Human Obesity Associated with an Intronic SNP in the Brain-Derived Neurotrophic Factor Locus

•BDNF rs12291063 minor C allele is associated with obesity in children and adults•Minor C allele disrupts binding and transactivation by hnRNPD0B•Minor C allele is associated with lower human hypothalamic BDNF expression•BDNF augmentation could be a CC genotype-specific targeted therapy for obesity

SummaryBrain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 BDNF SNPs. We observed that the minor C allele of rs12291063 is associated with lower human ventromedial hypothalamic BDNF expression (p < 0.001) and greater adiposity in both adult and pediatric cohorts (p values < 0.05). We further demonstrated that the major T allele for rs12291063 possesses a binding capacity for the transcriptional regulator, heterogeneous nuclear ribonucleoprotein D0B, knockdown of which disrupts transactivation by the T allele. Binding and transactivation functions are both disrupted by substituting C for T. These findings provide a rationale for BDNF augmentation as a targeted treatment for obesity in individuals who have the rs12291063 CC genotype.

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