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

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 -hippocampal prefrontal 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. Molecular Psychiatry (2009) 14, 681-695; doi:10.1038/mp.2008.143; published online 20 January 2009