title: Human Obesity Associated with an Intronic SNP in the Brain-Derived Neurotrophic Factor Locus.
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.
authors.affiliation: Unit 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.
authors.forename: Zongyang
authors.initials: Z
authors.lastname: Mou
authors.affiliation: The 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.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Hyde
authors.affiliation: Human Brain Collection Core, National Institute of Mental Health (NIMH), NIH, Bethesda, MD 20892, USA.
authors.forename: Barbara K
authors.initials: BK
authors.lastname: Lipska
authors.affiliation: The 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.
authors.forename: Keri
authors.initials: K
authors.lastname: Martinowich
authors.affiliation: Unit 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Wei
authors.affiliation: Unit 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.
authors.forename: Chiew-Jen
authors.initials: CJ
authors.lastname: Ong
authors.affiliation: Unit 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.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Hunter
authors.affiliation: Unit 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.
authors.forename: Gladys I
authors.initials: GI
authors.lastname: Palaguachi
authors.affiliation: Unit 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.
authors.forename: Eva
authors.initials: E
authors.lastname: Morgun
authors.affiliation: Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA.
authors.forename: Rujia
authors.initials: R
authors.lastname: Teng
authors.affiliation: Unit 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.
authors.forename: Chen
authors.initials: C
authors.lastname: Lai
authors.affiliation: Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA.
authors.forename: Tania A
authors.initials: TA
authors.lastname: Condarco
authors.affiliation: Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Demidowich
authors.affiliation: Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Krause
authors.affiliation: Preclinical Microbicide & Prevention Research Branch, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Marshall
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute and Southwest National Primate Research Center, San Antonio, TX 78245, USA.
authors.forename: Karin
authors.initials: K
authors.lastname: Haack
authors.affiliation: Department 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.
authors.forename: V Saroja
authors.initials: VS
authors.lastname: Voruganti
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute and Southwest National Primate Research Center, San Antonio, TX 78245, USA.
authors.forename: Shelley A
authors.initials: SA
authors.lastname: Cole
authors.affiliation: USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Nancy F
authors.initials: NF
authors.lastname: Butte
authors.affiliation: Department of Genetics, Texas Biomedical Research Institute and Southwest National Primate Research Center, San Antonio, TX 78245, USA.
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Comuzzie
authors.affiliation: Molecular Genetics Section, National Institute of Aging (NIA), Bethesda, MD 20892, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalls
authors.affiliation: Behavioral Epidemiology Section, NIA, Baltimore, MD 21224, USA.
authors.forename: Alan B
authors.initials: AB
authors.lastname: Zonderman
authors.affiliation: Molecular Genetics Section, National Institute of Aging (NIA), Bethesda, MD 20892, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.affiliation: Health Disparities Research Section, NIA, Baltimore, MD 21224, USA.
authors.forename: Michele K
authors.initials: MK
authors.lastname: Evans
authors.affiliation: Metabolism Unit, NIA, Baltimore, MD 21224, USA.
authors.forename: Bronwen
authors.initials: B
authors.lastname: Martin
authors.affiliation: Receptor 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.
authors.forename: Stuart
authors.initials: S
authors.lastname: Maudsley
authors.affiliation: Section 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.
authors.forename: Jack W
authors.initials: JW
authors.lastname: Tsao
authors.affiliation: The 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.
authors.forename: Joel E
authors.initials: JE
authors.lastname: Kleinman
authors.affiliation: Section on Growth and Obesity, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD 20892, USA.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Yanovski
authors.affiliation: Unit 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.
authors.forename: Joan C
authors.initials: JC
authors.lastname: Han
mesh_terms: D000293:Adolescent; D000328:Adult; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D005260:Female; D057809:HEK293 Cells; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000378:metabolism; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D007438:Introns; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C000630986:HNRNPD protein, human; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; C579455:BDNF protein, human
keywords: Mou et al. show that brain-derived neurotrophic factor (BDNF) rs12291063 minor C allele disrupts binding and transactivation by the transcriptional regulator; and it is associated with lower ventromedial hypothalamic BDNF expression and obesity. BDNF augmentation may be specifically beneficial for treating obesity in individuals with the CC genotype; heterogeneous nuclear ribonucleoprotein D0B