Contribution of NTRK2 to the genetic susceptibility to anorexia nervosa, Harm avoidance and minimum body mass index

Abstract

Anorexia nervosa (AN) and bulimia nervosa (BN) are eating disorders (ED) with complex genetic and environmental components. Genetic studies and animal models support the participation of brain-derived neurotrophic factor (BDNF) in the vulnerability to AN and BN. We investigated the genetic contribution of the BDNF-specific receptor neurotrophic tyrosine kinase receptor type 2 (NTRK2) to the susceptibility to ED. We have screened the entire NTRK2 gene in 91 patients with ED and have identified 14 single-nucleotide polymorphisms (SNPs). A population-based association study with six SNPs from the NTRK2 locus was performed in 164 ED patients and 121 controls. Significant evidence of association for markers -69C4G and IVS13 þ 40G4A was detected. We also observed a strong association between the C-A-insC haplotype (-69/IVS13 þ 40/2784-2785) and binge-eating/purging AN (ANP, P ¼ 0.006; OR ¼ 2.27), and a reduced frequency of haplotype G-A-delCl in BN patients (P ¼ 0.034; OR ¼ 0.6). The analysis of ED-related phenotypes revealed a clear association between NTRK2, high scores of Harm avoidance measured by the temperament and character inventory (TCI-R; P ¼ 0.003) and minimum body mass index (minBMI; Po0.001). Our data support a contribution of NTRK2 to the genetic susceptibility of ED, mainly ANP, and ED-related phenotypic traits, such as Harm avoidance and minBMI. Keywords: anorexia; bulimia; eating disorders; harm avoidance; BDNF; NTRK2 Eating disorders (ED) are complex psychiatric diseases characterized by alterations in eating behaviour, body shape perception and body weight regulation. Different genetic, psychological and environmental factors contribute to the vulnerability to both anorexia nervosa (AN) and bulimia nervosa (BN), but the pathophysiology of these disorders is still largely unknown. 1 Brain-derived neurotrophic factor (BDNF) encodes for a neurotrophic factor expressed in the hypothalamic nuclei that regulate eating behaviour and modulates synaptic efficiency and neuronal plasticity through the control of different neurotransmitter systems previously involved in ED.2,3 Intraventricular administration of Bdnf induces appetite suppression and body weight reduction in rats, while Bdnf knockout mice develop obesity associated to hyperphagia and serotonin dysfunctions.3-5 Moreover, we and others have previously reported a strong association between BDNF and both AN and BN in different populations. [6][7][8][9] Due to the strong association between BDNF and ED, we propose its high-affinity receptor neurotrophic tyrosine kinase receptor type 2 (NTRK2) as a candidate gene to participate in the aetiology of ED and suggest that alterations on its function or expression pattern could contribute to the development of AN and BN. Different lines of evidences support this hypothesis. NTRK2 is expressed in hypothalamic neurons that control food intake and energy expenditure. Infusion of the Ntrk2 specific ligands, Bdnf or Nt4/5, transiently reverse the eating behaviour and obesity of the Bdnf (7) knockout mice and the ...

Nucleotide sequence variation within the human tyrosine kinase B neurotrophin receptor gene: association with antisocial alcohol dependence

“…BDNF-deficient mice exhibited increased eating behavior that was transiently reversed when BDNF was infused. 27 Thus, increased TrkB expression or TrkB-mediated signaling may serve as a negative regulatory pathway involved in food 28 This study has a number of strengths and limitations. We used a relatively large number of SNP markers to capture as much variation as possible across NTRK2.…”

Genetic Susceptibility to Eating Disorders: Associated Polymorphisms and Pharmacogenetic Suggestions

“…Probands carrying both the hypofunctional 7R allele of DRD4 gene and the Met allele of BDNF gene had significantly higher maximum BMI than probands in the other gene-gene interaction groups. SNPs of the NTRK2 gene, which encodes a BDNF receptor, have been investigated for association with AN and BN in a single study with some positive results [123], that need replication (Table 2).…”

Family trios analysis of common polymorphisms in the obestatin/ghrelin, BDNF and AGRP genes in patients with Anorexia nervosa: Association with subtype, body-mass index, severity and age of onset

“…In rodents, genetic models with an altered BDNF/TrkB signalling display hyperphagia and obesity and pharmacological treatments with BDNF induce reduction in food intake (Hashimoto et al, 2005). Entire screening of the NTRK2 gene in eating disorder patients has revealed a strong association between certain haplotypes and ANB but failed to support the participation of epistatic effects between BDNF and NTRK2 in the risk to develop eating disorders (Ribases et al, 2005a). A recent study suggested that, while the 196G/A SNP of the human BDNF gene did not contribute to the genetic susceptibility to bulimia nervosa and binge eating disorder in their population, it may predispose these patients to a more severe binge eating behavior (Monteleone et al, 2006b).…”