Abstract
Bipolar disorder is a highly heritable illness that onsets in adolescence and young adulthood. We examined gene expression (mRNA) and protein levels of candidate immune and neurotrophic markers in well-characterized offspring of bipolar parents in order to identify reliable indicators of illness risk status and the early clinical stages of illness development. We measured mRNA expression and protein levels in candidate immune (TNF-α, IL-1β, IL-10, IFN-δ) and neurotrophic (brain-derived neurotrophic factor (BDNF)) markers from plasma. High-risk offspring were identified from families in which one parent had confirmed bipolar disorder. Control offspring were identified from families in which neither parent met lifetime criteria for a major psychiatric disorder. All parental Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnoses were based on Schedule for Affective Disorders - Lifetime Version (SADS-L) interviews and blind consensus review. As part of an ongoing study, all offspring were prospectively assessed using KSADS-PL format interviews and diagnoses confirmed on blind consensus review. High-risk offspring had significantly increased IL-6 (p = 0.050) and BDNF (p = 0.006) protein levels compared to controls. Those high-risk offspring in earlier compared to later clinical stages of illness development had higher IL-6 (p = 0.050) and BDNF (p = 0.045) protein levels. After adjustments, only differences in BDNF protein levels remained significant. There was a moderating effect of the BDNF genotype on both gene expression and protein levels in high-risk compared to control offspring. The BDNF genotype also moderated the association between clinical stage and gene expression levels in high-risk offspring. These findings provide support for detectable differences in candidate immune and neurotrophic markers in individuals at high risk of developing bipolar disorder and for detectable changes over the clinical stages of illness development. These associations appear to be moderated by genetic variants.Electronic supplementary materialThe online version of this article (doi:10.1186/2194-7511-2-4) contains supplementary material, which is available to authorized users.
Highlights
There is convergent evidence from longitudinal studies that bipolar disorder (BD) develops in a series of predictable clinical stages in those at genetic risk (Duffy et al 2014)
We present findings from a cross-sectional study of DNA polymorphisms, mRNA expression, and protein levels in candidate immune system (TNF-α, IL-1β, IL-10, IFN-δ) and neurotrophic (BDNF) markers from plasma collected in prospectively assessed high-risk offspring of well-characterized BD parents and from well offspring of psychiatrically unaffected parents
We studied DNA polymorphisms, gene expression, and protein levels of proinflammatory mediators IL-1β, IL-6, tumor necrosis factor-alpha (TNF-α), and IFN-δ, anti-inflammatory mediator IL-10, and brain-derived neurotrophic factor (BDNF) in lymphocytes and plasma collected from offspring at genetic high risk compared to low-risk offspring
Summary
There is convergent evidence from longitudinal studies that bipolar disorder (BD) develops in a series of predictable clinical stages in those at genetic risk (Duffy et al 2014). A large body of evidence supports the association between stress, clinically significant depression, and activation of the immune and neuroendocrine systems (Woiciechowsky et al 1999; Berk et al 2011; Gibney and Drexhage 2013), it still remains unclear if differential reactivity to stress reflects a predisposition or a marker of illness activity or both. In patients with established illness, hypothalamic-pituitaryadrenal (HPA) activation is associated with acute exacerbations as a state marker (Deshauer et al 1999), and recent evidence suggests that this defect in inhibitory feedback resulting in both immune and HPA axis activation may be a useful trait marker in high-risk individuals (Duffy et al 2012; Halligan et al 2007; Ellenbogen et al 2011)
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