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Human Molecular Genetics Advance Access first published online on January 18, 2008
This version published online on February 5, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn013
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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

Josep Maria Mercader1,2, Ester Saus1,2, Zaida Agüera3, Mònica Bayés1,2,4, Claudette Boni5, Anna Carreras1,2,4, Elena Cellini6, Rafael de Cid1,2,4, Mara Dierssen1,7, Geòrgia Escaramís2,1, Fernando Fernández-Aranda8,3, Laura Forcano3, Xavier Gallego1, Juan Ramón Gonzàlez9,4, Philip Gorwood5, Johannes Hebebrand10, Anke Hinney10, Benedetta Nacmias6, Anna Puig1,2,4, Marta Ribasés11, Valdo Ricca6, Lucia Romo12, Sandro Sorbi6, Audrey Versini13, Mònica Gratacòs2,1,4,* and Xavier Estivill1,2,4,14,*

1 Genes and Disease Program, Center for Genomic Regulation (CRG), 08003 Barcelona, Catalonia, Spain 2 CIBER en Epidemiología y Salud Pública (CIBERESP), 08003 Barcelona, Catalonia, Spain 3 CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), 08003 Barcelona, Catalonia, Spain 4 National Center of Genotyping (CEGEN), Barcelona Node, 08003 Barcelona, Catalonia, Spain 5 Hospital Louis Mourier, Pr Ades Department, 75014 Paris, France 6 Department of Neurological and Psychiatric Sciences, University of Florence, 50121 Florence, Italy. 7 CIBER Enfermedades Raras (CIBERER), 08003 Barcelona, Catalonia, Spain 8 Department of Psychiatry, University Hospital of Bellvitge, L'Hospitalet de Llobregat, 08907 Barcelona, Catalonia, Spain 9 Center for Research in Environmental Epidemiology (CREAL), 08003 Barcelona, Catalonia, Spain 10 Rheinische Kliniken Essen, Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, 45147 Essen, Germany 11 Department of Psychiatry, Hospital Universitari Vall d'Hebron, Universitat Autonoma de Barcelona, 08035 Barcelona, Catalonia, Spain 12 CMME Sainte Anne. 100 rue de la Santé. 75014 Paris, France 13 INSERM U675. University Xavir Bichat (IFR02), 75018 Paris, France 14 Experimental and Health Sciences Department, Pompeu Fabra University, 08003 Barcelona, Catalonia, Spain

* Corresponding author: Mònica Gratacòs CIBER en Epidemiología y Salud Pública (CIBERESP) Genes & Disease Program Center for Genomic Regulation (CRG) Plaça Charles Darwin s/n (Dr. Aiguader 88), PRBB Building, Room 521 08003 Barcelona, CATALUNYA, Spain Phone: 3493 316 0138 FAX: 3493 316 0099 E-mail: monica.gratacos{at}crg.es

Received October 26, 2007; Revised January 8, 2008; Accepted January 16, 2008

Eating disorders (ED) 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 ten 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 x 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 x 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 eating disorders.

This paper has been versioned to correct the tagging of the first author surname.


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