Brief report
Stressful life events and the brain-derived neurotrophic factor gene in bipolar disorder

https://doi.org/10.1016/j.jad.2010.01.071Get rights and content

Abstract

Background

Gene–environment interactions may contribute to the high heritability of bipolar affective disorder. The aim of the present study was to examine the interplay between the BDNF Val66Met polymorphism and stressful life events (SLEs) in bipolar disorder.

Method

A total of 1085 participants were recruited, including 487 bipolar I cases and 598 psychiatrically healthy controls. All participants completed the List of Threatening Life Events Questionnaire; bipolar subjects reported the events that occurred 6 months leading up to their worst manic episode and 6 months prior to their worst depressive episode, controls recorded events experienced 6 months before interview. The sample was genotyped for the BDNF Val66Met polymorphism (rs6265).

Results

Both Met carrier BDNF genotype and SLEs were significantly associated with the worst depressive episode of bipolar disorder. For the worst depressive episodes the effects of SLEs were also significantly moderated by BDNF genotype (gene × environment interaction).

Limitations

The use of a self report questionnaire to measure stressful life events may increase recall inaccuracies, therefore caution should be taken when interpreting these results.

Discussion

The findings of this study highlight the importance of the interplay between genes and the environment in bipolar disorder.

Introduction

Stressful life events (SLEs) are associated with the onset and relapse in bipolar disorder (BD) (Hosang et al., 2010, Johnson, 2005). Family and twin studies consistently show that BD is highly heritable with genetic factors accounting for as much as 80% of its variance (McGuffin et al., 2003). A growing body of research demonstrates that environmental factors such as SLEs are involved in the development of affective disorders may act by moderating the effects of genes, for example via gene–environment interactions (G × E) (Uher and McGuffin, 2008). While G × E have been demonstrated in unipolar depression, the role of G × E in BD is largely unknown. The aim of this study was to explore the relationship between SLEs and the Val66Met polymorphism in the brain-derived neurotrophic factor gene (BDNF) in BD.

BDNF is implicated in the proliferation, differentiation and survival of neuronal cells and regulating synaptic plasticity and connectivity in the adult brain (Post, 2007). Evidence suggests that BDNF may also be influential in stress vulnerability. According to the ‘Neutrophic Hypothesis’ of depression (Stein et al., 2008), stress reduces BDNF activity resulting in decreased hippocampal function, which is in turn associated with depressed mood. It has been suggested that antidepressant therapy reverses this effect (Stein et al., 2008). Consistent with this hypothesis, rodents exposed to both acute and chronic stress show decreased BDNF levels (Duman and Monteggie, 2006), which can be reversed by the administration of antidepressants and mood stabilizers (Einat et al., 2003). Furthermore, decreased BDNF levels have been observed in bipolar patients during both depressive and manic episodes (Cunha et al., 2006).

A polymorphism that has been widely investigated in psychiatric disorders is BDNF Val66Met which results in the substitution of Valine (Val) to Methionine (Met) (Rybakowski, 2008). The Met allele of BDNF Val66Met is associated with reduced BDNF activity (Egan et al., 2003) and harm avoidance (Jiang et al., 2005), as well as depression, schizophrenia and BD, although findings are inconsistent (Rybakowski, 2008). One reason for the disparity in results may be a consequence of a lack of environmental measures being factored into these studies (Moffitt et al., 2005).

Interestingly, human studies report decreased BDNF serum levels among bipolar patients who have experienced a traumatic event (e.g. childhood maltreatment) compared to those without such a history (Kauer-Sant'Anna et al., 2007). Furthermore several studies have shown that the effect of SLEs on unipolar depression is moderated by the Met allele of BDNF Val66Met (Kim et al., 2007, Drachmann Bukh et al., 2009).

The present study uses a sample of bipolar individuals and controls to explore the relationship between SLEs and BDNF Val66Met in BD, hypothesizing that the impact of SLEs will be moderated by the Met allele of BDNF Val66Met in predicting an episode of bipolar depression and mania.

Section snippets

Sample

The 1085 participants were initially recruited for 2 genetic case–control association studies. The demographic and clinical characteristics of the sample are presented in Table 1.

Results

The BDNF Val66Met was in Hardy–Weinberg equilibrium (χ2 (2) = 0.72, p > 0.05), the genotypic distribution is presented in Table 2.

The Met containing genotype was significantly associated with BD (β = 0.31, SE = 0.13, p < 0.05). However, age at both index periods did not differ by BDNF Val66Met genotype for the whole sample (controls and bipolar cases for the WME t(1027) =  0.16, p > 0.05; and WDE t(1027) =  0.13, p > 0.05). Genotype did not differ by gender for the whole sample (χ2 (1) = 0.06, p > 0.05).

BD cases

Discussion

This study demonstrates a significant interaction between the Met containing BDNF Val66Met genotype and SLEs for the WDE but not for the WME.

To our knowledge, this is the first study to examine the relationship between BDNF Val66Met and SLEs in BD. However, our results are in line with previous studies of unipolar depression which report significant interactions between the Met containing BDNF Val66Met genotype and SLEs (Drachmann Bukh et al., 2009) along with childhood adversity (Kaufman et

Role of the funding source

Funding for this study was provided Georgina Hosang was supported by a Medical Research Council (MRC) and Economic Research Council (ESRC) UK interdisciplinary Ph.D. studentship.by GlaxoSmithKline; the corporation had no further role in study design; in the collection, analysis and interpretation of data. Georgina Hosang was supported by a Medical Research Council (MRC) and Economic Research Council (ESRC) UK interdisciplinary Ph.D. studentship.

Conflict of interest

Julia Perry and Federica Tozzi are both employed by GlaxoSmithKline. No other conflict of interests is declared for the remaining authors.

Acknowledgements

We would like to thank Cerisse Gunasinghe, Katharine Mead, Joanna Gray, Ylva Dahlin, Amanda Elkin Audrey Morgan, Joanna O'Leary, Nathan O'Neill, Nicola Reynolds, Zainab Samaan, Abraham Stern, Linda Southwick, Kopal Tandon, Alison Wheatley, Richard Williamson, Julia Woods, Sarah Ball, Ophelia Beer, Julian Childs, Sam Keating, Rachel Marsh, Penny Machin, and Lucy Maddox who were involved with the data collection and management of the studies.

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