BDNF rs6265 methylation and genotype interact on risk for schizophrenia

Gianluca Ursini, Tommaso Cavalleri, Leonardo Fazio, Tiziana Angrisano, Luisa Iacovelli, Annamaria Porcelli, Giancarlo Maddalena, Giovanna Punzi, Marina Mancini, Barbara Gelao, Raffaella Romano, Rita Masellis, Francesca Calabrese, Antonio Rampino, Paolo Taurisano, Annabella Di Giorgio, Simona Keller, Letizia Tarantini, Lorenzo Sinibaldi, Tiziana QuartoTeresa Popolizio, Grazia Caforio, Giuseppe Blasi, Marco A. Riva, Antonio De Blasi, Lorenzo Chiariotti, Valentina Bollati, Alessandro Bertolino

Research output: Contribution to journalArticle

Abstract

Epigenetic mechanisms can mediate gene-environment interactions relevant for complex disorders. The BDNF gene is crucial for development and brain plasticity, is sensitive to environmental stressors, such as hypoxia, and harbors the functional SNP rs6265 (Val66Met), which creates or abolishes a CpG dinucleotide for DNA methylation. We found that methylation at the BDNF rs6265 Val allele in peripheral blood of healthy subjects is associated with hypoxia-related early life events (hOCs) and intermediate phenotypes for schizophrenia in a distinctive manner, depending on rs6265 genotype: in ValVal individuals increased methylation is associated with exposure to hOCs and impaired working memory (WM) accuracy, while the opposite is true for ValMet subjects. Also, rs6265 methylation and hOCs interact in modulating WM-related prefrontal activity, another intermediate phenotype for schizophrenia, with an analogous opposite direction in the 2 genotypes. Consistently, rs6265 methylation has a different association with schizophrenia risk in ValVals and ValMets. The relationships of methylation with BDNF levels and of genotype with BHLHB2 binding likely contribute to these opposite effects of methylation. We conclude that BDNF rs6265 methylation interacts with genotype to bridge early environmental exposures to adult phenotypes, relevant for schizophrenia. The study of epigenetic changes in regions containing genetic variation relevant for human diseases may have beneficial implications for the understanding of how genes are actually translated into phenotypes.

Original languageEnglish (US)
Pages (from-to)11-23
Number of pages13
JournalEpigenetics
Volume11
Issue number1
DOIs
StatePublished - Jan 2 2016

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Keywords

  • BDNF
  • DNA methylation
  • epigenetics
  • hypoxia
  • obstetric complications
  • prefrontal cortex
  • rs6265
  • schizophrenia
  • working memory

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Ursini, G., Cavalleri, T., Fazio, L., Angrisano, T., Iacovelli, L., Porcelli, A., Maddalena, G., Punzi, G., Mancini, M., Gelao, B., Romano, R., Masellis, R., Calabrese, F., Rampino, A., Taurisano, P., Giorgio, A. D., Keller, S., Tarantini, L., Sinibaldi, L., ... Bertolino, A. (2016). BDNF rs6265 methylation and genotype interact on risk for schizophrenia. Epigenetics, 11(1), 11-23. https://doi.org/10.1080/15592294.2015.1117736