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Association Study of Brain-Derived Neurotrophic Factor Gene Polymorphisms and Body Weight Change in Schizophrenic Patients Under Long-Term Atypical Antipsychotic Treatment

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Abstract

Schizophrenic patients treated with atypical antipsychotics (AAPs) often develop excessive body weight gain, which may lead to further morbidity and poor treatment compliance. This study examined whether genetic variants in the brain-derived neurotrophic factor (BDNF) gene may be associated with body weight change after AAP treatment. The study included 481 schizophrenic patients treated with clozapine (n = 266), olanzapine (n = 79), or risperidone (n = 136) for an average of 49.2 ± 28.2 months. Three common single-nucleotide polymorphisms (SNPs) of the BDNF gene were chosen as tagging SNPs. In single-marker-based analysis, the BDNF rs11030101-T homozygous genotype was found to be associated with significantly increased body weight gain (P = 0.037). The BDNF Val66Met (rs6265) polymorphism was not found to be associated with body weight gain. Haplotype analysis further showed that the rs11030101-T-allele-related haplotype is also associated with increased body weight gain (P = 0.047). Our findings suggest that there is a nominal association with rs11030101 but did not replicate the previously found relationship between the BDNF Val66Met polymorphism and body weight gain during long-term AAP treatment.

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Abbreviations

AAP:

Atypical antipsychotic

BWC:

Body weight change

BWG:

Body weight gain

SNP:

Single-nucleotide polymorphism

BDNF:

Brain-derived neurotrophic factor

LD:

Linkage disequilibrium

BMI:

Body mass index

FDR:

False discovery rate

References

  • Angelucci, F., Aloe, L., Iannitelli, A., Gruber, S. H., & Mathé, A. A. (2005). Effect of chronic olanzapine treatment on nerve growth factor and brain-derived neurotrophic factor in the rat brain. European Neuropsychopharmacology, 15, 311–317.

    Article  PubMed  CAS  Google Scholar 

  • Angelucci, F., Mathé, A. A., & Aloe, L. (2000). Brain-derived neurotrophic factor and tyrosine kinase receptor TrkB in rat brain are significantly altered after haloperidol and risperidone administration. Journal of Neuroscience Research, 60, 783–794.

    Article  PubMed  CAS  Google Scholar 

  • Beckers, S., Peeters, A., Zegers, D., Mertens, I., Van Gaal, L., & Van Hul, W. (2008). Association of the BDNF Val66Met variation with obesity in women. Molecular Genetics and Metabolism, 95, 110–112.

    Article  PubMed  CAS  Google Scholar 

  • Calarge, C. A., Ellingrod, V. L., Zimmerman, B., Acion, L., Sivitz, W. I., & Schlechte, J. A. (2009). Leptin gene -2548G/A variants predict risperidone-associated weight gain in children and adolescents. Psychiatric Genetics, 19, 320–327.

    Article  PubMed  Google Scholar 

  • Cho, S. C., Kim, J. W., Kim, H. W., Kim, B. N., Shin, M. S., Cho, D. Y., et al. (2011). Effect of ADRA2A and BDNF gene–gene interaction on the continuous performance test phenotype. Psychiatric Genetics, 21, 132–135.

    Article  PubMed  Google Scholar 

  • Egan, M. F., Kojima, M., Callicott, J. H., Goldberg, T. E., Kolachana, B. S., Bertolino, A., et al. (2003). The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell, 112, 257–269.

    Article  PubMed  CAS  Google Scholar 

  • Hong, C. J., Lin, C. H., Yu, Y. W., Yang, K. H., & Tsai, S. J. (2001). Genetic variants of the serotonin system and weight change during clozapine treatment. Pharmacogenetics and Genomics, 11, 265–268.

    CAS  Google Scholar 

  • Hong, C. J., Liou, Y. J., Bai, Y. M., Chen, T. T., Wang, Y. C., & Tsai, S. J. (2010). Dopamine receptor D2 gene is associated with weight gain in schizophrenic patients under long-term atypical antipsychotic treatment. Pharmacogenetics and Genomics, 20, 359–366.

    Article  PubMed  CAS  Google Scholar 

  • Kane, J. M., Barrett, E. J., Casey, D. E., Correll, C. U., Gelenberg, A. J., Klein, S., et al. (2004). Metabolic effects of treatment with atypical antipsychotics. Journal of Clinical Psychiatry, 65, 1447–1455.

    Article  PubMed  Google Scholar 

  • Kawachi, I. (1999). Physical and psychological consequences of weight gain. Journal of Clinical Psychiatry, 60(Suppl 21), 5–9.

