title: Association of NTRK3 and its interaction with NGF suggest an altered cross-regulation of the neurotrophin signaling pathway in eating disorders.
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 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 EDs.
authors.affiliation: Genes and Disease Program, Center for Genomic Regulation, 08003 Barcelona, Catalonia, Spain.
authors.forename: Josep Maria
authors.initials: JM
authors.lastname: Mercader
authors.forename: Ester
authors.initials: E
authors.lastname: Saus
authors.forename: Zaida
authors.initials: Z
authors.lastname: Agüera
authors.forename: Mònica
authors.initials: M
authors.lastname: Bayés
authors.forename: Claudette
authors.initials: C
authors.lastname: Boni
authors.forename: Anna
authors.initials: A
authors.lastname: Carreras
authors.forename: Elena
authors.initials: E
authors.lastname: Cellini
authors.forename: Rafael
authors.initials: R
authors.lastname: de Cid
authors.forename: Mara
authors.initials: M
authors.lastname: Dierssen
authors.forename: Geòrgia
authors.initials: G
authors.lastname: Escaramís
authors.forename: Fernando
authors.initials: F
authors.lastname: Fernández-Aranda
authors.forename: Laura
authors.initials: L
authors.lastname: Forcano
authors.forename: Xavier
authors.initials: X
authors.lastname: Gallego
authors.forename: Juan Ramón
authors.initials: JR
authors.lastname: González
authors.forename: Philip
authors.initials: P
authors.lastname: Gorwood
authors.forename: Johannes
authors.initials: J
authors.lastname: Hebebrand
authors.forename: Anke
authors.initials: A
authors.lastname: Hinney
authors.forename: Benedetta
authors.initials: B
authors.lastname: Nacmias
authors.forename: Anna
authors.initials: A
authors.lastname: Puig
authors.forename: Marta
authors.initials: M
authors.lastname: Ribasés
authors.forename: Valdo
authors.initials: V
authors.lastname: Ricca
authors.forename: Lucia
authors.initials: L
authors.lastname: Romo
authors.forename: Sandro
authors.initials: S
authors.lastname: Sorbi
authors.forename: Audrey
authors.initials: A
authors.lastname: Versini
authors.forename: Mònica
authors.initials: M
authors.lastname: Gratacòs
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D045744:Cell Line, Tumor; D019295:Computational Biology; D004195:Disease Models, Animal; D005190:Family; D001068:Feeding and Eating Disorders / Q000235:genetics*; D005260:Female; D005602:France; D005786:Gene Expression Regulation; D005858:Germany; D006239:Haplotypes; D006801:Humans; D051379:Mice; D020932:Nerve Growth Factor / Q000235:genetics*; D009414:Nerve Growth Factors / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D020812:Receptor, trkC / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D013030:Spain
chemical_list: C502240:NGF protein, human; D009414:Nerve Growth Factors; D020932:Nerve Growth Factor; D020812:Receptor, trkC