shinkai T, Hori H, Fukunata Y, Utsonomiy A, Sakata S. 2007. No
association between the brain-derived neurotrophic factor (BDNF)
Val66Met polymorphism and schizophrenia in Asian populations: Evidence from a case-control study and meta-analysis. Neurosci Lett
415:108–112.
Rybakowski JK, Borkowska A, Czerski PM, Dnitrzak-Weglarz M, Hauser J.
2003. Polymorphism of the brain-derived neurotrophic factor gene and
performance on a cognitive prefrontal test in bipolar patients. Bipolar
Disord 5:468–472.
Rybakowski JK, Borkowska A, Skibinska M, Szczepankiewicz A, Kapelski P,
Leszczynska-Rodziewicz A, et al. 2006. Illness-specific association of
val66met BDNF polymorphism with performance on Wisconsin Card
Sorting Test in bipolar mood disorder. Mol Psychiatry 11:122–124.
Sarchiapone M, Roy A, Carli V, et al. 2008. Association of polymorphism
(Val66Met) of brain-derived neurotrophic factor (BDNF) with attempting suicide in depressed patients. Neuropsychobiology 57(3):139–145.
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factors, polymorphism, neurotrophic, stud, bdnf, 512, case, brain, suicide, genetics, derived, val66met
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