Association of NTRK3 and its interaction with NGF suggest an altered cross-regulation of the neurotrophin signaling pathway in eating disorders

Josep Maria Mercader, Ester Saus, Zaida Agüera, Mònica Bayés, Claudette Boni, Anna Carreras, Elena Cellini, Rafael de Cid, Mara Dierssen, Geòrgia Escaramís, Fernando Fernández-Aranda, Laura Forcano, Xavier Gallego, Juan Ramón González, Philip Gorwood, Johannes Hebebrand, Anke Hinney, Benedetta Nacmias, Anna Puig, Marta Ribasés & 6 others Valdo Ricca, Lucia Romo, Sandro Sorbi, Audrey Versini, Mònica Gratacòs, Xavier P. Estivill

Research output: Contribution to journalArticle

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Abstract

Eating disorders (EDs) are complex psychiatric diseases that include anorexia nervosa and bulimia nervosa, and have higher than 50% heritability. Previous studies have found association of BDNF and NTRK2 to ED, while animal models suggest that other neurotrophin genes might also be involved in eating behavior. We have performed a family-based association study with 151 TagSNPs covering 10 neurotrophin signaling genes: NGFB, BDNF, NTRK1, NGFR/p75, NTF4/5, NTRK2, NTF3, NTRK3, CNTF and CNTFR in 371 ED trios of Spanish, French and German origin. Besides several nominal associations, we found a strong significant association after correcting for multiple testing (P = 1.04 × 10-4) between ED and rs7180942, located in the NTRK3 gene, which followed an overdominant model of inheritance. Interestingly, HapMap unrelated individuals carrying the rs7180942 risk genotypes for ED showed higher levels of expression of NTRK3 in lymphoblastoid cell lines. Furthermore, higher expression of the orthologous murine Ntrk3 gene was also detected in the hypothalamus of the anx/anx mouse model of anorexia. Finally, variants in NGFB gene appear to modify the risk conferred by the NTRK3 rs7180942 risk genotypes (P = 4.0 × 10-5) showing a synergistic epistatic interaction. The reported data, in addition to the previous reported findings for BDNF and NTRK2, point neurotrophin signaling genes as key regulators of eating behavior and their altered cross-regulation as susceptibility factors for EDs.

Original languageEnglish
Pages (from-to)1234-1244
Number of pages11
JournalHuman Molecular Genetics
Volume17
Issue number9
DOIs
Publication statusPublished - 1 May 2008
Externally publishedYes

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Nerve Growth Factors
Nerve Growth Factor
Brain-Derived Neurotrophic Factor
Genes
Feeding Behavior
Genotype
HapMap Project
Ciliary Neurotrophic Factor
Bulimia Nervosa
Anorexia Nervosa
Anorexia
Hypothalamus
Psychiatry
Feeding and Eating Disorders
Animal Models
Cell Line

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Association of NTRK3 and its interaction with NGF suggest an altered cross-regulation of the neurotrophin signaling pathway in eating disorders. / Mercader, Josep Maria; Saus, Ester; Agüera, Zaida; Bayés, Mònica; Boni, Claudette; Carreras, Anna; Cellini, Elena; de Cid, Rafael; Dierssen, Mara; Escaramís, Geòrgia; Fernández-Aranda, Fernando; Forcano, Laura; Gallego, Xavier; González, Juan Ramón; Gorwood, Philip; Hebebrand, Johannes; Hinney, Anke; Nacmias, Benedetta; Puig, Anna; Ribasés, Marta; Ricca, Valdo; Romo, Lucia; Sorbi, Sandro; Versini, Audrey; Gratacòs, Mònica; Estivill, Xavier P.

In: Human Molecular Genetics, Vol. 17, No. 9, 01.05.2008, p. 1234-1244.

