The CREB1-BDNF-NTRK2 pathway in depression: multiple gene-cognition-environment interactions

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• The neuroplastic pathway, including cyclic adenosine monophosphate response element-binding protein 1 (CREB1), brain-derived neurotrophic factor (BDNF), and its receptor neurotrophic tyrosine kinase receptor, type 2 (NTRK2), is vital for brain adaptation to stress.
• Variations in these genes are potential risk factors for depression.

Purpose of the Study:

• To investigate the association of nine polymorphisms in the CREB1-BDNF-NTRK2 pathway with depression and related cognitive and neural phenotypes.
• To explore gene-environment interactions, specifically the impact of childhood adversity on depression risk.

Main Methods:

• A population-based study involving interviews and functional magnetic resonance imaging (fMRI).
• Analysis of nine single nucleotide polymorphisms (SNPs) across the CREB1-BDNF-NTRK2 pathway.
• Structural equation modeling and fMRI were used to examine associations with lifetime depression, rumination, current depression severity, negative life events, and emotion processing.

Main Results:

• Major alleles of BDNF-rs6265 and CREB1-rs2253206 were associated with rumination and, consequently, current depression severity.
• Childhood adversity exacerbated depression risk in carriers of minor alleles for BDNF-rs6265 and CREB1-rs2253206, and other SNPs.
• fMRI revealed heightened activity in depression-related brain areas when viewing sad faces in healthy individuals with minor alleles of BDNF-rs6265 and CREB1-rs2253206.

Conclusions:

• Genetic variations in the CREB1-BDNF-NTRK2 pathway have complex effects on depression risk mechanisms.
• These genetic variations often amplify the impact of childhood adversity on depression.
• Integrating cognitive and neural intermediate phenotypes with a molecular pathway approach is crucial for understanding gene-environment interactions in depression.