PLoS Genetics (Apr 2010)

Two new Loci for body-weight regulation identified in a joint analysis of genome-wide association studies for early-onset extreme obesity in French and german study groups.

  • André Scherag,
  • Christian Dina,
  • Anke Hinney,
  • Vincent Vatin,
  • Susann Scherag,
  • Carla I G Vogel,
  • Timo D Müller,
  • Harald Grallert,
  • H-Erich Wichmann,
  • Beverley Balkau,
  • Barbara Heude,
  • Marjo-Riitta Jarvelin,
  • Anna-Liisa Hartikainen,
  • Claire Levy-Marchal,
  • Jacques Weill,
  • Jérôme Delplanque,
  • Antje Körner,
  • Wieland Kiess,
  • Peter Kovacs,
  • Nigel W Rayner,
  • Inga Prokopenko,
  • Mark I McCarthy,
  • Helmut Schäfer,
  • Ivonne Jarick,
  • Heiner Boeing,
  • Eva Fisher,
  • Thomas Reinehr,
  • Joachim Heinrich,
  • Peter Rzehak,
  • Dietrich Berdel,
  • Michael Borte,
  • Heike Biebermann,
  • Heiko Krude,
  • Dieter Rosskopf,
  • Christian Rimmbach,
  • Winfried Rief,
  • Tobias Fromme,
  • Martin Klingenspor,
  • Annette Schürmann,
  • Nadja Schulz,
  • Markus M Nöthen,
  • Thomas W Mühleisen,
  • Raimund Erbel,
  • Karl-Heinz Jöckel,
  • Susanne Moebus,
  • Tanja Boes,
  • Thomas Illig,
  • Philippe Froguel,
  • Johannes Hebebrand,
  • David Meyre

DOI
https://doi.org/10.1371/journal.pgen.1000916
Journal volume & issue
Vol. 6, no. 4
p. e1000916

Abstract

Read online

Meta-analyses of population-based genome-wide association studies (GWAS) in adults have recently led to the detection of new genetic loci for obesity. Here we aimed to discover additional obesity loci in extremely obese children and adolescents. We also investigated if these results generalize by estimating the effects of these obesity loci in adults and in population-based samples including both children and adults. We jointly analysed two GWAS of 2,258 individuals and followed-up the best, according to lowest p-values, 44 single nucleotide polymorphisms (SNP) from 21 genomic regions in 3,141 individuals. After this DISCOVERY step, we explored if the findings derived from the extremely obese children and adolescents (10 SNPs from 5 genomic regions) generalized to (i) the population level and (ii) to adults by genotyping another 31,182 individuals (GENERALIZATION step). Apart from previously identified FTO, MC4R, and TMEM18, we detected two new loci for obesity: one in SDCCAG8 (serologically defined colon cancer antigen 8 gene; p = 1.85x10(-8) in the DISCOVERY step) and one between TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase gene) and MSRA (methionine sulfoxide reductase A gene; p = 4.84x10(-7)), the latter finding being limited to children and adolescents as demonstrated in the GENERALIZATION step. The odds ratios for early-onset obesity were estimated at approximately 1.10 per risk allele for both loci. Interestingly, the TNKS/MSRA locus has recently been found to be associated with adult waist circumference. In summary, we have completed a meta-analysis of two GWAS which both focus on extremely obese children and adolescents and replicated our findings in a large followed-up data set. We observed that genetic variants in or near FTO, MC4R, TMEM18, SDCCAG8, and TNKS/MSRA were robustly associated with early-onset obesity. We conclude that the currently known major common variants related to obesity overlap to a substantial degree between children and adults.