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Association study of BDNF with completed suicide in the Japanese population
Psychiatry Research 209 (2013) 734–736
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Brief report
Association study of BDNF with completed suicide in the Japanese population Woraphat Ratta-apha a, Akitoyo Hishimoto a,n, Masakuni Yoshida a, Yasuhiro Ueno b, Migiwa Asano c, Osamu Shirakawa d, Ichiro Sora a a
Department of Psychiatry, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan Department of Legal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan c Department of Legal Medicine, Ehime University Graduate School of Medicine, Ehime, Japan d Department of Neuropsychiatry, Kinki University School of Medicine, Osaka, Japan b
art ic l e i nf o
a b s t r a c t
Article history: Received 21 March 2013 Received in revised form 22 May 2013 Accepted 25 May 2013
We explored the association between the brain-derived neurotrophic factor gene with suicide using 307 Japanese completed suicides, 380 healthy controls, and data from previously published samples. The meta-analyses of the valine with methionine in codon 66 (Val66Met) single nucleotide polymorphism (SNP) showed that the Met-allele tended to be associated with attempted suicide in Asian populations, but not with the completed suicide. & 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Brain-derived neurotrophic factor Suicide Association study
1. Introduction Brain-derived neurotrophic factor (BDNF) plays a crucial role in brain plasticity and neuronal development (Duman, 2002). A single nucleotide polymorphism (SNP) consisting of the substitution of valine with methionine in codon 66 (Val66Met, rs6265 SNP) was reported to be associated with suicidal behavior in depressive disorder (Iga et al., 2007), and suicide attempt in bipolar disorder (Kim et al., 2008) and schizophrenia (Huang and Lee, 2007). Furthermore, a trend has been reported for genotypes carrying the Met-allele and history of suicide attempt (Zai et al., 2011). We hypothesized that BDNF containing the common Val66Met SNP is associated with suicide. We conducted an association study between completed suicides and healthy control subjects. In addition, we performed the meta-analyses of the BDNF Val66Met SNP in attempted or completed suicide using data from the present study as well as seven previously published studies.
2. Methods This association study consisted of 307 completed suicide subjects (210 males: mean age7 S.D.; 49.9 7 16.5 years, 97 females: 48.17 19.5 years) and 380 unrelated healthy volunteers (164 males: 39.5 7 15.8years, 216 females: 45.3 7 17.1 years). The verdict of completed suicide and psychiatric assessment were conducted as previously described (Supriyanto et al., 2011). Informed consent was
n
Corresponding author. Tel.: +81 78 382 6065; fax: +81 78 382 6079. E-mail addresses: [email protected], [email protected] (A. Hishimoto). 0165-1781/$ - see front matter & 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.psychres.2013.05.030
obtained from all participants and closed relatives of the completed suicides. This study was conducted with the approval of the ethical committee for genetic studies of the Kobe University Graduate School of Medicine. The seven SNPs were selected by the tagger program within the Haploview (Barrett et al., 2005). We also included the C270T polymorphism, which has been intensively examined before (Kawashima et al., 2009). A Taqman probe assay was used for genotyping (Applied Biosystems, Foster City, CA, USA). Data were analyzed with Haploview 4.2, the PS v2.1.31 software (Dupont and Plummer, 1998), and the Cochran-Armitage test for trend. The statistical significance was set at p-value o 0.05. Next, we performed meta-analyses of the BDNF Val66Met SNP in suicidal attempt in Asian population and in completed suicide using data from seven published samples plus our present sample. Meta-analyses were performed using the comprehensive meta-analysis version 2.0 (Biostat Inc., http://meta-analysis.com/). Experimental details are available in the Supporting Information.
3. Results The distributions of all eight SNPs in the control group and seven SNPs (except rs1519480) in the completed suicide group did not differ from Hardy–Weinberg equilibrium. The exception might be due to the small sample size. The results showed no significant difference in either the genotypic distributions or the allelic frequencies of the eight SNPs in the completed suicide and control groups (Supplementary Table 1). The samples yielded a power of 0.050–0.123 for each detection of nominal significance. In subgroup analyses by using gender, age, and violent method as variables, we did not find any association between any subgroups and selected SNPs (Supplementary Tables 2 and 3). Two LD blocks were found by the solid spine of LD method (Supplementary Fig. 1). However, no statistically significant
W. Ratta-apha et al. / Psychiatry Research 209 (2013) 734–736
735
Fig. 1. Meta-analysis and forest plot of the Val66Met polymorphism and suicide. (I) Includes data from previously published Val66Met association studies of suicidal behavior in Asian population. (II) Includes data from previously published Val66Met association studies of completed suicide.