    Google Scholar 

  • Lane, H. Y., Liu, Y. C., Huang, C. L., Chang, Y. C., Wu, P. L., Lu, C. T., et al. (2006). Risperidone-related weight gain: Genetic and nongenetic predictors. Journal of Clinical Psychopharmacology, 26, 128–134.

    Article  PubMed  CAS  Google Scholar 

  • Le Hellard, S., Theisen, F. M., Haberhausen, M., Raeder, M. B., Fernø, J., Gebhardt, S., et al. (2009). Association between the insulin-induced gene 2 (INSIG2) and weight gain in a German sample of antipsychotic-treated schizophrenic patients: Perturbation of SREBP-controlled lipogenesis in drug-related metabolic adverse effects? Molecular Psychiatry, 14, 308–317.

    Article  PubMed  CAS  Google Scholar 

  • Leadbetter, R., Shutty, M., Pavalonis, D., Vieweg, V., Higgins, P., & Downs, M. (1992). Clozapine-induced weight gain: Prevalence and clinical relevance. The American Journal of Psychiatry, 149, 68–72.

    PubMed  CAS  Google Scholar 

  • Lebrun, B., Bariohay, B., Moyse, E., & Jean, A. (2006). Brain-derived neurotrophic factor (BDNF) and food intake regulation: A minireview. Autonomic Neuroscience, 126, 30–38.

    Article  PubMed  Google Scholar 

  • Licinio, J., Dong, C., & Wong, M. L. (2009). Novel sequence variations in the brain-derived neurotrophic factor gene and association with major depression and antidepressant treatment response. Archives of General Psychiatry, 66, 488–497.

    Article  PubMed  CAS  Google Scholar 

  • Müller, D. J., & Kennedy, J. L. (2006). Genetics of antipsychotic treatment emergent weight gain in schizophrenia. Pharmacogenomics, 7, 863–887.

    Article  PubMed  Google Scholar 

  • Müller, D. J., Klempan, T. A., De Luca, V., Sicard, T., Volavka, J., Czobor, P., et al. (2005). The SNAP-25 gene may be associated with clinical response and weight gain in antipsychotic treatment of schizophrenia. Neuroscience Letters, 379, 81–89.

    Article  PubMed  Google Scholar 

  • Petryshen, T. L., Sabeti, P. C., Aldinger, K. A., Fry, B., Fan, J. B., Schaffner, S. F., et al. (2010). Population genetic study of the brain-derived neurotrophic factor (BDNF) gene. Molecular Psychiatry, 15, 810–815.

    Article  PubMed  CAS  Google Scholar 

  • Popp, J., Leucht, S., Heres, S., & Steimer, W. (2009). DRD4 48 bp VNTR but not 5-HT 2C Cys23Ser receptor polymorphism is related to antipsychotic-induced weight gain. The Pharmacogenomics Journal, 9, 71–77.

    Article  PubMed  CAS  Google Scholar 

  • Reynolds, G. P., Zhang, Z. J., & Zhang, X. B. (2002). Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism. Lancet, 359, 2086–2087.

    Article  PubMed  CAS  Google Scholar 

  • Ribasés, M., Gratacòs, M., Fernández-Aranda, F., Bellodi, L., Boni, C., Anderluh, M., et al. (2005). Association of BDNF with restricting anorexia nervosa and minimum body mass index: A family-based association study of eight European populations. European Journal of Human Genetics, 13, 428–434.

    Article  PubMed  Google Scholar 

  • Russell, J. M., & Mackell, J. A. (2001). Bodyweight gain associated with atypical antipsychotics: Epidemiology and therapeutic implications. CNS Drugs, 15, 537–551.

    Article  PubMed  CAS  Google Scholar 

  • Sickert, L., Müller, D. J., Tiwari, A. K., Shaikh, S., Zai, C., De Souza, R., et al. (2009). Association of the alpha2A adrenergic receptor -1291C/G polymorphism and antipsychotic-induced weight gain in European-Americans. Pharmacogenomics, 10, 1169–1176.

    Article  PubMed  CAS  Google Scholar 

  • Storey, J. D. (2002). A direct approach to false discovery rate. Journal of the Royal Statistical Society: Series B, 64, 479–498.

    Article  Google Scholar 

  • Theisen, F. M., Gebhardt, S., Haberhausen, M., Heinzel-Gutenbrunner, M., Wehmeier, P. M., Krieg, J. C., et al. (2005). Clozapine-induced weight gain: A study in monozygotic twins and same-sex sib pairs. Psychiatric Genetics, 15, 285–289.

    Article  PubMed  Google Scholar 

  • Toriya, M., Maekawa, F., Maejima, Y., Onaka, T., Fujiwara, K., Nakagawa, T., et al. (2010). Long-term infusion of brain-derived neurotrophic factor reduces food intake and body weight via a corticotrophin-releasing hormone pathway in the paraventricular nucleus of the hypothalamus. Journal of Neuroendocrinology, 22, 987–995.

