Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety

Abstract

The Brain Resource International Database and Brain Resource, Sydney, NSW, Australia and San Francisco, CA, USA Individual risk markers for depression and anxiety disorders have been identified but the explicit pathways that link genes and environment to these markers remain unknown. Here we examined the explicit interactions between the brain-derived neurotrophic factor (BDNF) Val66Met gene and early life stress (ELS) exposure in brain (amygdala-hippocampalprefrontal gray matter volume), body (heart rate), temperament and cognition in 374 healthy European volunteers assessed for depression and anxiety symptoms. Brain imaging data were based on a subset of 89 participants. Multiple regression analysis revealed main effects of ELS for body arousal (resting heart rate, P = 0.005) and symptoms (depression and anxiety, P < 0.001) in the absence of main effects for BDNF. In addition, significant BDNF-ELS interactions indicated that BDNF Met carriers exposed to greater ELS have smaller hippocampal and amygdala volumes (P = 0.013), heart rate elevations (P = 0.0002) and a decline in working memory (P = 0.022). Structural equation path modeling was used to determine if this interaction predicts anxiety and depression by mediating effects on the brain, body and cognitive measures. The combination of Met carrier status and exposure to ELS predicted reduced gray matter in hippocampus (P < 0.001), and associated lateral prefrontal cortex (P < 0.001) and, in turn, higher depression (P = 0.005). Higher depression was associated with poorer working memory (P = 0.005), and slowed response speed. The BDNF Met-ELS interaction also predicted elevated neuroticism and higher depression and anxiety by elevations in body arousal (P < 0.001). In contrast, the combination of BDNF V/V genotype and ELS predicted increases in gray matter of the amygdala (P = 0.003) and associated medial prefrontal cortex (P < 0.001), which in turn predicted startle-elicited heart rate variability (P = 0.026) and higher anxiety (P = 0.026). Higher anxiety was linked to verbal memory, and to impulsivity. These effects were specific to the BDNF gene and were not evident for the related 5HTT-LPR polymorphism. Overall, these findings are consistent with the correlation of depression and anxiety, yet suggest that partially differentiated gene-brain cognition pathways to these syndromes can be identified, even in a nonclinical sample. Such findings may aid establishing an evidence base for more tailored intervention strategies.

No gene-by-environment interaction of BDNF Val66Met polymorphism and childhood maltreatment on anxiety sensitivity in a mixed race adolescent sample

“…The following genotype frequencies were evident in our mixed race sample: Val66Val (75.65%, 233/308), Val66Met (22.08%, 68/308) and Met66Met (2.3%, 7/308). These frequencies are generally in line with those determined in Caucasian samples (Carver et al, 2011; Gatt et al, 2009; Pivac et al, 2009; Surtees et al, 2007; Zeni et al, 2013) and in South African mixed race samples (Dalvie et al, 2014), and confirm the low rates of Met66 allele carriers evident in ethnic groups in sub-Saharan Africa (Petryshen et al, 2009). Given the low frequency of Met66Met genotype carriers, Val66Met and Met66Met genotypes were combined (24.35%, 75/308) for genotypic analyses to increase statistical power.…”

“…This finding is not consistent with studies that found that the low-functioning BDNF Met66 allele and CM/childhood trauma or early life adversity or stress interact to predict increased susceptibility for psychopathology, including anxiety-related temperamental traits, such as neuroticism (Gatt et al, 2009) and guilt-proneness (Szentágotai-Tətar et al, 2015), anxiety symptoms (Gatt et al, 2009) and mood disorders and associated symptoms (Aguilera et al, 2009; Carver et al, 2011; Gutiérrez et al, 2015). Our findings are also not in agreement with G x E studies that found an interactive effect of the higher functioning Val66 allele and environmental exposures (i.e.…”

“…Firstly, the grouping of Met66 allele carriers (i.e. Met66Met and Val66Met genotypes), as is frequently carried out in studies in which the rate of the Met66Met genotype is relatively low, such as in Caucasian samples (Gatt et al, 2009; Lehto, Maestu, Kiive, Veidebaum, & Harro, 2016; Nedic et al, 2013; Pivac et al, 2009), may introduce a bias in which a main effect of genotype is not detected due to the exclusion of the Met66Met genotype in analyses (Notaras et al, 2015). Secondly, the Val66Met and Met66Met genotypes, respectively, may have dissimilar effects (Hong et al, 2012).…”

“…BDNF Val66Met and early life stress exposure) have previously been found to be associated with abnormalities in brain structures, physiological indicators, deficits in cognition (i.e. poorer working memory), higher levels of depression and anxiety, and elevated temperamental traits (Gatt et al, 2009). However, data on the interactive effects of CM and genetic factors, such as the BDNF Val66Met polymorphism, on susceptibility to anxiety-related temperamental traits, such as AS, in adolescents is limited.…”

BDNF Val66Met modifies the risk of childhood trauma on obsessive-compulsive disorder

“…A number of studies have indicated that brain-derived neurotrophic factor (BDNF) plays a role in modulating the outcome of childhood trauma in terms of psychopathology (Perroud et al, 2008;Aguilera et al, 2009;Gatt et al, 2009;Pregelj et al, 2011). BDNF is a key neurotrophin that is widely expressed in the mammalian brain, where it plays a crucial role in neurodevelopment, morphology and differentiation, and synaptic plasticity (Hoglinger et al, 1998;Huang and Reichardt, 2001;Lu, 2003;Duman and Monteggia, 2006).…”