Brain derived neurotrophic factor (BDNF) genetic polymorphism (Val66Met) in suicide A study of 512 cases.код для вставкиСкачать
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: email@example.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.