    Article  PubMed  CAS  Google Scholar 

  • Ujike, H., Nomura, A., Morita, Y., Morio, A., Okahisa, Y., Kotaka, T., et al. (2008). Multiple genetic factors in olanzapine-induced weight gain in schizophrenia patients: A cohort study. Journal of Clinical Psychiatry, 69, 1416–1422.

    Article  PubMed  CAS  Google Scholar 

  • Unger, T. J., Calderon, G. A., Bradley, L. C., Sena-Esteves, M., & Rios, M. (2007). Selective deletion of Bdnf in the ventromedial and dorsomedial hypothalamus of adult mice results in hyperphagic behavior and obesity. The Journal of Neuroscience, 27, 14265–14274.

    Article  PubMed  CAS  Google Scholar 

  • Wang, Y. C., Bai, Y. M., Chen, J. Y., Lin, C. C., Lai, I. C., & Liou, Y. J. (2005). C825T polymorphism in the human G protein beta3 subunit gene is associated with long-term clozapine treatment-induced body weight change in the Chinese population. Pharmacogenetics and Genomics, 15, 743–748.

    Article  PubMed  CAS  Google Scholar 

  • Wehmeier, P. M., Gebhardt, S., Schmidtke, J., Remschmidt, H., Hebebrand, J., & Theisen, F. M. (2005). Clozapine: Weight gain in a pair of monozygotic twins concordant for schizophrenia and mild mental retardation. Psychiatry Research, 133, 273–276.

    Article  PubMed  CAS  Google Scholar 

  • Yia, Z., Yu, S., & Fang, Y. (2011). Association of the brain-derived neurotrophic factor (BDNF) gene polymorphisms with early-onset and female schizophrenia in the Chinese population. European Psychiatry, 26(Suppl 1), 863.

    Google Scholar 

  • Zeilinger, S., Pinto, L. A., Nockher, W. A., Depner, M., Klopp, N., Illig, T., et al. (2009). The effect of BDNF gene variants on asthma in German children. Allergy, 64, 1790–1794.

    Article  PubMed  CAS  Google Scholar 

  • Zhang, X. Y., Tan, Y. L., Zhou, D. F., Cao, L. Y., Wu, G. Y., Xu, Q., et al. (2007). Serum BDNF levels and weight gain in schizophrenic patients on long-term treatment with antipsychotics. Journal of Psychiatric Research, 41, 997–1004.

    Article  PubMed  Google Scholar 

  • Zhang, X. Y., Zhou, D. F., Wu, G. Y., Cao, L. Y., Tan, Y. L., Haile, C. N., et al. (2008). BDNF levels and genotype are associated with antipsychotic-induced weight gain in patients with chronic schizophrenia. Neuropsychopharmacology, 33, 2200–2205.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors would like to thank National Genotyping Center of National Research Program for Genomic Medicine, National Science Council, for the support in SNP genotyping. We would also like to acknowledge the National Genotyping Center of National Research Program for Genomic Medicine, Taiwan (NSC98-3112-B-001-022), especially Dr Jer-Yuan Wu his technical support. This work was supported by grant V98C1-061 from Taipei Veterans General Hospital, Taiwan, and grants NSC 95-2314-B-075-011 and NSC 97-2314-B-075-001-MY3 from National Science Council Grant, Taiwan.

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Integrative Biology, University of California, Berkeley, CA, US

    Ashley Tsai

  2. Department of Psychiatry, Taipei Veterans General Hospital, No. 201, Shih-Pai Road, Sec. 2, 11217, Taipei, Taiwan

    Ying-Jay Liou, Chen-Jee Hong, Shih-Jen Tsai & Ya Mei Bai

  3. Division of Psychiatry, School of Medicine, National Yang-Ming University, Taipei, Taiwan

    Ying-Jay Liou, Chen-Jee Hong, Shih-Jen Tsai & Ya Mei Bai

  4. Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan

    Chen-Jee Hong

  5. Department of Psychiatry, Yuli Veterans Hospital, Hualien, Taiwan

    Chia-Liang Wu

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  1. Ashley Tsai
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  2. Ying-Jay Liou
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Correspondence to Shih-Jen Tsai or Ya Mei Bai.

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Tsai, A., Liou, YJ., Hong, CJ. et al. Association Study of Brain-Derived Neurotrophic Factor Gene Polymorphisms and Body Weight Change in Schizophrenic Patients Under Long-Term Atypical Antipsychotic Treatment. Neuromol Med 13, 328–333 (2011). https://doi.org/10.1007/s12017-011-8159-5

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  • DOI: https://doi.org/10.1007/s12017-011-8159-5

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