title: Fine Mapping of a GWAS-Derived Obesity Candidate Region on Chromosome 16p11.2.
abstract: BACKGROUND
  Large-scale genome-wide association studies (GWASs) have identified 97 chromosomal loci associated with increased body mass index in population-based studies on adults. One of these SNPs, rs7359397, tags a large region (approx. 1MB) with high linkage disequilibrium (r2>0.7), which comprises five genes (SH2B1, APOBR, sulfotransferases: SULT1A1 and SULT1A2, TUFM). We had previously described a rare mutation in SH2B1 solely identified in extremely obese individuals but not in lean controls.
  
  
  METHODS
  The coding regions of the genes APOBR, SULT1A1, SULT1A2, and TUFM were screened for mutations (dHPLC, SSCP, Sanger re-sequencing) in 95 extremely obese children and adolescents. Detected non-synonymous variants were genotyped (TaqMan SNP Genotyping, MALDI TOF, PCR-RFLP) in independent large study groups (up to 3,210 extremely obese/overweight cases, 485 lean controls and 615 obesity trios). In silico tools were used for the prediction of potential functional effects of detected variants.
  
  
  RESULTS
  Except for TUFM we detected non-synonymous variants in all screened genes. Two polymorphisms rs180743 (APOBR p.Pro428Ala) and rs3833080 (APOBR p.Gly369_Asp370del9) showed nominal association to (extreme) obesity (uncorrected p = 0.003 and p = 0.002, respectively). In silico analyses predicted a functional implication for rs180743 (APOBR p.Pro428Ala). Both APOBR variants are located in the repetitive region with unknown function.
  
  
  CONCLUSIONS
  Variants in APOBR contributed as strongly as variants in SH2B1 to the association with extreme obesity in the chromosomal region chr16p11.2. In silico analyses implied no functional effect of several of the detected variants. Further in vitro or in vivo analyses on the functional implications of the obesity associated variants are warranted.
authors.affiliation: Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Volckmar
authors.affiliation: Institute of Child and Adolescent Health, School of Public Health, Peking University, Beijing, China.
authors.forename: Jie-Yun
authors.initials: JY
authors.lastname: Song
authors.affiliation: Institute of Medical Biometry and Epidemiology, University of Marburg, Marburg, Germany.
authors.forename: Ivonne
authors.initials: I
authors.lastname: Jarick
authors.affiliation: Institute for Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Pütter
authors.affiliation: Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Göbel
authors.affiliation: Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Lucie
authors.initials: L
authors.lastname: Horn
authors.affiliation: Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Struve
authors.affiliation: Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Haas
authors.affiliation: Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Knoll
authors.affiliation: Institute of Epidemiology, Helmholtz-Zentrum Munich, Munich, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Grallert
authors.affiliation: Institute of Epidemiology, Helmholtz-Zentrum Munich, Munich, Germany; Hannover Unified Biobank, Hannover Medical School, Hannover, Germany; Institute for Human Genetics, Hannover Medical School, Hannover, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.affiliation: Vestische Hospital for Clinic of Children and Adolescents Medicine, Datteln, University of Witten/Herdecke, Witten, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Reinehr
authors.affiliation: Institute of Child and Adolescent Health, School of Public Health, Peking University, Beijing, China.
authors.forename: Hai-Jun
authors.initials: HJ
authors.lastname: Wang
authors.affiliation: Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Hebebrand
authors.affiliation: Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Hinney
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000293:Adolescent; D000328:Adult; D015239:Arylsulfotransferase / Q000235:genetics; D015992:Body Mass Index; D002648:Child; D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics; D009765:Obesity / Q000235:genetics* / Q000473:pathology; D010444:Peptide Elongation Factor Tu / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D018110:Receptors, Lipoprotein / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D024101:Mitochondrial Proteins; D018110:Receptors, Lipoprotein; C518910:SH2B1 protein, human; C091648:TUFM protein, human; C072413:apolipoprotein B receptor; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human; C513290:SULT1A2 protein, human; D010444:Peptide Elongation Factor Tu