Research output: Contribution to journalArticle

Mercader, JM, Saus, E, Agüera, Z, Bayés, M, Boni, C, Carreras, A, Cellini, E, de Cid, R, Dierssen, M, Escaramís, G, Fernández-Aranda, F, Forcano, L, Gallego, X, González, JR, Gorwood, P, Hebebrand, J, Hinney, A, Nacmias, B, Puig, A, Ribasés, M, Ricca, V, Romo, L, Sorbi, S, Versini, A, Gratacòs, M & Estivill, XP 2008, 'Association of NTRK3 and its interaction with NGF suggest an altered cross-regulation of the neurotrophin signaling pathway in eating disorders', Human Molecular Genetics, vol. 17, no. 9, pp. 1234-1244. https://doi.org/10.1093/hmg/ddn013
Mercader, Josep Maria ; Saus, Ester ; Agüera, Zaida ; Bayés, Mònica ; Boni, Claudette ; Carreras, Anna ; Cellini, Elena ; de Cid, Rafael ; Dierssen, Mara ; Escaramís, Geòrgia ; Fernández-Aranda, Fernando ; Forcano, Laura ; Gallego, Xavier ; González, Juan Ramón ; Gorwood, Philip ; Hebebrand, Johannes ; Hinney, Anke ; Nacmias, Benedetta ; Puig, Anna ; Ribasés, Marta ; Ricca, Valdo ; Romo, Lucia ; Sorbi, Sandro ; Versini, Audrey ; Gratacòs, Mònica ; Estivill, Xavier P. / Association of NTRK3 and its interaction with NGF suggest an altered cross-regulation of the neurotrophin signaling pathway in eating disorders. In: Human Molecular Genetics. 2008 ; Vol. 17, No. 9. pp. 1234-1244.
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T1 - Association of NTRK3 and its interaction with NGF suggest an altered cross-regulation of the neurotrophin signaling pathway in eating disorders

AU - Mercader, Josep Maria

AU - Saus, Ester

AU - Agüera, Zaida

AU - Bayés, Mònica

AU - Boni, Claudette

AU - Carreras, Anna

AU - Cellini, Elena

AU - de Cid, Rafael

AU - Dierssen, Mara

AU - Escaramís, Geòrgia

AU - Fernández-Aranda, Fernando

AU - Forcano, Laura

AU - Gallego, Xavier

AU - González, Juan Ramón

AU - Gorwood, Philip

AU - Hebebrand, Johannes

AU - Hinney, Anke

AU - Nacmias, Benedetta

AU - Puig, Anna

AU - Ribasés, Marta

AU - Ricca, Valdo

AU - Romo, Lucia

AU - Sorbi, Sandro

AU - Versini, Audrey

AU - Gratacòs, Mònica

AU - Estivill, Xavier P.

PY - 2008/5/1

Y1 - 2008/5/1

N2 - Eating disorders (EDs) are complex psychiatric diseases that include anorexia nervosa and bulimia nervosa, and have higher than 50% heritability. Previous studies have found association of BDNF and NTRK2 to ED, while animal models suggest that other neurotrophin genes might also be involved in eating behavior. We have performed a family-based association study with 151 TagSNPs covering 10 neurotrophin signaling genes: NGFB, BDNF, NTRK1, NGFR/p75, NTF4/5, NTRK2, NTF3, NTRK3, CNTF and CNTFR in 371 ED trios of Spanish, French and German origin. Besides several nominal associations, we found a strong significant association after correcting for multiple testing (P = 1.04 × 10-4) between ED and rs7180942, located in the NTRK3 gene, which followed an overdominant model of inheritance. Interestingly, HapMap unrelated individuals carrying the rs7180942 risk genotypes for ED showed higher levels of expression of NTRK3 in lymphoblastoid cell lines. Furthermore, higher expression of the orthologous murine Ntrk3 gene was also detected in the hypothalamus of the anx/anx mouse model of anorexia. Finally, variants in NGFB gene appear to modify the risk conferred by the NTRK3 rs7180942 risk genotypes (P = 4.0 × 10-5) showing a synergistic epistatic interaction. The reported data, in addition to the previous reported findings for BDNF and NTRK2, point neurotrophin signaling genes as key regulators of eating behavior and their altered cross-regulation as susceptibility factors for EDs.

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