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)-map...

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Published in:Biological psychiatry (1969) 2008-03, Vol.63 (6), p.619-628
Main Authors: Alonso, Pino, Gratacòs, Mónica, Menchón, José M, Saiz-Ruiz, Jerónimo, Segalàs, Cinto, Baca-García, Enrique, Labad, Javier, Fernández-Piqueras, José, Real, Eva, Vaquero, Concepción, Pérez, Mercedes, Dolengevich, Helen, González, Juan R, Bayés, Mónica, de Cid, Rafael, Vallejo, Julio, Estivill, Xavier
Format: Article
Language:English
Subjects:
Adolescent
Adult
Adult and adolescent clinical studies
Anxiety disorders. Neuroses
Association
BDNF
Biological and medical sciences
Brain-Derived Neurotrophic Factor - genetics
Case-Control Studies
Female
Genetic Predisposition to Disease - genetics
Genetic Predisposition to Disease - psychology
Genotype
haplotype
Haplotypes - genetics
Humans
Linkage Disequilibrium
Male
Medical sciences
Middle Aged
NTRK2
obsessive-compulsive disorder
Obsessive-Compulsive Disorder - diagnosis
Obsessive-Compulsive Disorder - genetics
Obsessive-Compulsive Disorder - psychology
Obsessive-compulsive disorders
Phenotype
Polymorphism, Single Nucleotide - genetics
Psychiatry
Psychology. Psychoanalysis. Psychiatry
Psychopathology. Psychiatry
Receptor, trkB - genetics
tagSNPs
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Summary: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.
ISSN:0006-3223
1873-2402
DOI:10.1016/j.biopsych.2007.06.020