Relatively little is known about genetic determinants of cognitive dysfunction in schizophrenia. Recent studies suggest that a BDNF prodomain SNP, resulting in valine to methionine substitution, is associated with impaired declarative memory in healthy volunteers and in schizophrenia patients. These studies indicate that BDNFMet variant may mediate hippocampal cognitive functions by modulating intracellular trafficking and activity-dependent BDNF release. How this functional SNP affects other neurocognitive measures have not been examined. Its role in determining cognitive deficits in schizophrenia has not been systematically studied either.
To characterize the neurocognitive and brain morphometric phenotypic correlates of BDNF val66met polymorphism, and test the specificity of BDNFMet variant on cognitive dysfunction in schizophrenia.
Design, Setting and Participants
A comprehensive battery of standardized neuropsychological tests was administered to 144 healthy volunteers and 293 schizophrenia-spectrum disorder patients at a tertiary-care university hospital. Approximately two-thirds of the sample also underwent high-resolution MRI brain scans.
Main Outcome Measures
Genotype effects (Met-allele-carriers versus Val homozygotes) on five cognitive domain z-scores and MRI gray matter (GM) brain volume measures (Talairach-atlas based cerebral lobes and optimized voxel-based morphometry (VBM)) were examined using general linear models.
On verbal memory, there was a significant genotype effect but no genotype-by-diagnosis effects. In both patients and healthy volunteers, Met-allele-carriers had poorer verbal memory performance than their Val/Val counterparts. On visuospatial abilities, there were significant genotype and genotype-by-diagnosis effects. Met allele-associated visuospatial impairment was specific to patients, but not healthy volunteers. There were significant genotype effects on GM volumes within brain regions known to subserve these two cognitive domains, with Met-allele-carriers having smaller temporal and occipital lobar GM. Optimized VBM further suggests that parietal heteromodal cortical GM deficits may underlie visuospatial impairment in Met-allele-carrier patients.
We replicated the association between BDNFMet variant and poor medial temporal lobe-related memory performance. The consonance of our cognitive and brain morphology findings further suggests that BDNFMet variant may have a specific role in conferring visuospatial dysfunction in schizophrenia.