title: Studies of metabolic phenotypic correlates of 15 obesity associated gene variants.
abstract: OBJECTIVE
  Genome-wide association studies have identified novel BMI/obesity associated susceptibility loci. The purpose of this study is to determine associations with overweight, obesity, morbid obesity and/or general adiposity in a Danish population. Moreover, we want to investigate if these loci associate with type 2 diabetes and to elucidate potential underlying metabolic mechanisms.
  
  
  METHODS
  15 gene variants in 14 loci including TMEM18 (rs7561317), SH2B1 (rs7498665), KCTD15 (rs29941), NEGR1 (rs2568958), ETV5 (rs7647305), BDNF (rs4923461, rs925946), SEC16B (rs10913469), FAIM2 (rs7138803), GNPDA2 (rs10938397), MTCH2 (rs10838738), BAT2 (rs2260000), NPC1 (rs1805081), MAF (rs1424233), and PTER (rs10508503) were genotyped in 18,014 middle-aged Danes.
  
  
  RESULTS
  Five of the 15 gene variants associated with overweight, obesity and/or morbid obesity. Per allele ORs ranged from 1.15-1.20 for overweight, 1.10-1.25 for obesity, and 1.41-1.46 for morbid obesity. Five of the 15 variants moreover associated with increased measures of adiposity. BDNF rs4923461 displayed a borderline BMI-dependent protective effect on type 2 diabetes (0.87 (0.78-0.96, p = 0.008)), whereas SH2B1 rs7498665 associated with nominally BMI-independent increased risk of type 2 diabetes (1.16 (1.07-1.27, p = 7.8×10(-4))).
  
  
  CONCLUSIONS
  Associations with overweight and/or obesity and measures of obesity were confirmed for seven out of the 15 gene variants. The obesity risk allele of BDNF rs4923461 protected against type 2 diabetes, which could suggest neuronal and peripheral distinctive ways of actions for the protein. SH2B1 rs7498665 associated with type 2 diabetes independently of BMI.
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. cila@novonordisk.com
authors.forename: Camilla Helene
authors.initials: CH
authors.lastname: Sandholt
authors.forename: Marie Aare
authors.initials: MA
authors.lastname: Vestmar
authors.forename: Dorthe Sadowa
authors.initials: DS
authors.lastname: Bille
authors.forename: Anders
authors.initials: A
authors.lastname: Borglykke
authors.forename: Katrine
authors.initials: K
authors.lastname: Almind
authors.forename: Lars
authors.initials: L
authors.lastname: Hansen
authors.forename: Annelli
authors.initials: A
authors.lastname: Sandbæk
authors.forename: Torsten
authors.initials: T
authors.lastname: Lauritzen
authors.forename: Daniel
authors.initials: D
authors.lastname: Witte
authors.forename: Torben
authors.initials: T
authors.lastname: Jørgensen
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
mesh_terms: D000886:Anthropometry; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D005787:Gene Frequency; D056426:Genetic Loci / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D008875:Middle Aged; D009765:Obesity / Q000235:genetics* / Q000378:metabolism*; D009767:Obesity, Morbid / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors