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:10.1371/journal.pgen.1000916

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. RaynerInga 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

Lehrstuhl für Molekulare Ernährungsmedizin

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269 Zitate (Scopus)

Abstract

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 populationbased 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 = 1.85×10^-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 = 4.84×10^-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 ~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.

Originalsprache	Englisch
Fachzeitschrift	PLoS Genetics
Jahrgang	6
Ausgabenummer	4
DOIs	https://doi.org/10.1371/journal.pgen.1000916
Publikationsstatus	Veröffentlicht - Apr. 2010

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Scherag, A., Dina, C., Hinney, A., Vatin, V., Scherag, S., Vogel, C. I. G., Müller, T. D., Grallert, H., Wichmann, H. E., Balkau, B., Heude, B., Jarvelin, M. R., Hartikainen, A. L., Levy-Marchal, C., Weill, J., Delplanque, J., Körner, A., Kiess, W., Kovacs, P., ... Meyre, D. (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. PLoS Genetics, 6(4). https://doi.org/10.1371/journal.pgen.1000916

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title = "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",

abstract = "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 populationbased 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 = 1.85×10-8 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 = 4.84×10-7), 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 ~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.",

author = "Andr{\'e} Scherag and Christian Dina and Anke Hinney and Vincent Vatin and Susann Scherag and Vogel, {Carla I.G.} and M{\"u}ller, {Timo D.} and Harald Grallert and Wichmann, {H. Erich} and Beverley Balkau and Barbara Heude and Jarvelin, {Marjo Riitta} and Hartikainen, {Anna Liisa} and Claire Levy-Marchal and Jacques Weill and J{\'e}r{\^o}me Delplanque and Antje K{\"o}rner and Wieland Kiess and Peter Kovacs and Rayner, {Nigel W.} and Inga Prokopenko and McCarthy, {Mark I.} and Helmut Sch{\"a}fer and Ivonne Jarick and Heiner Boeing and Eva Fisher and Thomas Reinehr and Joachim Heinrich and Peter Rzehak and Dietrich Berdel and Michael Borte and Heike Biebermann and Heiko Krude and Dieter Rosskopf and Christian Rimmbach and Winfried Rief and Tobias Fromme and Martin Klingenspor and Annette Sch{\"u}rmann and Nadja Schulz and N{\"o}then, {Markus M.} and M{\"u}hleisen, {Thomas W.} and Raimund Erbel and J{\"o}ckel, {Karl Heinz} and Susanne Moebus and Tanja Boes and Thomas Illig and Philippe Froguel and Johannes Hebebrand and David Meyre",

year = "2010",

month = apr,

doi = "10.1371/journal.pgen.1000916",

language = "English",

volume = "6",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "4",

}

Scherag, A, Dina, C, Hinney, A, Vatin, V, Scherag, S, Vogel, CIG, Müller, TD, Grallert, H, Wichmann, HE, Balkau, B, Heude, B, Jarvelin, MR, Hartikainen, AL, Levy-Marchal, C, Weill, J, Delplanque, J, Körner, A, Kiess, W, Kovacs, P, Rayner, NW, Prokopenko, I, McCarthy, MI, Schäfer, H, Jarick, I, Boeing, H, Fisher, E, Reinehr, T, Heinrich, J, Rzehak, P, Berdel, D, Borte, M, Biebermann, H, Krude, H, Rosskopf, D, Rimmbach, C, Rief, W, Fromme, T, Klingenspor, M, Schürmann, A, Schulz, N, Nöthen, MM, Mühleisen, TW, Erbel, R, Jöckel, KH, Moebus, S, Boes, T, Illig, T, Froguel, P, Hebebrand, J & Meyre, D 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', PLoS Genetics, Jg. 6, Nr. 4. https://doi.org/10.1371/journal.pgen.1000916

TY - JOUR

T1 - 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

AU - Scherag, André

AU - Dina, Christian

AU - Hinney, Anke

AU - Vatin, Vincent

AU - Scherag, Susann

AU - Vogel, Carla I.G.

AU - Müller, Timo D.

AU - Grallert, Harald

AU - Wichmann, H. Erich

AU - Balkau, Beverley

AU - Heude, Barbara

AU - Jarvelin, Marjo Riitta

AU - Hartikainen, Anna Liisa

AU - Levy-Marchal, Claire

AU - Weill, Jacques

AU - Delplanque, Jérôme

AU - Körner, Antje

AU - Kiess, Wieland

AU - Kovacs, Peter

AU - Rayner, Nigel W.

AU - Prokopenko, Inga

AU - McCarthy, Mark I.

AU - Schäfer, Helmut

AU - Jarick, Ivonne

AU - Boeing, Heiner

AU - Fisher, Eva

AU - Reinehr, Thomas

AU - Heinrich, Joachim

AU - Rzehak, Peter

AU - Berdel, Dietrich

AU - Borte, Michael

AU - Biebermann, Heike

AU - Krude, Heiko

AU - Rosskopf, Dieter

AU - Rimmbach, Christian

AU - Rief, Winfried

AU - Fromme, Tobias

AU - Klingenspor, Martin

AU - Schürmann, Annette

AU - Schulz, Nadja

AU - Nöthen, Markus M.

AU - Mühleisen, Thomas W.

AU - Erbel, Raimund

AU - Jöckel, Karl Heinz

AU - Moebus, Susanne

AU - Boes, Tanja

AU - Illig, Thomas

AU - Froguel, Philippe

AU - Hebebrand, Johannes

AU - Meyre, David

PY - 2010/4

Y1 - 2010/4

N2 - 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 populationbased 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 = 1.85×10-8 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 = 4.84×10-7), 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 ~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.

AB - 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 populationbased 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 = 1.85×10-8 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 = 4.84×10-7), 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 ~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.

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U2 - 10.1371/journal.pgen.1000916

DO - 10.1371/journal.pgen.1000916

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SN - 1553-7390

VL - 6

JO - PLoS Genetics

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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

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