Abstract
BackgroundGenetic variations in brain-derived neurotrophic factor (BDNF) are associated with various psychiatric disorders including depression, obsessive-compulsive disorder, substance use disorders, and schizophrenia; altered gene expression triggered by these genetic variants may serve to create these phenotypes. But genotype-expression interactions for this gene have not been well-studied across brain regions relevant for psychiatric disorders.ResultsAt false discovery rate (FDR) of 10% (q < 0.1), a total of 61 SNPs were associated with BDNF expression in cerebellum (n = 209), 55 SNPs in cortex (n = 205), 48 SNPs in nucleus accumbens (n = 202), 47 SNPs in caudate (n = 194), and 58 SNPs in cerebellar hemisphere (n = 175). We identified a set of 30 SNPs in 2 haplotype blocks that were associated with alterations in expression for each of these 5 regions. The first haplotype block included variants associated in the literature with panic disorders (rs16917204), addiction (rs11030104), bipolar disorder (rs16917237/rs2049045), and obsessive-compulsive disorder (rs6265). Likewise, variants in the second haplotype block have been previously associated with disorders such as nicotine addiction, major depressive disorder (rs988748), and epilepsy (rs6484320/rs7103411).ConclusionsThis work supports the association of variants within BDNF for expression changes in these key brain regions that may contribute to common behavioral phenotypes for disorders of compulsion, impulsivity, and addiction. These SNPs should be further investigated as possible therapeutic and diagnostic targets to aid in management of these and other psychiatric disorders.
Highlights
Genetic variations in brain-derived neurotrophic factor (BDNF) are associated with various psychiatric disorders including depression, obsessive-compulsive disorder, substance use disorders, and schizophrenia; altered gene expression triggered by these genetic variants may serve to create these phenotypes
Human subject and tissue sample data Expression levels from a total of 985 tissue samples from 300 unique subjects were matched to genetic sequencing data for BDNF for our 5 brain regions of interest (Table 1)
Association between BDNF expression by demographics Age, sex, and body mass index (BMI) were not associated with BDNF expression for any of our five brain regions of interest in this sample (p > 0.08; Table 3)
Summary
Genetic variations in brain-derived neurotrophic factor (BDNF) are associated with various psychiatric disorders including depression, obsessive-compulsive disorder, substance use disorders, and schizophrenia; altered gene expression triggered by these genetic variants may serve to create these phenotypes. In schizophrenia, prefrontal cortex BDNF protein levels were found to be significantly lower in patients versus healthy controls [11,12,13], while decreases in BDNF levels in the temporal cortex and occipital cortex, and increases in the parietal cortex and frontal cortex, were found in postmortem samples [14] Despite these findings, and other evidence that expression changes are associated with psychiatric behavioral profiles, it is still unclear how genotypic variation is associated with expression of BDNF across these relevant human brain regions. We will address this gap by using the Genotype-Tissue Expression (GTEx) database to determine the associations of variations in BDNF with expression across five brain regions relevant to neuropsychiatric conditions Understanding these differences will allow better comprehension of regional variations in expression and how genetic variation contributes to differential expression by brain region. This information is the first step toward future work in BDNF signal regulation and the development of related therapeutics
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