Met66 in the brain-derived neurotrophic factor (BDNF) precursor is associated with anorexia nervosa restrictive type

Abstract

Several lines of evidence support a role for brain-derived neurotrophic factor (BDNF) alterations in the etiology of eating disorders (EDs). BDNF heterozygous knockout mice show alterations in eating behavior, increased body weight and adipocyte hypertrophy. BDNF also regulates the synaptic efficiency through the modulation of key neurotransmitter systems previously known to be involved in ED. These findings, together with the fact that this neurotrophin is expressed in the hypothalamus nuclei associated with weight regulation and feeding control, led us to propose BDNF as a candidate gene for ED. To investigate the possible involvement of this neurotrophin in eating behavior, we screened the BDNF gene in 95 ED patients and identified four sequence variants. Two of them, À374A/T and À256G/A, were found in two patients with anorexia nervosa (AN) and consisted of single-nucleotide mutations within the 5 0 untranslated region (5 0 UTR). The other two polymorphisms resulted in a C to T transition located at the 5 0 UTR of the BDNF gene and an amino-acid substitution within the BDNF precursor protein (Val66Met). We performed a case-control study for these two Single-nucleotide polymorphisms in a sample of 143 ED patients and 112 unrelated controls and found a strong association of restricting AN (ANR) with the Met allele of the Val66Met BDNF polymorphism (2p ¼ 0.002). There was also evidence for a significant effect of this sequence variant on the minimum body mass index (MBMI) (2p ¼ 0.006). These results suggest that the BDNF Met66 variant may be a susceptibility factor to ED, mainly to ANR and low MBMI. Keywords: anorexia; bulimia; brain-derived neurotrophic factor; BDNF; single-nucleotide polymorphism Eating disorders (EDs) are complex and multifactorial, with the involvement of both psychosocial and biological factors. 1-6 A genetic contribution in ED is widely accepted 6-9 and genes involved in eating behavior, weight regulation, satiety and metabolism, as well as those under hormonal control are considered candidate genes for their role in anorexia nervosa (AN) and bulimia nervosa (BN). Among these candidates, we propose brain-derived neurotrophic factor (BDNF), which encodes for a neurotrophic factor with an essential role in neuronal survival and differentiation, and is also involved in synaptic efficiency and neuronal plasticity. 10-13 BDNF maps to 11p13-p14 14 and, although the structure of the coding exon is well known, 15 the genomic organization of the 5 0 noncoding exons has not been described.Several lines of evidence indicate a role of this neurotrophin in eating behavior and suggest that alterations in its function or expression pattern could be considered susceptibility factors to ED. To test this hypothesis we have characterized the genomic structure of the human BDNF gene. BDNF is composed of, at least, four 5 0 nontranslated exons and a single 3 0 coding exon (exon 5; Figure 1b). Since mRNA transcripts were different at their 5 0 ends, we determined the existence of four 5 0 untranslated exons th...

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

“…If our population (n = 114) was to be compared to this control group, no association would have been observed. The frequency of healthy subjects carrying the Met66BDNF allele seems to differ widely from one country to another, being higher in japanese (41.1 %) than in Italians (29.7 %) or Americans (18.0 %) , and a frequency of 15.2 % has been observed in a Spanish control group (Ribases et al, 2003). Different methods have been proposed to correct for population stratification (Devlin et al, 2001) but an important advantage of the TDT is that it is largely protected from population stratification (Spielman et al, 1993).…”

“…Case-control studies showed interpopulation variations ranging from no association with eating disorders in a german population (Friedel et al, 2005) and in a dutch population (de Krom et al, 2005), association with different subtypes of anorexia nervosa or bulimia nervosa in Spanish and Japanese samples (Ribases et al, 2003;Koizumi et al, 2004), to association with both eating disorders in a joint analysis of five European countries' populations (Ribases et al, 2004). This last study included a french population of 163 anorexics which showed an excess of Met66BDNF allele, especially in the ANB group, compared to a group of 510 control subjects including 56…”

“…Moreover, since ghrelin regulates AgRP orexigenic neurons and the Ala67Thr polymorphism of AgRP (Thr67AGRP) has been associated with AN (Vink et al, 2001), and also since BDNF has been involved in body weight regulation and its Val66Met polymorphism (Met66BDNF) associated with AN (Ribases et al, 2003;Ribases et al, 2004;Hashimoto et al, 2005;Ribases et al, 2005), these polymorphisms were analysed.…”

Relevance of animal models to human eating disorders and obesity

“…We will give here an example of how the behavior of genetically modified animals can inform the search for candidate genes. Observations of altered feeding behavior leading to increased body weight in brain-derived neurotrophic factor (BDNF) knockout mice and reports that intraventricular administration of BDNF in rats resulted in reduced feeding and weight loss prompted Ribases et al (2003) to study the BDNF gene in AN. The investigators observed a strong association between restricting AN, as well as minimum body weight, and an amino acid substitution within the BDNF precursor protein (Val66Met); they replicated the findings in an independent sample (Ribases et al 2005).…”

Mutant huntingtin Impairs the Post-Golgi Trafficking of Brain-Derived Neurotrophic Factor But Not Its Val66Met Polymorphism

“…In fact, several studies have associated this polymorphism with increased susceptibility to anorexia nervosa (Ribases et al, 2003), obsessive-compulsive disorders (Hall et al, 2003), eating disorders (Friedel et al, 2005), depression (Sen et al, 2003), schizophrenia (Skibinska et al, 2004), Alzheimer's disease (Ventriglia et al, 2002), and Parkinson's disease (Momose et al, 2002).…”