TY - JOUR
T1 - BDNF rs6265 methylation and genotype interact on risk for schizophrenia
AU - Ursini, Gianluca
AU - Cavalleri, Tommaso
AU - Fazio, Leonardo
AU - Angrisano, Tiziana
AU - Iacovelli, Luisa
AU - Porcelli, Annamaria
AU - Maddalena, Giancarlo
AU - Punzi, Giovanna
AU - Mancini, Marina
AU - Gelao, Barbara
AU - Romano, Raffaella
AU - Masellis, Rita
AU - Calabrese, Francesca
AU - Rampino, Antonio
AU - Taurisano, Paolo
AU - Giorgio, Annabella Di
AU - Keller, Simona
AU - Tarantini, Letizia
AU - Sinibaldi, Lorenzo
AU - Quarto, Tiziana
AU - Popolizio, Teresa
AU - Caforio, Grazia
AU - Blasi, Giuseppe
AU - Riva, Marco A.
AU - De Blasi, Antonio
AU - Chiariotti, Lorenzo
AU - Bollati, Valentina
AU - Bertolino, Alessandro
N1 - Funding Information:
We thank Dr. Chris W Pug and Dr. Zuzana Bencokova for providing anti-HIFα antibody; Riccarda Lomuscio, BA, Maria Teresa Attrotto, MD, Lucia Colagiorgio, MD, Giuseppe Rizzo, MD, for helping with data acquisition, and Dr. Daniel R. Weinberger for helpful discussions. This work was supported by Fondazione Con Il Sud “Capitale Umano ad Alta Qualificazione” grant (awarded to AB); Brain & Behavior Research Foundation Independent Investigator grant (AB); Regione Campania l.5 and EPIGEN Flagship Project CNR grant.
Publisher Copyright:
© 2016 Taylor & Francis Group, LLC.
PY - 2016/1/2
Y1 - 2016/1/2
N2 - 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.
AB - 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.
KW - BDNF
KW - DNA methylation
KW - epigenetics
KW - hypoxia
KW - obstetric complications
KW - prefrontal cortex
KW - rs6265
KW - schizophrenia
KW - working memory
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U2 - 10.1080/15592294.2015.1117736
DO - 10.1080/15592294.2015.1117736
M3 - Article
C2 - 26889735
AN - SCOPUS:84961589263
SN - 1559-2294
VL - 11
SP - 11
EP - 23
JO - Epigenetics
JF - Epigenetics
IS - 1
ER -