Extensive Genotyping of the BDNF and NTRK2 Genes Define Protective Haplotypes Against Obsessive-Compulsive Disorder

Pino Alonso, Mónica Gratacòs, José M. Menchón, Jerónimo Saiz-Ruiz, Cinto Segalàs, Enrique Baca-García, Javier Labad, José Fernández-Piqueras, Eva Real, Concepción Vaquero, Mercedes Pérez, Helen Dolengevich, Juan R. González, Mónica Bayés, Rafael de Cid, Julio Vallejo, Xavier P. Estivill

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Abstract

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.

Original languageEnglish
Pages (from-to)619-628
Number of pages10
JournalBiological Psychiatry
Volume63
Issue number6
DOIs
Publication statusPublished - 15 Mar 2008
Externally publishedYes

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trkB Receptor
Obsessive-Compulsive Disorder
Brain-Derived Neurotrophic Factor
Haplotypes
Genes
Single Nucleotide Polymorphism
Odds Ratio
Tic Disorders
Confidence Intervals
Twin Studies
Chromosome Mapping
Linkage Disequilibrium
Valine
Genetic Predisposition to Disease
Methionine
Introns

Keywords

  • Association
  • BDNF
  • haplotype
  • NTRK2
  • obsessive-compulsive disorder
  • tagSNPs

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Extensive Genotyping of the BDNF and NTRK2 Genes Define Protective Haplotypes Against Obsessive-Compulsive Disorder. / 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 P.

In: Biological Psychiatry, Vol. 63, No. 6, 15.03.2008, p. 619-628.

Research output: Contribution to journalArticle

Alonso, P, Gratacòs, M, Menchón, JM, Saiz-Ruiz, J, Segalàs, C, Baca-García, E, Labad, J, Fernández-Piqueras, J, Real, E, Vaquero, C, Pérez, M, Dolengevich, H, González, JR, Bayés, M, de Cid, R, Vallejo, J & Estivill, XP 2008, 'Extensive Genotyping of the BDNF and NTRK2 Genes Define Protective Haplotypes Against Obsessive-Compulsive Disorder', Biological Psychiatry, vol. 63, no. 6, pp. 619-628. https://doi.org/10.1016/j.biopsych.2007.06.020
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 P. / Extensive Genotyping of the BDNF and NTRK2 Genes Define Protective Haplotypes Against Obsessive-Compulsive Disorder. In: Biological Psychiatry. 2008 ; Vol. 63, No. 6. pp. 619-628.
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AU - Gratacòs, Mónica

AU - Menchón, José M.

AU - Saiz-Ruiz, Jerónimo

AU - Segalàs, Cinto

AU - Baca-García, Enrique

AU - Labad, Javier

AU - Fernández-Piqueras, José

AU - Real, Eva

AU - Vaquero, Concepción

AU - Pérez, Mercedes

AU - Dolengevich, Helen

AU - González, Juan R.

AU - Bayés, Mónica

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AU - Vallejo, Julio

AU - Estivill, Xavier P.

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N2 - 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.

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