Mutation screen of the brain derived neurotrophic factor gene (BDNF): Identification of several genetic variants and association studies in patients with obesity, eating disorders, and attention‐deficit/hyperactivity disorder

Abstract

Several lines of evidence indicate an involvement of brain derived neurotrophic factor (BDNF) in body weight regulation and activity: heterozygous Bdnf knockout mice (Bdnf(+/-)) are hyperphagic, obese, and hyperactive; furthermore, central infusion of BDNF leads to severe, dose-dependent appetite suppression and weight loss in rats. We searched for the role of BDNF variants in obesity, eating disorders, and attention-deficit/hyperactivity disorder (ADHD). A mutation screen (SSCP and DHPLC) of the translated region of BDNF in 183 extremely obese children and adolescents and 187 underweight students was performed. Additionally, we genotyped two common polymorphisms (rs6265: p.V66M; c.-46C > T) in 118 patients with anorexia nervosa, 80 patients with bulimia nervosa, 88 patients with ADHD, and 96 normal weight controls. Three rare variants (c.5C > T: p.T2I; c.273G > A; c.*137A > G) and the known polymorphism (p.V66M) were identified. A role of the I2 allele in the etiology of obesity cannot be excluded. We found no association between p.V66M or the additionally genotyped variant c.-46C > T and obesity, ADHD or eating disorders. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299:1/suppmat/index.html.

Association between brain-derived neurotrophic factor Val66Met and obesity in children and adolescents

“…This finding partially replicates a recent report showing that girls who were Met carriers had a tendency for higher BMI (Akkermann et al, 2011), however in contrast to our participants, these Caucasian girls of Estonian origin practiced extreme weight restriction behaviors. On the other hand, our results diverge from a study of young participants of German origin that failed to detect significant differences in the distribution of the BDNF Val66Met variants between extremely obese children and adolescents, underweight students, patients with attention deficit hyperactivity disorder, anorexia nervosa, bulimia nervosa and normal weight controls (Friedel et al, 2005), and from the data showing no association between BDNF Val66Met and susceptibility to develop eating disorders in Spanish schoolchildren of Caucasian background (Arija et al, 2010). The discrepancies between our and the aforementioned results might be explained by the fact that we included only healthy young participants, while other studies (Akkermann et al, 2011;Arija et al, 2010;Friedel et al, 2005) included either extremely obese or underweight participants, as well as subjects with eating disorders or risk for eating disorders.…”

“…Studies examining the possible association between the BDNF Val66Met variants and obesity in healthy children and adolescents are still rare, and one genome wide association study (GWAS) reported significant association between BDNF gene and BMI in healthy children (Zhao et al, 2009), while other studies failed to find any significant association between BDNF Val66Met and obesity (Arija et al, 2010;Friedel et al, 2005). Most of the studies evaluated the role of BDNF Val66Met in eating disorders, and found either a significant association (Akkermann et al, 2011;Gratacos et al, 2007), or no association (Arija et al, 2010;Friedel et al, 2005) between the Met allele and eating disorders.…”

“…Most of the studies evaluated the role of BDNF Val66Met in eating disorders, and found either a significant association (Akkermann et al, 2011;Gratacos et al, 2007), or no association (Arija et al, 2010;Friedel et al, 2005) between the Met allele and eating disorders. The ethnic (Pivac et al, 2009), as well as population-related genetic differences (Petryshen et al, 2010) might explain the conflicting association results showing either that BDNF Val66Met Met/Met genotype was more frequently found in adult women with higher (Beckers et al, 2008) or with lower (Shugart et al, 2009) BMI.…”

Dock3 regulates BDNF‐TrkB signaling for neurite outgrowth by forming a ternary complex with Elmo and RhoG

“…In addition to having physiological functions, BDNF has recently been associated with neurological diseases. For example, Val66Met functional polymorphism in human BDNF is involved in the pathogenesis of attentiondeficit hyperactivity disorder (ADHD) (Egan et al 2003;Friedel et al 2005;Kent et al 2005). Interestingly, a pericentric inversion breakpoint in the DOCK3 gene has been described in ADHD patients (de Silva et al 2003).…”

Association of the paternally transmitted copy of common Valine allele of the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene with susceptibility to ADHD

“…The second study failed to find any association between Val66Met and childhood ADHD using a small sample (N ¼ 88), but this study's power to detect an association with an effect size of 1.6, at an alpha of 0.05 was only 45%. 31 It is also important to consider that different diagnostic practices between the UK, other parts of Europe and the US may be an issue with regards to the failure to replicate findings, particularly in terms of the differing frequencies of ADHD subtypes and comorbidity seen in other samples.…”