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

Abstract

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.

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Acknowledgements

This project was supported by an ARC-linkage grant (LP0455104), with Brain Resource as industry partner. LMW had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. LMW holds a peer-reviewed Pfizer foundation Senior Research Fellowship, and PRS held an NHMRC Senior Principal Research Fellowship (no. 157209). CBN was supported by NIMH MH-42088, MH-52899 and MH-39415. CDS was supported by a European Molecular Biology Organisation postdoctoral fellowship (ALTF 166-2004). AHK holds an NHMRC Peter Doherty Fellowship (no. 358770). We acknowledge the support of the Brain Resource International Database (under the auspices of Brain Resource, www.brainresource.com) for use of normative data. We thank the individuals who gave their time to participate in the database. Access to the database for scientific purposes was administered independently through the scientific network (BRAINnet, www.brainnet.net), which is coordinated independently of the commercial operations of BR. We also thank Scott Norrie (scottnorrie@hotmail.com) for graphical design.

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Brain Resource Ltd (BR) was the industry partner on the ARC-linkage grant that funded this study, but had no further role in design or implementation of the project. EG is the CEO of BR, and holds significant equity and stock options in the company (however, scientific decisions about access to the Brain Resource International Database are made through an independently administered network of scientists; BRAINnet, www.brainnet.net). PRS and JMG hold stock options, and LMW is a small equity holder in BR. JMG is employed as a postdoctoral researcher on the ARC-linkage grant that funded this project. LMW, RHP, JMG and AHK have received fees from BR for consultancies unrelated to this study. CBN is a member of the scientific advisory board of American Foundation for Suicide Prevention (AFSP), Johnson and Johnson, Forest Laboratories, AstraZeneca, Quintiles, Janssen/Ortho-McNeil and PharmaNeuroboost. He holds equity and/or stock options in Corept, CeNeRx, Reevax and NovaDel Pharma and PharmaNeuroboost. CBN is on the board of directors for AFSP, George West Mental Health Foundation, NovaDel Pharma and Mt Cook Pharma. His patents include method and devices for transdermal delivery of lithium (US 6,375,990 B1) and method to estimate serotonin and norepinephrine transporter occupancy after drug treatment using patient or animal serum (provisional filing April 2001).

Author Contributions

JMG undertook the statistical analyses, with a leading role in developing the structural equation model and theoretical approach, and was responsible for all sections of each draft of this paper. LMW developed the project, its theoretical basis and experimental design, with significant input into interpretation of analyses and each draft of the paper. PRS and RHP were principal investigators and EG, partner investigator, in developing the project and design. EG was responsible for establishing the testing platforms used in this study. CBN and RB contributed significantly to the theoretical basis of this study, and to interpretation of analyses. CD-S and PRS performed the DNA genotyping. All authors have contributed to the final paper.

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Gatt, J., Nemeroff, C., Dobson-Stone, C. et al. Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety. Mol Psychiatry 14, 681–695 (2009). https://doi.org/10.1038/mp.2008.143

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