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Title: Human obesity associated with an intronic SNP in the brain-derived neurotrophic factor locus

Author
item MOU, ZONGYANG - National Institutes Of Health (NIH)
item HYDE, THOMAS - Johns Hopkins University School Of Medicine
item LIPSKA, BARBARA - National Institutes Of Health (NIH)
item MARTINOWICH, KERI - Johns Hopkins University School Of Medicine
item WEI, PETER - National Institutes Of Health (NIH)
item ONG, CHIEW-JEN - National Institutes Of Health (NIH)
item HUNTER, LINDSAY - National Institutes Of Health (NIH)
item PALAGUACHI, GLADYS - National Institutes Of Health (NIH)
item MORGUN, EVA - National Institutes Of Health (NIH)
item TENG, RUJIA - National Institutes Of Health (NIH)
item LAI, CHEN - National Institutes Of Health (NIH)
item CONDARCO, TANIA - National Institutes Of Health (NIH)
item DEMIDOWICH, ANDREW - National Institutes Of Health (NIH)
item KRAUSE, AMANDA - National Institutes Of Health (NIH)
item MARSHALL, LESLIE - National Institutes Of Health (NIH)
item HAACK, KARIN - Southwest Foundation For Biomedical Research (SFBR)
item VORUGANTI, V - University Of North Carolina
item COLE, SHELLEY - Southwest Foundation For Biomedical Research (SFBR)
item BUTTE, NANCY - Children'S Nutrition Research Center (CNRC)
item COMUZZIE, ANTHONY - Southwest Foundation For Biomedical Research (SFBR)
item NALLS, MICHAEL - National Institutes Of Health (NIH)
item ZONDERMAN, ALAN - National Institutes Of Health (NIH)
item SINGLETON, ANDREW - National Institutes Of Health (NIH)
item EVANS, MICHELE - National Institutes Of Health (NIH)
item MARTIN, BRONWEN - National Institutes Of Health (NIH)
item MAUDSLEY, STUART - National Institutes Of Health (NIH)
item TSAO, JACK - National Institutes Of Health (NIH)
item KLEINMAN, JOEL - Johns Hopkins University School Of Medicine
item YANOVSKI, JACK - National Institutes Of Health (NIH)
item HAN, JOAN - National Institutes Of Health (NIH)

Submitted to: Cell Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/23/2015
Publication Date: 11/10/2015
Citation: Mou, Z., Hyde, T.M., Lipska, B.K., Martinowich, K., Wei, P., Ong, C., Hunter, L.A., Palaguachi, G.I., Morgun, E., Teng, R., Lai, C., Condarco, T.A., Demidowich, A.P., Krause, A.J., Marshall, L.J., Haack, K., Voruganti, V.S., Cole, S.A., Butte, N.F., Comuzzie, A.G., Nalls, M.A., Zonderman, A.B., Singleton, A.B., Evans, M.K., Martin, B., Maudsley, S., Tsao, J.W., Kleinman, J.E., Yanovski, J.A., Han, J.C. 2015. Human obesity associated with an intronic SNP in the brain- derived neurotrophic factor locus. Cell Reports. 13(6):1073-1080.

Interpretive Summary: In this experiment, researchers examined the effect of 44 variants in a gene called brain-derived neurotrophic factor (BDNF) on obesity. They found that a specific variant (rs12291063) in BDNF disrupts the expression of BDNF in the brain and is associated with obesity. Increasing the expression of BDNF may benefit obese individuals with this specific genetic variant.

Technical Abstract: Brain-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.