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
Genes and Disease Program, Center for Genomic Regulation, 08003 Barcelona, Catalonia, Spain.
Hum Mol Genet. 2008 May 1;17(9):1234-44. doi: 10.1093/hmg/ddn013. Epub 2008 Jan 18.
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.
饮食失调（EDs）是复杂的精神疾病，包括神经性厌食症和神经性贪食症，其遗传度高于50%。先前的研究发现BDNF和NTRK2与饮食失调有关，而动物模型表明其他神经营养因子基因可能也参与饮食行为。我们对来自西班牙、法国和德国的371个饮食失调三联体进行了一项基于家系的关联研究，研究涉及10个神经营养因子信号基因的151个标签单核苷酸多态性（TagSNPs）：NGFB、BDNF、NTRK1、NGFR/p75、NTF4/5、NTRK2、NTF3、NTRK3、CNTF和CNTFR。除了几个名义上的关联外，我们在对多重检验进行校正后（P = 1.04 x 10(-4)）发现，饮食失调与位于NTRK3基因中的rs7180942之间存在强烈的显著关联，该关联遵循超显性遗传模型。有趣的是，携带rs7180942饮食失调风险基因型的HapMap无关个体在淋巴母细胞系中显示出较高水平的NTRK3表达。此外，在神经性厌食症的anx/anx小鼠模型的下丘脑中也检测到直系同源鼠Ntrk3基因的较高表达。最后，NGFB基因中的变异似乎会改变由NTRK3 rs7180942风险基因型所带来的风险（P = 4.0 x 10(-5)），显示出协同上位相互作用。除了先前报道的BDNF和NTRK2的研究结果外，本文报道的数据表明神经营养因子信号基因是饮食行为的关键调节因子，其交叉调节改变是饮食失调的易感性因素。
