BDNF genetic variants and methylation: effects on cognition in major depressive disorder

Alex Ferrer,Neus Salvat-Pujol,Mikel Urretavizcaya,Ángel Carracedo,Javier Costas,Marta Barrachina,Javier Labad,José M Menchón,Aida De Arriba-Arnau,José M Crespo,Carles Soriano-Mas,Virginia Soria

doi:10.1038/s41398-019-0601-8

Abstract

Brain-derived neurotrophic factor (BDNF) gene regulation has been linked to the pathophysiology of major depressive disorder (MDD). MDD patients show cognitive deficits, and altered BDNF regulation has a relevant role in neurocognitive functions. Our goal was to explore the association between BDNF genetic and epigenetic variations with neurocognitive performance in a group of MDD patients and healthy controls considering possible modulating factors. The sample included 134 subjects, 64 MDD patients, and 70 healthy controls. Clinical data, childhood maltreatment, and neurocognitive performance were assessed in all participants. Eleven single nucleotide polymorphisms (SNPs) and two promoter regions in the BDNF gene were selected for genotype and methylation analysis. The role of interactions between BDNF genetic and epigenetic variations with MDD diagnosis, sex, and Childhood Trauma Questionnaire (CTQ) scores was also explored. We observed significant associations between neurocognitive performance and two BDNF SNPs (rs908867 and rs925946), an effect that was significantly mediated by methylation values at specific promoter I sites. We identified significant associations between neurocognitive results and methylation status as well as its interactions with MDD diagnosis, sex, and CTQ scores. Our results support the hypothesis that BDNF gene SNPs and methylation status, as well as their interactions with modulating factors, can influence cognition. Further studies are required to confirm the effect of BDNF variations and cognitive function in larger samples.

Highlights

Major depressive disorder (MDD) is a complex and highly prevalent psychiatric disorder with a high impact on quality of life and negative effects on mood, behavior, and cognition[1]
We have studied the contribution of brain-derived neurotrophic factor (BDNF) genetic and epigenetic variations to cognitive functioning in MDD patients and HCs
Our main findings include the association between two single nucleotide polymorphisms (SNPs) as well as promoter methylation levels with several cognitive tasks and statistically significant interactions with sex, Childhood Trauma Questionnaire (CTQ) scores and MDD diagnosis

Summary

Introduction

Major depressive disorder (MDD) is a complex and highly prevalent psychiatric disorder with a high impact on quality of life and negative effects on mood, behavior, and cognition[1]. Cognitive dysfunction in MDD patients is a source of disability involving deficits in visual, verbal and working memory, attention, executive function, and processing speed[1]. Several neurobiological mechanisms have been involved in the pathogenesis of MDD and related cognitive phenotypes, such as the neurotrophic signaling pathway. The brain-derived neurotrophic factor (BDNF) gene codes for a neurotrophin that is highly expressed in the central nervous system (CNS), mediates a variety of neuroplasticity processes, and has relevant influences on cognition and behavior[2]. Blood BDNF concentrations, that have been observed to correlate with BDNF expression levels in the brain[4], are lower in MDD patients than in healthy controls[5]

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