Preliminary study of anxiety symptoms, family dysfunction, and the brain-derived neurotrophic factor (BDNF) Val66Met genotype in offspring of parents with bipolar disorder
Introduction
Children of parents with bipolar disorder (BD) (BD offspring) are at higher risk for developing BD (Axelson et al., 2011, Chang et al., 2003) as well as other psychiatric disorders (Lapalme et al., 1997, Singh et al., 2007) than the general population. Anxiety disorders have attracted special attention not only because of their high prevalence in BD offspring but also because the presence of anxiety disorders may serve as a predictor for developing BD (Duffy et al., 2013, Henin et al., 2005). Even subclinical levels of anxiety can predispose individuals to developing BD, suggesting that having early anxiety symptoms may represent an endophenotype of BD (Contreras et al., 2010).
The brain-derived neurotrophic factor (BDNF) gene has been implicated in the pathophysiology of both bipolar and anxiety disorders. BDNF is a member of the neurotrophin family of growth factors and is concentrated in brain regions involved in learning and memory, such as the hippocampus and amygdala (Hofer et al., 1990, Rakofsky et al., 2012). Reduced BDNF levels have been observed in patients with BD during manic and depressive episodes and these levels have normalized with episode recovery (Cunha et al., 2006, de Oliveira et al., 2009, Lin, 2009). Post-mortem studies have also demonstrated decreased hippocampal BDNF in patients with BD (Dunham et al., 2009, Knable et al., 2004). Similarly, reduced BDNF levels have been observed in individuals with anxiety disorders compared to those without anxiety disorders (Suliman et al., 2013). Finally, acute and chronic stress have been associated with decreased BDNF expression in the hippocampus with subsequent enhancement of anxiety-related behaviors (McEwen, 2001, Russo-Neustadt, 2003). Several lines of evidence suggest that youth offspring of parents with BD may also be vulnerable to aberrant BDNF function. In addition to high rates of mood and anxiety disorders, bipolar offspring have increased cortisol levels in response to chronic stress (Ostiguy et al., 2009, Ostiguy et al., 2011) and typically live in disorganized and conflictual family environments (Belardinelli et al., 2008, Chang et al., 2001).
Decreased BDNF levels in humans has also been associated with the met allele of BDNF Val66Met polymorphism (rs6265) (Chen et al., 2006, Egan et al., 2003). However, studies on the association between the BDNF Val66Met polymorphism and BD or anxiety have been mixed, with a number of studies that have also found that the val/val allele also confers risk for anxiety (Hünnerkopf et al., 2007, Lang et al., 2004) or BD (Geller et al., 2004, Neves-Pereira et al., 2002, Sklar et al., 2002, Strauss et al., 2005, Tang et al., 2008). This inconsistency across studies may be due to the heterogenous nature of these disorders or unidentified moderating factors between the BDNF genotype and psychiatric symptoms.
Although, anxiety may serve as a predisposing factor for BD development in BD offspring, no study has investigated the relation between anxiety and the BDNF genotype in cohorts at high-risk for BD, or the moderating effects of family dysfunction on this relation. Young offspring of parents with BD who have not yet developed BD themselves represent a unique risk cohort that can permit researchers to simultaneously assess these key genetic and environmental risk factors for developing BD. We aimed to compare levels of anxiety, as measured by the Multidimensional Anxiety Scale for Children (MASC) (March et al., 1997), family dysfunction, measured by the Family Adaptability and Cohesion Evaluation Scales, version IV (FACES-IV) (Olson, 2011), and their associations with the BDNF genotype in BD offspring and healthy control (HC) groups. Based on prior studies (Gatt et al., 2009, Hartmann et al., 2001, Rasmusson et al., 2002), we hypothesized that the BDNF genotype will exert its effects when combined with the stress of being a BD offspring and having associated family dysfunction (Belardinelli et al., 2008, Chang et al., 2001), and that (1) BD offspring would have higher levels of anxiety than the HC group; (2) the BDNF Val66Met genotype would be associated with the levels of anxiety in BD offspring but not in healthy controls, such that group status would moderate the relation between the BDNF Val66Met genotype and anxiety; and (3) compared to HC youth, youth offspring of parents with BD would have lower levels of family cohesion, organization, and satisfaction, and that these dysfunctional family characteristics would moderate the effect of the BDNF genotype on anxiety symptoms, as well as BD offspring status.
Section snippets
Participant recruitment and assessment
The protocol was approved by the Stanford University Panel of Medical Research in Human Subjects. Written and oral informed consent was obtained from at least one parent, and written and oral assent was obtained from the youth. One hundred BD offspring and 60 HC were recruited from the Stanford Adult and Pediatric Bipolar Disorders Programs and from the community.
Inclusion criteria for BD offspring was age 9–18 years, having a biological parent with bipolar I or II disorder, and being healthy
Results
Among 100 BD offspring and 60 HC, 36 BD offspring and 9 HC were excluded due to incomplete MASC data, leaving 64 BD offspring (mean age: 13.73 (3.45) M = 30, F = 34) and 51 HC (mean age: 13.68 (2.68) M = 23, F = 28) to be included for statistical analysis. The majority of the participants included in the analysis were Caucasian (BD offspring: 58 Caucasian, 6 Hispanic; HC: 31 Caucasian, 3 Black, 7 Asian, 5 Hispanic, 5 mixed). Participant demographic and clinical characteristics are provided in
Discussion
In this study, we demonstrated that as hypothesized, BD offspring have higher levels of anxiety than typically developing healthy controls, and anxiety symptoms associated with BDNF genotype in BD offspring but not in healthy controls. Specifically, BD offspring with the val/val genotype showed higher anxiety symptoms than BD offspring with other genotypes. Further, we found BD offspring group showed significantly more family dysfunction when compared with the HC group and the family
Role of the funding source
Funding for this study was provided by the NIMH (R01 MH077047 and K23 MH064460 to KDC and K23 MH085919 to MKS). The NIMH had no further role in study design, in the collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication.
Contributors
Drs Singh and Chang designed the study, wrote the protocol, and wrote and edited all drafts of the manuscript. Dr. Park conducted the literature search, analyses, and wrote the first draft of the manuscript. Dr. Hong contributed to the statistical analysis. Drs. Park, Chang, Hallmayer, Kim, Hong and Singh, and Ms. Howe contributed to and approved the final manuscript.
Conflict of interest
Dr. Chang is a consultant for GlaxoSmithKline, Bristol-Myers Squibb, Merck, and Sunovion. The other authors have nothing to disclose.
Acknowledgments
The authors gratefully acknowledge funding from the NIMH (R01 MH077047 and K23 MH064460 to KDC and K23 MH085919 to MKS). We thank the participants who gave their time for this study.
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