The association of the BDNF Val66Met polymorphism and the hippocampal volumes in healthy humans: a joint meta-analysis of published and new data

F Harrisberger; K Spalek; R Smieskova; A Schmidt; D Coynel; A Milnik; M Fastenrath; V Freytag; L Gschwind; A Walter; T Vogel; K Bendfeldt; D J-F de Quervain; A Papassotiropoulos; S Borgwardt

doi:10.1016/j.neubiorev.2014.03.011

The association of the BDNF Val66Met polymorphism and the hippocampal volumes in healthy humans: a joint meta-analysis of published and new data

Neurosci Biobehav Rev. 2014 May:42:267-78. doi: 10.1016/j.neubiorev.2014.03.011. Epub 2014 Mar 24.

Authors

F Harrisberger¹, K Spalek², R Smieskova¹, A Schmidt¹, D Coynel³, A Milnik⁴, M Fastenrath², V Freytag⁴, L Gschwind², A Walter⁵, T Vogel⁵, K Bendfeldt⁶, D J-F de Quervain⁷, A Papassotiropoulos⁸, S Borgwardt⁹

Affiliations

¹ University of Basel, Department of Psychiatry (UPK), Wilhelm Klein-Strasse 27, 4056 Basel, Switzerland; University Hospital Basel, Medical Image Analysis Center, Schanzenstrasse 55, 4031 Basel, Switzerland.
² University of Basel, Department of Psychology, Division of Cognitive Neuroscience, Birmannsgasse 8, 4055 Basel, Switzerland.
³ University of Basel, Department of Psychology, Division of Cognitive Neuroscience, Birmannsgasse 8, 4055 Basel, Switzerland; University of Basel, Department of Psychology, Division of Molecular Neuroscience, Birmannsgasse 8, 4055 Basel, Switzerland.
⁴ University of Basel, Department of Psychology, Division of Molecular Neuroscience, Birmannsgasse 8, 4055 Basel, Switzerland.
⁵ University of Basel, Department of Psychiatry (UPK), Wilhelm Klein-Strasse 27, 4056 Basel, Switzerland.
⁶ University Hospital Basel, Medical Image Analysis Center, Schanzenstrasse 55, 4031 Basel, Switzerland.
⁷ University of Basel, Department of Psychiatry (UPK), Wilhelm Klein-Strasse 27, 4056 Basel, Switzerland; University of Basel, Department of Psychology, Division of Cognitive Neuroscience, Birmannsgasse 8, 4055 Basel, Switzerland.
⁸ University of Basel, Department of Psychiatry (UPK), Wilhelm Klein-Strasse 27, 4056 Basel, Switzerland; University of Basel, Department of Psychology, Division of Molecular Neuroscience, Birmannsgasse 8, 4055 Basel, Switzerland; University of Basel, Department Biozentrum, Life Science Training Facility, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.
⁹ University of Basel, Department of Psychiatry (UPK), Wilhelm Klein-Strasse 27, 4056 Basel, Switzerland; University Hospital Basel, Medical Image Analysis Center, Schanzenstrasse 55, 4031 Basel, Switzerland; King's College London, Department of Psychosis Studies, Institute of Psychiatry, De Crespigny Park 16, SE5 8AF London, UK. Electronic address: [email protected].

PMID: 24674929
DOI: 10.1016/j.neubiorev.2014.03.011

Abstract

Background: The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (refSNP Cluster Report: rs6265) is a common and functionally relevant single nucleotide polymorphism (SNP). The gene itself, as well as the SNP rs6265, have been implicated in hippocampal learning and memory. However, imaging genetic studies have produced controversial results about the impact of this SNP on hippocampal volumes in healthy subjects.

Methods: We examined the association between the rs6265 polymorphism and hippocampal volume in 643 healthy young subjects using automatic segmentation and subsequently included these data in a meta-analysis based on published studies with 5298 healthy subjects in total.

Results: We found no significant association between SNP rs6265 and hippocampal volumes in our sample (g=0.05, p=0.58). The meta-analysis revealed a small, albeit significant difference in hippocampal volumes between genotype groups, such that Met-carriers had slightly smaller hippocampal volumes than Val/Val homozygotes (g=0.09, p=0.04), an association that was only evident when manual (g=0.22, p=0.01) but not automatic tracing approaches (g=0.04, p=0.38) were used. Studies using manual tracing showed evidence for publication bias and a significant decrease in effect size over the years with increasing sample sizes.

Conclusions: This study does not support the association between SNP rs6265 and hippocampal volume in healthy individuals. The weakly significant effect observed in the meta-analysis is mainly driven by studies with small sample sizes. In contrast, our original data and the meta-analysis of automatically segmented hippocampal volumes, which was based on studies with large samples sizes, revealed no significant genotype effect. Thus, meta-analyses of the association between rs6265 and hippocampal volumes should consider possible biases related to measuring technique and sample size.

Keywords: BDNF; BDNF Val66Met; Brain-derived neurotrophic factor; Hippocampus; MRI; Structural; rs6265; sMRI.

Publication types

Meta-Analysis
Review

MeSH terms

Adolescent
Adult
Brain-Derived Neurotrophic Factor / genetics*
Female
Hippocampus / anatomy & histology*
Humans
Image Processing, Computer-Assisted / methods
Magnetic Resonance Imaging
Male
Organ Size
Pattern Recognition, Automated
Polymorphism, Single Nucleotide*
Young Adult

Substances

Brain-Derived Neurotrophic Factor
BDNF protein, human