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 RibasésValdo Ricca, Lucia Romo, Sandro Sorbi, Audrey Versini, Mònica Gratacòs, Xavier Estivill

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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

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ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Mercader, J. M., 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, J. R., Gorwood, P., Hebebrand, J., Hinney, A., Nacmias, B., Puig, A., ... Estivill, X. (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, 17(9), 1234-1244. https://doi.org/10.1093/hmg/ddn013