Association of NTRK3 and its interaction with NGF suggest an altered cross-regulation of the neurotrophin signaling pathway in eating disorders.
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.
Mercader
Josep Maria
JM
Genes and Disease Program, Center for Genomic Regulation, 08003 Barcelona, Catalonia, Spain.
Saus
Ester
E
Agüera
Zaida
Z
Bayés
Mònica
M
Boni
Claudette
C
Carreras
Anna
A
Cellini
Elena
E
de Cid
Rafael
R
Dierssen
Mara
M
Escaramís
Geòrgia
G
Fernández-Aranda
Fernando
F
Forcano
Laura
L
Gallego
Xavier
X
González
Juan Ramón
JR
Gorwood
Philip
P
Hebebrand
Johannes
J
Hinney
Anke
A
Nacmias
Benedetta
B
Puig
Anna
A
Ribasés
Marta
M
Ricca
Valdo
V
Romo
Lucia
L
Sorbi
Sandro
S
Versini
Audrey
A
Gratacòs
Mònica
M
Estivill
Xavier
X
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
C502240:NGF protein, human; D009414:Nerve Growth Factors; D020932:Nerve Growth Factor; D020812:Receptor, trkC