differences were found between the two groups for any haplotypes in the two LD blocks. The meta-analysis, including five studies using Asian subjects plus the present study, was performed (Hong et al., 2003; Huang and Lee, 2007; Hwang et al., 2006; Iga et al., 2007; Kim et al., 2008) (Supplementary Table 4). The results showed that the Met-allele tended to be associated with the risk of attempt suicide (number of Met-alleles¼437: total number¼1428, pool OR¼1.37, 95% CI¼ 1.01– 1.86, Z-value¼ 2.047, p-value¼ 0.041) (Fig. 1). Next, the meta-analysis including the three studies using completed suicide as subjects was performed (Pregelj et al., 2011; Zarrilli et al., 2009). These results showed no association between the Met-allele and the risk of completed suicide (number of Met-alleles in completed suicide¼515: total number¼ 1746, pool OR¼1.03, 95% CI¼ 0.88–1.19, Z-value¼0.315, p-value¼0.753) (Fig. 1).
4. Discussion We found no genetic association of BDNF SNPs with completed suicide, which is consistent with two previous reports recruiting completed suicides in European populations (Pregelj et al., 2011; Zarrilli et al., 2009). In Asian populations, BDNF Val66Met SNP was both positively and negatively associated with attempted suicide. To our knowledge, no studies have examined the association between BDNF and completed suicides in Asian populations. The inconsistent results between the completed suicide and attempted suicide groups may be due to different genetic components, which the two groups might be considered as distinct phenomena (Zarrilli et al., 2009). The pathogenesis of suicidal behavior and/ or attempt may be more complex than that of completed suicide. The Met-allele of Val66Met SNP was also reported to be associated with the violent suicidal methods in female completed suicides (Pregelj et al., 2011). Zai et al. also conducted the meta-analysis for
the Val66Met SNP with suicide and found the significant association of the Met-allele with attempted suicide like the present study (Zai et al., 2011). Because the Met-allele frequency between Asians (0.41) and Caucasians (0.22) are different, these findings should be carefully interpreted. The present study has some limitations. First, the number of subjects was still limited. We did not have completed psychological autopsy data that may relate to BDNF expression, e.g., body mass index, education. It was not clear what psychopathology the completed suicide victims had and whether they were treated with psychotropic medications or not. We cannot exclude all the potential subjects who would be able to complete suicide among the control groups. Finally, only a limited number of studies were included to perform meta-analyses. In conclusion, our findings suggest that BDNF may play a role in the pathogenesis of suicide attempt at least in Asian populations. Because multiple factors are involved in the pathogenesis of suicide, it is necessary to conduct further case-control studies between BDNF and completed suicide in a larger population to confirm this finding.
Acknowledgments This work was supported in part by research grants from the Ministry of Education, Culture, Sports, Science and Technology (MECSS) in Japan. We thank Ms. Y. Nagashima for her technical assistance.
Appendix A. Supporting information Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.psychres.2013.05.030.
