Novel sequence variations in the brain-derived neurotrophic factor gene and association with major depression and antidepressant treatment response

Abstract

Context: Variations in the brain-derived neurotrophic factor gene (BDNF) have been associated with psychiatric disorders. Deep sequencing of the BDNF gene may identify new variations and bring further insight into psychiatric genetics.

Objective: To better characterize sequence variability in the BDNF gene by resequencing a genomic DNA region of 22 kilobases that contained all BDNF exons and their flanking regions.

Design: Case-control study.

Setting: University of California, Los Angeles, and University of Miami.

Participants: Two hundred sixty-four controls and 272 Mexican Americans with major depressive disorder (MDD) from Los Angeles who were assessed by the same bilingual clinical research team.

Main outcome measures: Identification of novel genetic polymorphisms in the BDNF gene and assessment of their frequencies and associations with MDD or antidepressant response.

Results: We identified 83 novel single-nucleotide polymorphisms (SNPs): 30 in untranslated regions, 4 in coding sequences, 37 in introns, and 12 in upstream regions; 3 of 4 rare novel coding SNPs were nonsynonymous. Association analyses of patients with MDD and controls showed that 6 SNPs were associated with MDD (rs12273539, rs11030103, rs6265, rs28722151, rs41282918, and rs11030101) and 2 haplotypes in different blocks (one including Val66, another near exon VIIIh) were significantly associated with MDD. One recently reported 5' untranslated region SNP, rs61888800, was associated with antidepressant response after adjusting for age, sex, medication, and baseline score on the 21-item Hamilton Depression Rating Scale.

Conclusions: Our data support the concept that extensive resequencing of key candidate genes can lead to the discovery of substantial numbers of new variants. Further studies using larger independent samples are needed to confirm the association of the rs61888800 SNP with antidepressant response.

Trial registration: clinicaltrials.gov Identifier: NCT00265291.

Figures

Figure 1. Linkage disequilibrium (LD) pattern in BDNF

Standard color scheme in Haploview program is used to display the level of logarithm of odds (LOD) and the D′ (right inserted key). Estimated statistics of the D′ are shown in each box. They indicate the LD relationship between each pair of SNPs and they are not labeled if D′=1.00. The BDNF gene structure is illustrated by a long horizontal white bar with vertical lines indicating the relative positions of SNPs and black box representing alternative exons named by Pruunsild et al. SNPs associated with depression are marked in orange (UTR), red (coding) and blue (intronic) circles. Left inset shows haplotype frequencies in cases and controls and the p values for the association analysis between haplotype and diagnosis of depression in blocks 3 and 4.