A systematic review and meta‐analysis on the association between BDNF val⁶⁶met and hippocampal volume—A genuine effect or a winners curse?

Abstract

Inconsistenties have been reported with regard to an association between val(66)met, a polymorphism on the BDNF gene, and hippocampal volume. We performed a systematic review and a meta-analysis to determine the magnitude and direction of this putative association and estimated the potential influence of demographic, clinical, and methodological characteristics of studies. Tests of publication bias and time-related trends were performed and statistical power of the included studies was calculated. The literature search for MRI studies on differences in total hippocampal volume as a function of BDNF val(66)met returned 25 records that fulfilled our criteria (total N = 3,620). Meta-analysis showed that carriers of a met allele had lower hippocampal volumes relative to val/val homozygotes (d = 0.13, P = 0.02). Between-study heterogeneity in effect size estimates was substantial (Q = 54.47, P < .001) and this could not be explained by demographic, clinical, and methodological differences across studies. Funnel plot inspection and trim-and-fill estimations suggested evidence for publication bias and effect sizes decreased substantially over the years (Pearson's r = -0.54, P < .01). All included studies were underpowered. This meta-analysis shows that carriers of a met allele have lower total hippocampal volumes relative to val/val homozygotes. However, effect sizes converged closer to null with virtually each attempt at replication and were based on underpowered studies. Altogether, this may call into question whether the observed effect is a genuine biological effect of the met allele or whether it is subject to a winners curse, with large effect sizes found in a few early studies and increasingly smaller effect sizes in later studies.

BDNF gene polymorphisms and haplotypes in relation to cognitive performance in Polish healthy subjects

“…In volumetric studies Met-carriers were found to have a hippocampal volume reduction in both healthy cohorts and psychiatric patients with schizophrenia, bipolar disorder, major depression and anxiety disorders (Pezewas et al 2004, Szeszko et al 2005, Bueller et al 2006, Frodl et al 2007, Chepenik et al 2009, Mueller et al 2013). These observations were confirmed in three meta-analytic reviews (Hajek et al 2012, Kambeitz et al 2012, Molendijk et al 2012. However, the most recent meta-analyses showed no association between Val66Met polymorphism and hippocampal volumes neither in healthy subjects nor clinical groups (Harrisberger et al 2014(Harrisberger et al , 2015.…”

The BDNF gene Val66Met polymorphism as a modifier of psychiatric disorder susceptibility: progress and controversy

“…43 Consistent with these individual reports, two meta-analyses (n = 399 and 3620, respectively) have confirmed that 66Met allele carriers have smaller bilateral hippocampi relative to 66Val homozygote controls. 44,45 However, these meta-analyses noted that the effect size of the 66Met allele on reduced hippocampal volume is relatively small 44 and that most studies suffer from underpowered samples. 45 This small effect size, when coupled with heterogeneous sampling and nuisance variability between studies, may explain why some studies have failed to report an effect of the Val66Met polymorphism on hippocampal structure and function.…”

DISC1 gene and affective psychopathology: A combined structural and functional MRI study

“…This could be related to other factors influencing brain physiology, including SSRI use, other genes (e.g. brain-derived neurotrophic factor [BDNF] (Molendijk et al, 2012), depressive state (Van Tol et al, 2011), or epigenetic influences ). However, previous studies by our group have shown no effects of SSRI use in this sample on brain morphology or activation during visuospatial or memory processing (Van Tol et al, 2012;Van Tol et al, 2011;Van Tol et al, 2010).…”