736
W. Ratta-apha et al. / Psychiatry Research 209 (2013) 734–736
References Barrett, J.C., Fry, B., Maller, J., Daly, M.J., 2005. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265. Duman, R.S., 2002. Synaptic plasticity and mood disorders. Molecular Psychiatry 7 (Suppl. 1), S29–34. Dupont, W.D., Plummer Jr., W.D., 1998. Power and sample size calculations for studies involving linear regression. Controlled Clinical Trials 19, 589–601. Hong, C.J., Huo, S.J., Yen, F.C., Tung, C.L., Pan, G.M., Tsai, S.J., 2003. Association study of a brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior. Neuropsychobiology 48, 186–189. Huang, T.L., Lee, C.T., 2007. Associations between brain-derived neurotrophic factor G196A gene polymorphism and clinical phenotypes in schizophrenia patients. Chang Gung Medical Journal 30, 408–413. Hwang, J.P., Tsai, S.J., Hong, C.J., Yang, C.H., Lirng, J.F., Yang, Y.M., 2006. The Val66Met polymorphism of the brain-derived neurotrophic-factor gene is associated with geriatric depression. Neurobiology of Aging 27, 1834–1837. Iga, J., Ueno, S., Yamauchi, K., Numata, S., Tayoshi-Shibuya, S., Kinouchi, S., Nakataki, M., Song, H., Hokoishi, K., Tanabe, H., Sano, A., Ohmori, T., 2007. The Val66Met polymorphism of the brain-derived neurotrophic factor gene is associated with psychotic feature and suicidal behavior in Japanese major depressive patients. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 144B, 1003–1006. Kawashima, K., Ikeda, M., Kishi, T., Kitajima, T., Yamanouchi, Y., Kinoshita, Y., Okochi, T., Aleksic, B., Tomita, M., Okada, T., Kunugi, H., Inada, T., Ozaki, N., Iwata, N.,
2009. BDNF is not associated with schizophrenia: data from a Japanese population study and meta-analysis. Schizophrenia Research 112, 72–79. Kim, B., Kim, C.Y., Hong, J.P., Kim, S.Y., Lee, C., Joo, Y.H., 2008. Brain-derived neurotrophic factor Val/Met polymorphism and bipolar disorder. Association of the Met allele with suicidal behavior of bipolar patients. Neuropsychobiology 58, 97–103. Pregelj, P., Nedic, G., Paska, A.V., Zupanc, T., Nikolac, M., Balazic, J., Tomori, M., Komel, R., Seler, D.M., Pivac, N., 2011. The association between brain-derived neurotrophic factor polymorphism (BDNF Val66Met) and suicide. Journal of Affective Disorders 128, 287–290. Supriyanto, I., Sasada, T., Fukutake, M., Asano, M., Ueno, Y., Nagasaki, Y., Shirakawa, O., Hishimoto, A., 2011. Association of FKBP5 gene haplotypes with completed suicide in the Japanese population. Progress in Neuro-Psychopharmacology and Biological Psychiatry 35, 252–256. Zai, C.C., Manchia, M., De Luca, V., Tiwari, A.K., Chowdhury, N.I., Zai, G.C., Tong, R.P., Yilmaz, Z., Shaikh, S.A., Strauss, J., Kennedy, J.L., 2011. The brain-derived neurotrophic factor gene in suicidal behaviour: a meta-analysis. International Journal of Neuropsychopharmacology, 1–6. 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. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 150B, 599–600.
Contents lists available at ScienceDirect
Psychiatry Research journal homepage: www.elsevier.com/locate/psychres
Brief report
Association study of BDNF with completed suicide in the Japanese population Woraphat Ratta-apha a, Akitoyo Hishimoto a,n, Masakuni Yoshida a, Yasuhiro Ueno b, Migiwa Asano c, Osamu Shirakawa d, Ichiro Sora a a
Department of Psychiatry, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan Department of Legal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan c Department of Legal Medicine, Ehime University Graduate School of Medicine, Ehime, Japan d Department of Neuropsychiatry, Kinki University School of Medicine, Osaka, Japan b
art ic l e i nf o
a b s t r a c t
Article history: Received 21 March 2013 Received in revised form 22 May 2013 Accepted 25 May 2013
We explored the association between the brain-derived neurotrophic factor gene with suicide using 307 Japanese completed suicides, 380 healthy controls, and data from previously published samples. The meta-analyses of the valine with methionine in codon 66 (Val66Met) single nucleotide polymorphism (SNP) showed that the Met-allele tended to be associated with attempted suicide in Asian populations, but not with the completed suicide. & 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Brain-derived neurotrophic factor Suicide Association study
1. Introduction Brain-derived neurotrophic factor (BDNF) plays a crucial role in brain plasticity and neuronal development (Duman, 2002). A single nucleotide polymorphism (SNP) consisting of the substitution of valine with methionine in codon 66 (Val66Met, rs6265 SNP) was reported to be associated with suicidal behavior in depressive disorder (Iga et al., 2007), and suicide attempt in bipolar disorder (Kim et al., 2008) and schizophrenia (Huang and Lee, 2007). Furthermore, a trend has been reported for genotypes carrying the Met-allele and history of suicide attempt (Zai et al., 2011). We hypothesized that BDNF containing the common Val66Met SNP is associated with suicide. We conducted an association study between completed suicides and healthy control subjects. In addition, we performed the meta-analyses of the BDNF Val66Met SNP in attempted or completed suicide using data from the present study as well as seven previously published studies.
