Journal Articles

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

October 27, 2015

Human Obesity Associated with an Intronic SNP in the Brain-Derived Neurotrophic Factor Locus, Cell Rep. 2015 Oct 27, Mou Z1, Hyde TM2, Lipska BK3, Martinowich K4, Wei P5, Ong CJ5, Hunter LA5, Palaguachi GI5, Morgun E1, Teng R6, Lai C5, Condarco TA7, Demidowich AP7,Krause AJ7, Marshall LJ8, Haack K9, Voruganti VS10, Cole SA9, Butte NF11, Comuzzie AG9, Nalls MA12, Zonderman AB13, Singleton AB12, Evans MK14, Martin B15, Maudsley S16, Tsao JW17, Kleinman JE2, Yanovski JA7, Han JC18.

  • 1Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA; Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA.
  • 2The Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 3Human Brain Collection Core, National Institute of Mental Health (NIMH), NIH, Bethesda, MD 20892, USA.
  • 4The Lieber Institute for Brain Development, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 5Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA; Departments of Neurology and Physical Medicine and Rehabilitation, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
  • 6Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA.
  • 7Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA.
  • 8Preclinical Microbicide & Prevention Research Branch, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
  • 9Department of Genetics, Texas Biomedical Research Institute and Southwest National Primate Research Center, San Antonio, TX 78245, USA.
  • 10Department of Genetics, Texas Biomedical Research Institute and Southwest National Primate Research Center, San Antonio, TX 78245, USA; Department of Nutrition and UNC Nutrition Research Institute, University of North Carolina, Chapel Hill, Kannapolis, NC 28081, USA.
  • 11USDA/ARS Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, USA.
  • 12Molecular Genetics Section, National Institute of Aging (NIA), Bethesda, MD 20892, USA.
  • 13Behavioral Epidemiology Section, NIA, Baltimore, MD 21224, USA.
  • 14Health Disparities Research Section, NIA, Baltimore, MD 21224, USA.
  • 15Metabolism Unit, NIA, Baltimore, MD 21224, USA.
  • 16Receptor Pharmacology Unit, NIA, Baltimore, MD 21224, USA; Translational Neurobiology Group, VIB Department of Molecular Genetics, University of Antwerp, 2610 Wilrijk, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, 2610 Wilrijk, Belgium.
  • 17Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA; Departments of Neurology and Physical Medicine and Rehabilitation, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA; Department of Neurology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
  • 18Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA; Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA; Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Children’s Foundation Research Institute, Le Bonheur Children’s Hospital, Memphis, TN 38103, USA. Electronic address: jhan14@uthsc.edu.

Abstract

Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked toobesity, 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.

Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

 

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