Family-based association study between brain-derived neurotrophic factor gene and major depressive disorder of Chinese descent

Abstract

The genetic pathogenesis of major depressive disorder (MDD) has not been elucidated. It has been proposed that brain-derived neurotrophic factor (BDNF), as a member of the neurotrophin family, may be involved in the etiology and antidepressant response of MDD. The present study investigated the possible presence of an association between the BDNF gene and MDD. Single-marker transmission disequilibrium test (TDT), pairwise-SNP linkage disequilibrium (LD) and haplotype-based TDT analyses were performed on single nucleotide polymorphisms (SNPs) rs6265, rs10835210 and rs2030324 in 105 Chinese trios. No significant associations with MDD were demonstrated for three SNPs. Pairwise LD analysis revealed substantial LD among three SNPs. Multiple-marker TDT analysis indicated that there was no association between the haplotypes from rs6265–rs10835210–rs2030324 and MDD. The statistical power of the present study was calculated so we had an idea what kind of effects could be identified. We conclude that SNPs rs6265, rs10835210 and rs2030324 of the BDNF gene are unlikely to play a critical role in the pathogenesis of MDD.

Introduction

Recently, accumulating evidence has indicated that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of major depressive disorder (MDD) as well as the mechanism of antidepressants. BDNF, an important member of the neurotrophin family, is widely expressed in hippocampus, cortex, striatum corpora, basal forebrain, thalamus, and peripheral nervous system of the adult mammalian brain. It is known that BDNF is responsible for neuron proliferation, survival, differentiation and synaptic connectivity (Hashimoto et al., 2004). The infusion of BDNF into the midbrain and dentate gyrus of the hippocampus had an antidepressant-like effect on learned helplessness and forced swim animal models of depression (Siuciak et al., 1997, Shirayama et al., 2002).

Chronic administration of antidepressants has been reported to increase BDNF gene expression in CA3 and dentate gyrus of the rat, and to change the BDNF immunoreactivity in rat hippocampus in a dose-dependent manner (Nibuya et al., 1995, Xu et al., 2003). Several human studies have also provided evidence suggestive of the roles played by BDNF. In a human postmortem study, Chen et al. (2001) found increased BDNF immunoreactivity in dentate gyrus, hilus and supragranular regions of subjects treated with antidepressants at the time of death, compared with antidepressant-naïve subjects. Serum BDNF levels were significantly lower in the antidepressant-naïve subjects than in the treated or in the control subjects, and were negatively correlated to severity of symptoms. Moreover, antidepressants administration was found to normalize serum BDNF levels (Karege et al., 2002, Shimizu et al., 2003, Gervasoni et al., 2005). Therefore, we propose that the BDNF gene may be a candidate gene that confers susceptibility to MDD.

The human BDNF gene is located on chromosome 11p13 (Maisonpierre et al., 1991). To date, several case–control association studies between this gene and MDD have been reported. Unfortunately, the results obtained have been inconsistent (Hong et al., 2003, Tsai et al., 2003, Schumacher et al., 2005, Hwang et al., 2006). In the present study, we performed the transmission disequilibrium test (TDT), pairwise-SNP linkage disequilibrium (LD) and haplotype-based TDT analyses on three single nucleotide polymorphisms (SNPs) of BDNF gene in 105 Chinese trios in an exploration of the role of the BDNF gene in the etiology of MDD.