Longitudinal associations between BDNF promoter methylation and late-life depression

Abstract

Reduced brain-derived neurotrophic factor (BDNF) function has been suggested as a risk factor for late-life depression. BDNF secretion is influenced by epigenetic (DNA promoter methylation) and genetic (val66met polymorphism) profiles. We investigated the independent and interactive effects of BDNF methylation and val66met polymorphism on late-life depression. In total, 732 Korean community residents aged ≥65 years were evaluated, and 521 of them without depression at baseline were followed up 2 years later. Depression was determined using the Geriatric Mental State Schedule, and depression severity was evaluated with the Geriatric Depression Scale. Demographic and clinical covariates were obtained. The effects of BDNF methylation and polymorphism on the diagnosis of depression were investigated using a multivariate logistic regression model, and the relationships between BDNF methylation and depression severity were evaluated using partial correlation tests. Higher BDNF methylation was independently associated with the prevalence and incidence of depression and severe depressive symptoms. No significant methylation-genotype interactions were found. BDNF promoter methylation could be a proxy biomarker for depression late in life.

Introduction

Depression is the most common psychiatric disorder among elderly people (Alexopoulos, 2005). Late-life depression is associated with an elevated risk of suicide and functional and cognitive impairments, which confer a risk of dementia (Alexopoulos and Kelly, 2009, Diniz et al., 2013). Considering these negative consequences of geriatric depression, understanding the etiology of depression is an important step toward early detection and effective treatment of depression in the elderly population.

Studies have suggested that late-life depression has a complex and multifactorial etiology. The complex interplay between biological factors (e.g., hypothalamic-pituitary-adrenal axis dysfunction, neurodegenerative changes, and vascular and genetic mechanisms) and psychosocial factors (e.g., stressful life events and decreased social support) reportedly contributes to the occurrence of late-life depression (Belmaker and Agam, 2008, Kim et al., 2007, Smith et al., 2007). Among those etiologies, there is growing interest in brain-derived neurotrophic factor (BDNF) as a neurobiological mechanism of depression. BDNF is critical for the growth, survival, and differentiation of neuronal cells and for neuronal plasticity (Hu and Russek, 2008, Huang and Reichardt, 2001). Several studies that assessed BDNF levels in patients with depression found that plasma BDNF levels were significantly lower in geriatric depressed patients compared with controls (Chu et al., 2012, Laske et al., 2010, Shi et al., 2010). Genetic studies have shown that BDNF val66met polymorphisms are associated with an increased risk of depression in elderly patients (Hwang et al., 2006, Taylor et al., 2007). Additionally, studies on the association between BDNF val66met polymorphisms and brain parameters such as hippocampal volume and white-matter hyperintensities have suggested that the met allele is associated with decreased BDNF secretion (Egan et al., 2003), conferring a risk of depression (Kanellopoulos et al., 2011, Taylor et al., 2011).

BDNF expression is also regulated by epigenetic chromatin remodeling in gene promoter regions. In the central nervous system, DNA methylation of cytosines in cytosine-guanine (CpG) dinucleotides is regarded as the representative component of broader epigenetic modification at a given locus (Hochberg et al., 2010). Increased CpG methylation at promoter regions of the BDNF gene is reportedly correlated with the decreased synthesis of BDNF in neurons (Martinowich et al., 2003). Such studies focused on the adult population and showed that increased BDNF methylation was correlated with depression in the general population (Fuchikami et al., 2011) and with suicidal ideation in patients with major depression (Kang et al., 2013a). Based on these findings, we hypothesized that the BDNF DNA methylation status is associated with depression in elderly individuals. To our knowledge, no investigation has been conducted on the role of BDNF promoter methylation and its interaction with BDNF polymorphism in the higher prevalence and burden of depression among older adults. This study aimed to investigate whether BDNF promoter methylation and val66met polymorphism are independently or interactively associated with the prevalence and incidence of depression in late life using data from a longitudinal study of an older Korean community population.