title: Analysis of Genes Involved in Body Weight Regulation by Targeted Re-Sequencing.
abstract: BACKGROUND
  Genes involved in body weight regulation that were previously investigated in genome-wide association studies (GWAS) and in animal models were target-enriched followed by massive parallel next generation sequencing.
  
  
  METHODS
  We enriched and re-sequenced continuous genomic regions comprising FTO, MC4R, TMEM18, SDCCAG8, TKNS, MSRA and TBC1D1 in a screening sample of 196 extremely obese children and adolescents with age and sex specific body mass index (BMI) ≥ 99th percentile and 176 lean adults (BMI ≤ 15th percentile). 22 variants were confirmed by Sanger sequencing. Genotyping was performed in up to 705 independent obesity trios (extremely obese child and both parents), 243 extremely obese cases and 261 lean adults.
  
  
  CONCLUSIONS
  We detected 20 different non-synonymous variants, one frame shift and one nonsense mutation in the 7 continuous genomic regions in study groups of different weight extremes. For SNP Arg695Cys (rs58983546) in TBC1D1 we detected nominal association with obesity (pTDT = 0.03 in 705 trios). Eleven of the variants were rare, thus were only detected heterozygously in up to ten individual(s) of the complete screening sample of 372 individuals. Two of them (in FTO and MSRA) were found in lean individuals, nine in extremely obese. In silico analyses of the 11 variants did not reveal functional implications for the mutations. Concordant with our hypothesis we detected a rare variant that potentially leads to loss of FTO function in a lean individual. For TBC1D1, in contrary to our hypothesis, the loss of function variant (Arg443Stop) was found in an obese individual. Functional in vitro studies are warranted.
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, Essen, Germany.
authors.forename: Anna-Lena
authors.initials: AL
authors.lastname: Volckmar
authors.affiliation: Nutrigenomics and Gene Regulation, Max-Planck-Institute for Molecular Genetics, Berlin, Germany.|Genomics, Core Facilities and Technology, Institute of Molecular Biology (IMB), Mainz, Germany.
authors.forename: Chung Ting
authors.initials: CT
authors.lastname: Han
authors.affiliation: Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University Hospital Essen, Essen, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Pütter
authors.affiliation: Nutrigenomics and Gene Regulation, Max-Planck-Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Haas
authors.affiliation: Department of Animal and Food Production, Santa Catarina State University, Lages, Brazil.
authors.forename: Carla I G
authors.initials: CI
authors.lastname: Vogel
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, Essen, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Knoll
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, Essen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Struve
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, Essen, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Göbel
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, Essen, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Haas
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, Essen, Germany.
authors.forename: Nikolas
authors.initials: N
authors.lastname: Herrfurth
authors.affiliation: Institute of Medical Biometry and Epidemiology, Philipps-University of Marburg, Marburg, Germany.
authors.forename: Ivonne
authors.initials: I
authors.lastname: Jarick
authors.affiliation: Institute of Epidemiology, Helmholtz-Zentrum Munich, Munich, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Grallert
authors.affiliation: Institute of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.|German Center for Diabetes Research (DZD), München-Neuherberg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Schürmann
authors.affiliation: German Center for Diabetes Research (DZD), München-Neuherberg, Germany.|Institute of Pathobiochemistry, German Diabetes Center and German Center for Diabetes Research, Düsseldorf, Germany.
authors.forename: Hadi
authors.initials: H
authors.lastname: Al-Hasani
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, Essen, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Hebebrand
authors.affiliation: Nutrigenomics and Gene Regulation, Max-Planck-Institute for Molecular Genetics, Berlin, Germany.|CU Systems Medicine, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Sauer
authors.affiliation: Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, Essen, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Hinney
mesh_terms: D000293:Adolescent; D000328:Adult; D001835:Body Weight / Q000235:genetics*; D002648:Child; D003198:Computer Simulation; D004252:DNA Mutational Analysis; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D009765:Obesity / Q000235:genetics; D011786:Quality Control; D015203:Reproducibility of Results; D013851:Thinness / Q000235:genetics
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