2. Methods This association study consisted of 307 completed suicide subjects (210 males: mean age7 S.D.; 49.9 7 16.5 years, 97 females: 48.17 19.5 years) and 380 unrelated healthy volunteers (164 males: 39.5 7 15.8years, 216 females: 45.3 7 17.1 years). The verdict of completed suicide and psychiatric assessment were conducted as previously described (Supriyanto et al., 2011). Informed consent was
n
Corresponding author. Tel.: +81 78 382 6065; fax: +81 78 382 6079. E-mail addresses: [email protected], [email protected] (A. Hishimoto). 0165-1781/$ - see front matter & 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.psychres.2013.05.030
obtained from all participants and closed relatives of the completed suicides. This study was conducted with the approval of the ethical committee for genetic studies of the Kobe University Graduate School of Medicine. The seven SNPs were selected by the tagger program within the Haploview (Barrett et al., 2005). We also included the C270T polymorphism, which has been intensively examined before (Kawashima et al., 2009). A Taqman probe assay was used for genotyping (Applied Biosystems, Foster City, CA, USA). Data were analyzed with Haploview 4.2, the PS v2.1.31 software (Dupont and Plummer, 1998), and the Cochran-Armitage test for trend. The statistical significance was set at p-value o 0.05. Next, we performed meta-analyses of the BDNF Val66Met SNP in suicidal attempt in Asian population and in completed suicide using data from seven published samples plus our present sample. Meta-analyses were performed using the comprehensive meta-analysis version 2.0 (Biostat Inc., http://meta-analysis.com/). Experimental details are available in the Supporting Information.
3. Results The distributions of all eight SNPs in the control group and seven SNPs (except rs1519480) in the completed suicide group did not differ from Hardy–Weinberg equilibrium. The exception might be due to the small sample size. The results showed no significant difference in either the genotypic distributions or the allelic frequencies of the eight SNPs in the completed suicide and control groups (Supplementary Table 1). The samples yielded a power of 0.050–0.123 for each detection of nominal significance. In subgroup analyses by using gender, age, and violent method as variables, we did not find any association between any subgroups and selected SNPs (Supplementary Tables 2 and 3). Two LD blocks were found by the solid spine of LD method (Supplementary Fig. 1). However, no statistically significant
W. Ratta-apha et al. / Psychiatry Research 209 (2013) 734–736
735
Fig. 1. Meta-analysis and forest plot of the Val66Met polymorphism and suicide. (I) Includes data from previously published Val66Met association studies of suicidal behavior in Asian population. (II) Includes data from previously published Val66Met association studies of completed suicide.
differences were found between the two groups for any haplotypes in the two LD blocks. The meta-analysis, including five studies using Asian subjects plus the present study, was performed (Hong et al., 2003; Huang and Lee, 2007; Hwang et al., 2006; Iga et al., 2007; Kim et al., 2008) (Supplementary Table 4). The results showed that the Met-allele tended to be associated with the risk of attempt suicide (number of Met-alleles¼437: total number¼1428, pool OR¼1.37, 95% CI¼ 1.01– 1.86, Z-value¼ 2.047, p-value¼ 0.041) (Fig. 1). Next, the meta-analysis including the three studies using completed suicide as subjects was performed (Pregelj et al., 2011; Zarrilli et al., 2009). These results showed no association between the Met-allele and the risk of completed suicide (number of Met-alleles in completed suicide¼515: total number¼ 1746, pool OR¼1.03, 95% CI¼ 0.88–1.19, Z-value¼0.315, p-value¼0.753) (Fig. 1).
4. Discussion We found no genetic association of BDNF SNPs with completed suicide, which is consistent with two previous reports recruiting completed suicides in European populations (Pregelj et al., 2011; Zarrilli et al., 2009). In Asian populations, BDNF Val66Met SNP was both positively and negatively associated with attempted suicide. To our knowledge, no studies have examined the association between BDNF and completed suicides in Asian populations. The inconsistent results between the completed suicide and attempted suicide groups may be due to different genetic components, which the two groups might be considered as distinct phenomena (Zarrilli et al., 2009). The pathogenesis of suicidal behavior and/ or attempt may be more complex than that of completed suicide. The Met-allele of Val66Met SNP was also reported to be associated with the violent suicidal methods in female completed suicides (Pregelj et al., 2011). Zai et al. also conducted the meta-analysis for
the Val66Met SNP with suicide and found the significant association of the Met-allele with attempted suicide like the present study (Zai et al., 2011). Because the Met-allele frequency between Asians (0.41) and Caucasians (0.22) are different, these findings should be carefully interpreted. The present study has some limitations. First, the number of subjects was still limited. We did not have completed psychological autopsy data that may relate to BDNF expression, e.g., body mass index, education. It was not clear what psychopathology the completed suicide victims had and whether they were treated with psychotropic medications or not. We cannot exclude all the potential subjects who would be able to complete suicide among the control groups. Finally, only a limited number of studies were included to perform meta-analyses. In conclusion, our findings suggest that BDNF may play a role in the pathogenesis of suicide attempt at least in Asian populations. Because multiple factors are involved in the pathogenesis of suicide, it is necessary to conduct further case-control studies between BDNF and completed suicide in a larger population to confirm this finding.
