Assessing Causality Between Plasma Brain-Derived Neurotrophic Factor With Major Depression Disorder: A Bidirectional Mendelian Randomization Study.

Purpose: This study employed a two-sample Mendelian randomization (MR) approach to investigate the bidirectional relationship between brain-derived neurotrophic factor (BDNF) and major depressive disorder (MDD), addressing gaps left by prior observational studies.

Methods: We utilized Genome-Wide Association Study (GWAS) datasets, including MDD information from the Psychiatric Genomics Consortium (PGC) and the UK Biobank (N = 500,199), along with plasma BDNF measurements from the FinnGen Consortium (N = 619). In a subsequent phase, we analyzed MDD data from FinnGen (N = 448,069) with plasma BDNF data from three additional GWAS sources: UK Biobank (N = 33,924), deCODE (N = 35,353), and INTERVAL (N = 3301). Multiple MR methods were applied to ensure a robust analysis.

Results: The inverse variance weighted (IVW) method revealed no significant association between plasma BDNF levels and the risk of developing MDD (IVW odds ratio [OR] = 1.00, 95% confidence interval [CI] = 0.99-1.01, p = 0.769). Similarly, no causal effect of the BDNF gene on MDD was identified (OR = 0.91, CI = 0.23-3.56, p = 0.893). Furthermore, there was no evidence supporting a causal link between MDD and plasma BDNF levels (OR = 0.99, CI = 0.89-1.09, p = 0.783). The second phase of analysis confirmed the absence of bidirectional causal relationships.

Conclusion: This bidirectional MR analysis provides no evidence of a causal association between plasma BDNF levels and MDD. These findings prompt a re-evaluation of plasma BDNF as a biomarker for MDD and emphasize the need for further investigation into its functional role within the plasma as well as its levels and activity in the brain and cerebrospinal fluid.