BDNF rs6265 methylation and genotype interact on risk for schizophrenia

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 (Val 66 Met), 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.

The Role of Working Memory for Cognitive Control in Anorexia Nervosa versus Substance Use Disorder

“…Specific epigenetic effects of early life deprivation (social isolation) on WM-related brain structures in rats has been shown to increase H3 acetylation at the BDNF gene and BDNF protein expression, specifically in the medial prefrontal cortex, and decreased BDNF mRNA levels, H3 acetylation of the BDNF gene and BDNF protein expression in the hippocampus ( Li et al, 2016 ). Similarly, the BDNF SNP rs6265 (Val (66) Met), which creates or abolishes a CpG dinucleotide for DNA methylation, is associated with modulation of prefrontal cortex activation, impaired WM accuracy and increased methylation in ValVal subjects, but improved WM and reduced methylation in ValMet subjects ( Ursini et al, 2016 ). Epigenetic effects in terms of DNA methylation in the MB-COMT promoter gene, which is associated with WM function, have recently been found to correlate with left DLPFC activation during the performance of a WM task in humans ( Walton et al, 2014 ).…”

A search of target regions for association studies between DNA methylation and cognitive impairment in schizophrenia

“…обзоры 25, 26]. Исследование метилирования гена вблизи rs6265 показало, что его уровень связан с точностью выполнения теста, оценивающего рабочую память, и изменением активности префронтальной коры по результатам функциональной магнитно-резонансной томографии (ф-МРТ) у здоровых людей [27].…”

A methylome-wide mQTL analysis reveals associations of methylation sites with GAD1 and HDAC3 SNPs and a general psychiatric risk score

“… 13 Higher levels of DNA methylation repress transcription by inhibiting the binding of transcription factors or by changing microRNA expression. 14 These findings indicate that changes in DNA methylation may contribute to the compensation and/or modulation of interindividual genetic variation 15 and may be able to induce alterations in the complex regulatory landscape of gene expression levels in psychiatric disorders.…”