Gene–Gene Interactions of the Brain-Derived Neurotrophic-Factor and Neurotrophic Tyrosine Kinase Receptor 2 Genes in Geriatric Depression

Abstract

Brain-derived neurotrophic-factor (BDNF) and its receptor neurotrophic tyrosine kinase receptor 2 (NTRK2) have been implicated in both major depression and cognitive function. This study examines the main effects of single loci and multilocus interactions to test the hypothesis that the BDNF and NTRK2 genes may contribute to the etiology of geriatric depression independently and/or through complex interactions. We genotyped the BDNF gene Val66Met (rs6265) polymorphism and four single-nucleotide polymorphisms (SNPs) (including rs1187323, rs1187329, rs1778929, and rs1545285) in the NTRK2 gene in 155 elderly inpatients diagnosed with major depression and 195 age- and sex-similar control subjects. All patients were assessed with the Hamilton Rating Scale for Depression (HAM-D) for depression severity and the Mini-Mental Status Examination (MMSE) for cognitive function after admission. The genotype distributions of all five SNPs tested were significantly different between depressed patients and control subjects. BDNF rs6265, NTRK2 rs1187323, and NTRK2 rs1778929 (p = 0.0031, 0.002, and 0.0014, respectively) also displayed statistically significant differences in the genotypic tests after Bonferroni correction (p < 0.05/5 = 0.01). In addition, the 2-marker haplotype derived from the rs1187323 and rs1187329 polymorphisms demonstrated a significant difference between geriatric depression and control groups according to haplotype distribution (global p = 0.003). Furthermore, BDNF and NTRK2 interactions were found in the significant 2-locus, 3-locus, 4-locus, and 5-locus gene-gene interaction models (p = 0.014, <0.001, 0.007, and 0.032, respectively) using a generalized multifactor dimensionality reduction (GMDR) method. Analyses using logistic regression models confirmed the gene-gene interactions. The results suggest that the BDNF and NTRK2 genes may contribute to the risk of geriatric depression independently and in an interactive manner.