title: Pleiotropic effects of obesity-susceptibility loci on metabolic traits: a meta-analysis of up to 37,874 individuals.
abstract: OBJECTIVE
  Genetic pleiotropy may contribute to the clustering of obesity and metabolic conditions. We assessed whether genetic variants that are robustly associated with BMI and waist-to-hip ratio (WHR) also influence metabolic and cardiovascular traits, independently of obesity-related traits, in meta-analyses of up to 37,874 individuals from six European population-based studies.
  
  
  METHODS
  We examined associations of 32 BMI and 14 WHR loci, individually and combined in two genetic predisposition scores (GPSs), with glycaemic traits, blood lipids and BP, with and without adjusting for BMI and/or WHR.
  
  
  RESULTS
  We observed significant associations of BMI-increasing alleles at five BMI loci with lower levels of 2 h glucose (RBJ [also known as DNAJC27], QPTCL: effect sizes -0.068 and -0.107 SD, respectively), HDL-cholesterol (SLC39A8: -0.065 SD, MTCH2: -0.039 SD), and diastolic BP (SLC39A8: -0.069 SD), and higher and lower levels of LDL- and total cholesterol (QPTCL: 0.041 and 0.042 SDs, respectively, FLJ35779 [also known as POC5]: -0.042 and -0.041 SDs, respectively) (all p < 2.4 × 10(-4)), independent of BMI. The WHR-increasing alleles at two WHR loci were significantly associated with higher proinsulin (GRB14: 0.069 SD) and lower fasting glucose levels (CPEB4: -0.049 SD), independent of BMI and WHR. A higher GPS-BMI was associated with lower systolic BP (-0.005 SD), diastolic BP (-0.006 SD) and 2 h glucose (-0.013 SD), while a higher GPS-WHR was associated with lower HDL-cholesterol (-0.015 SD) and higher triacylglycerol levels (0.014 SD) (all p < 2.9 × 10(-3)), independent of BMI and/or WHR.
  
  
  CONCLUSIONS
  These pleiotropic effects of obesity-susceptibility loci provide novel insights into mechanisms that link obesity with metabolic abnormalities.
authors.affiliation: Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: J V
authors.initials: JV
authors.lastname: van Vliet-Ostaptchouk
authors.forename: M
authors.initials: M
authors.lastname: den Hoed
authors.forename: J
authors.initials: J
authors.lastname: Luan
authors.forename: J H
authors.initials: JH
authors.lastname: Zhao
authors.forename: K K
authors.initials: KK
authors.lastname: Ong
authors.forename: P J
authors.initials: PJ
authors.lastname: van der Most
authors.forename: A
authors.initials: A
authors.lastname: Wong
authors.forename: R
authors.initials: R
authors.lastname: Hardy
authors.forename: D
authors.initials: D
authors.lastname: Kuh
authors.forename: M M
authors.initials: MM
authors.lastname: van der Klauw
authors.forename: M
authors.initials: M
authors.lastname: Bruinenberg
authors.forename: K T
authors.initials: KT
authors.lastname: Khaw
authors.forename: B H R
authors.initials: BH
authors.lastname: Wolffenbuttel
authors.forename: N J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: H
authors.initials: H
authors.lastname: Snieder
authors.forename: R J F
authors.initials: RJ
authors.lastname: Loos
mesh_terms: D000483:Alleles; D015992:Body Mass Index; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D009765:Obesity / Q000235:genetics / Q000378:metabolism*