Acknowledgments This work was supported in part by research grants from the Ministry of Education, Culture, Sports, Science and Technology (MECSS) in Japan. We thank Ms. Y. Nagashima for her technical assistance.
Appendix A. Supporting information Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.psychres.2013.05.030.
736
W. Ratta-apha et al. / Psychiatry Research 209 (2013) 734–736
References Barrett, J.C., Fry, B., Maller, J., Daly, M.J., 2005. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265. Duman, R.S., 2002. Synaptic plasticity and mood disorders. Molecular Psychiatry 7 (Suppl. 1), S29–34. Dupont, W.D., Plummer Jr., W.D., 1998. Power and sample size calculations for studies involving linear regression. Controlled Clinical Trials 19, 589–601. Hong, C.J., Huo, S.J., Yen, F.C., Tung, C.L., Pan, G.M., Tsai, S.J., 2003. Association study of a brain-derived neurotrophic-factor genetic polymorphism and mood disorders, age of onset and suicidal behavior. Neuropsychobiology 48, 186–189. Huang, T.L., Lee, C.T., 2007. Associations between brain-derived neurotrophic factor G196A gene polymorphism and clinical phenotypes in schizophrenia patients. Chang Gung Medical Journal 30, 408–413. Hwang, J.P., Tsai, S.J., Hong, C.J., Yang, C.H., Lirng, J.F., Yang, Y.M., 2006. The Val66Met polymorphism of the brain-derived neurotrophic-factor gene is associated with geriatric depression. Neurobiology of Aging 27, 1834–1837. Iga, J., Ueno, S., Yamauchi, K., Numata, S., Tayoshi-Shibuya, S., Kinouchi, S., Nakataki, M., Song, H., Hokoishi, K., Tanabe, H., Sano, A., Ohmori, T., 2007. The Val66Met polymorphism of the brain-derived neurotrophic factor gene is associated with psychotic feature and suicidal behavior in Japanese major depressive patients. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 144B, 1003–1006. Kawashima, K., Ikeda, M., Kishi, T., Kitajima, T., Yamanouchi, Y., Kinoshita, Y., Okochi, T., Aleksic, B., Tomita, M., Okada, T., Kunugi, H., Inada, T., Ozaki, N., Iwata, N.,
2009. BDNF is not associated with schizophrenia: data from a Japanese population study and meta-analysis. Schizophrenia Research 112, 72–79. Kim, B., Kim, C.Y., Hong, J.P., Kim, S.Y., Lee, C., Joo, Y.H., 2008. Brain-derived neurotrophic factor Val/Met polymorphism and bipolar disorder. Association of the Met allele with suicidal behavior of bipolar patients. Neuropsychobiology 58, 97–103. Pregelj, P., Nedic, G., Paska, A.V., Zupanc, T., Nikolac, M., Balazic, J., Tomori, M., Komel, R., Seler, D.M., Pivac, N., 2011. The association between brain-derived neurotrophic factor polymorphism (BDNF Val66Met) and suicide. Journal of Affective Disorders 128, 287–290. Supriyanto, I., Sasada, T., Fukutake, M., Asano, M., Ueno, Y., Nagasaki, Y., Shirakawa, O., Hishimoto, A., 2011. Association of FKBP5 gene haplotypes with completed suicide in the Japanese population. Progress in Neuro-Psychopharmacology and Biological Psychiatry 35, 252–256. Zai, C.C., Manchia, M., De Luca, V., Tiwari, A.K., Chowdhury, N.I., Zai, G.C., Tong, R.P., Yilmaz, Z., Shaikh, S.A., Strauss, J., Kennedy, J.L., 2011. The brain-derived neurotrophic factor gene in suicidal behaviour: a meta-analysis. International Journal of Neuropsychopharmacology, 1–6. 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. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 150B, 599–600.