title: The association of the BDNF Val66Met polymorphism and the hippocampal volumes in healthy humans: a joint meta-analysis of published and new data.
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.
authors.affiliation: 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.
authors.forename: F
authors.initials: F
authors.lastname: Harrisberger
authors.affiliation: University of Basel, Department of Psychology, Division of Cognitive Neuroscience, Birmannsgasse 8, 4055 Basel, Switzerland.
authors.forename: K
authors.initials: K
authors.lastname: Spalek
authors.affiliation: 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.
authors.forename: R
authors.initials: R
authors.lastname: Smieskova
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: Schmidt
authors.affiliation: 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.
authors.forename: D
authors.initials: D
authors.lastname: Coynel
authors.affiliation: University of Basel, Department of Psychology, Division of Molecular Neuroscience, Birmannsgasse 8, 4055 Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Milnik
authors.affiliation: University of Basel, Department of Psychology, Division of Cognitive Neuroscience, Birmannsgasse 8, 4055 Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Fastenrath
authors.affiliation: University of Basel, Department of Psychology, Division of Molecular Neuroscience, Birmannsgasse 8, 4055 Basel, Switzerland.
authors.forename: V
authors.initials: V
authors.lastname: Freytag
authors.affiliation: University of Basel, Department of Psychology, Division of Cognitive Neuroscience, Birmannsgasse 8, 4055 Basel, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Gschwind
authors.affiliation: University of Basel, Department of Psychiatry (UPK), Wilhelm Klein-Strasse 27, 4056 Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Walter
authors.affiliation: University of Basel, Department of Psychiatry (UPK), Wilhelm Klein-Strasse 27, 4056 Basel, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Vogel
authors.affiliation: University Hospital Basel, Medical Image Analysis Center, Schanzenstrasse 55, 4031 Basel, Switzerland.
authors.forename: K
authors.initials: K
authors.lastname: Bendfeldt
authors.affiliation: 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.
authors.forename: D J-F
authors.initials: DJ
authors.lastname: de Quervain
authors.affiliation: 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.
authors.forename: A
authors.initials: A
authors.lastname: Papassotiropoulos
authors.affiliation: 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: stefan.borgwardt@upkbs.ch.
authors.forename: S
authors.initials: S
authors.lastname: Borgwardt
mesh_terms: D000293:Adolescent; D000328:Adult; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D005260:Female; D006624:Hippocampus / Q000033:anatomy & histology*; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D008279:Magnetic Resonance Imaging; D008297:Male; D009929:Organ Size; D010363:Pattern Recognition, Automated; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C579455:BDNF protein, human
keywords: BDNF; BDNF Val66Met; Brain-derived neurotrophic factor; Hippocampus; MRI; Structural; rs6265; sMRI