Brain-derived neurotrophic factor Val66met polymorphism and volume of the hippocampal formation

Abstract

Magnetic resonance (MR) imaging studies have identified hippocampal structural alterations in the pathogenesis of schizophrenia. Brain-derived neurotrophic factor (BDNF) is one of the neurotrophins that is widely expressed in the hippocampal formation and has been implicated in the neurobiology of schizophrenia. Polymorphisms in the BDNF gene may therefore confer risk for schizophrenia through hippocampal pathogenesis and/or making the hippocampus more susceptible to environmental insults. In this study, we investigated whether val66met, a functional and abundant missense polymorphism in the coding region of the BDNF gene, was associated with the volume of the hippocampal formation in 19 patients with first-episode schizophrenia and 25 healthy volunteers. A total of 124 contiguous T1-weighted coronal MR images (slice thickness ¼ 1.5 mm) were acquired through the whole head using a 3D Fast SPGR IR Prep sequence on a 1.5 T GE imaging system. Volumes of the right and left hippocampal formation were measured manually by an operator blind to group status and genotype. All participants were genotyped for the BDNF val66met locus. Mixed model analyses revealed a main effect of BDNF val66met genotype such that in the combined sample of patients and healthy volunteers, val/val homozygotes (N ¼ 27) had larger volumes of the hippocampal formation compared to val/met heterozygotes (N ¼ 17). In separate analyses by group, however, val66met genotype accounted for a greater proportion of the variance in the volume of the hippocampal formation in patients compared to healthy volunteers. These findings implicate genetic involvement of BDNF in variation of human hippocampal volume and suggest that this effect may be greater among patients compared to healthy volunteers. Molecular Psychiatry (2005) 10, 631-636.

A CYP46 T/C SNP modulates parahippocampal and hippocampal morphology in young subjects

“…This is in contrast with the literature where the BDNF val66met-allele Hariri et al, 2003;Pezawas et al, 2004;Szeszko et al, 2005;Bueller et al, 2006) Memory performance in the CYP46 genotypes is listed in Table 1. We correlated memory performance with the parahippocampal and hippocampal GM volumes derived from the VOIs (Table 3).…”

“…The MRI T1-weighted intensity profiles, on which morphometric MRI studies are based, have been shown to be best explained by a weighted sum of cytoarchitectonic and myeloarchitectonic profiles (Eickhoff et al, 2005), suggesting that the volumetric differences originate in differences in neuronal and synaptic compartments, which are very important for brain functions, rather than differences in the stroma (including interstitial fluid) or edema. Although several morphometric imaging studies found support for an association of the BDNF val66met SNP (rs6265) with volumetric differences in MTL structures and memory performance Hariri et al, 2003;Pezawas et al, 2004;Szeszko et al, 2005;Bueller et al, 2006), we were unable to replicate the finding of smaller hippocampal volumes in BDNF val66met carriers compared with val66val carriers within our dataset. Possible explanations include the diversity of methodological approaches applied to measure the volume of interest, the restricted age range of our subjects, the high level of education of our academic sample, the fact that we controlled for genetic variation in additional SNPs as well as background genetic heterogeneity, and/or the different numbers of BDNF met66met carriers…”

“…Although the allelic frequency of the BDNF SNP was not statistically different between the three CYP46 genotypes it was included in our statistical models as a covariate because of its relevance on medial temporal lobe morphometry as well as memory functions Hariri et al, 2003;Pezawas et al, 2004;Szeszko et al, 2005;Bueller et al, 2006). VBM results were thresholded with an error probability of p < 0.001 (uncorrected for multiple comparisons) combined with a cluster extent threshold of k = 50 voxels (uncorrected).…”

“…Gender and TGMV are collinear variables (Spearman correlation: r = -0.657, p = 2.82*10 -11 , male coded as 1, female coded as 2), i.e., TGMV explains most of the gender-related variance in brain morphology; hence, gender was not included in our statistical models to preserve statistical power. Education, handedness, and age showed no significant influence on morphology (tested were not significantly different between the CYP46 genotypes and were not considered further.Although the allelic frequency of the BDNF SNP was not statistically different between the three CYP46 genotypes it was included in our statistical models as a covariate because of its relevance on medial temporal lobe morphometry as well as memory functions Hariri et al, 2003;Pezawas et al, 2004;Szeszko et al, 2005;Bueller et al, 2006). VBM results were thresholded with an error probability of p < 0.001 (uncorrected for multiple comparisons) combined with a cluster extent threshold of k = 50 voxels (uncorrected).…”

Cortical mapping of genotype–phenotype relationships in schizophrenia

“…Although here we did not examine specific candidate genes that may contribute to the observed hippocampal alterations, brain-derived neurotrophic factor (BDNF) is widely expressed in the hippocampus and has been implicated in the neurobiology of schizophrenia. Szeszko et al [2005] found differences in hippocampal volume as a function of BDNF (val66met) genotype in a combined sample of schizophrenia patients and controls and, secondly, that genotype explained more variance in hippocampal volume for schizophrenia patients relative to healthy volunteers. This suggests that the BDNF gene may contribute to variation in human hippocampal volume, and that this effect may be amplified in patients with schizophrenia.…”