Extensive genotyping of the BDNF and NTRK2 genes define protective haplotypes against obsessive-compulsive disorder.

BACKGROUND

Family, twin and molecular studies provide increasing evidence for the importance of genetic factors in obsessive-compulsive disorder (OCD). Recent work suggests that brain-derived neurotrophic factor (BDNF) may be involved in OCD pathophysiology. We used a linkage disequilibrium (LD)-mapping approach to investigate the role that BDNF and its specific receptor neurotrophic tyrosine kinase receptor type 2 (NTRK2) may play in increasing susceptibility to OCD.

METHODS

Eight tag single nucleotide polymorphisms (tagSNPs) covering the BDNF gene region and 46 tagSNPs in the NTRK2 region were genotyped in 215 OCD patients and 342 control subjects. Single nucleotide polymorphism association and haplotype analysis were performed. The possible relationship between genetic factors and clinical characteristics including age of OCD onset, tic disorders, clinical dimensions, and family history of OCD were investigated.

RESULTS

Haplotype analysis revealed a significant association between OCD and a five-marker protective haplotype located toward the 5' of the BDNF gene (odds ratio [OR] = .80; 95% confidence interval [CI] = .69-.92; permutation p value = .006) containing the functional valine (Val)66-to-methionine (Met) variant. A significant association between a NTRK2 intronic SNP (rs2378672) and OCD was identified (p < .0001) in female patients under an additive model. A protective haplotype located in intron 19 of NTRK2 was also associated with OCD (OR = .76; 95% CI = .66-.87; permutation p value = .001).

CONCLUSIONS

These findings support a role for the BDNF/NTRK2 signaling pathway in genetic susceptibility to OCD.