Meta-analysis of brain-derived neurotrophic factor p.Val66Met in adult ADHD in four European populations

Attention-deficit hyperactivity disorder (ADHD) is a multifactorial, neurodevelopmental disorder that often persists into adolescence and adulthood and is characterized by inattention, hyperactivity and impulsiveness. Before the advent of the first genome-wide association studies in ADHD, genetic research had mainly focused on candidate genes related to the dopaminergic and serotoninergic systems, although several other genes had also been assessed. Pharmacological data, analysis of animal models and association studies suggest that Brain-Derived Neurotrophic Factor (BDNF) is also a strong candidate gene for ADHD. Several polymorphisms in BDNF have been reported and studied in psychiatric disorders but the most frequent is the p.Val66Met (rs6265G > A) single nucleotide polymorphism (SNP), with functional effects on the intracellular trafficking and secretion of the protein. To deal with the inconsistency raised among different case-control and family-based association studies regarding the p.Val66Met contribution to ADHD, we performed a meta-analysis of published as well as unpublished data from four different centers that are part of the International Multicentre Persistent ADHD CollaboraTion (IMpACT). A total of 1,445 adulthood ADHD patients and 2,247 sex-matched controls were available for the study. No association between the p.Val66Met polymorphism and ADHD was found in any of the four populations or in the pooled sample. The meta-analysis also showed that the overall gene effect for ADHD was not statistically significant when gender or comorbidity with mood disorders were considered. Despite the potential role of BDNF in ADHD, our data do not support the involvement of p.Val66Met in the pathogenesis of this neuropsychiatric disorder.