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.
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.
Scherag
André
A
Institute for Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Essen, Germany. andre.scherag@uk-essen.de
Dina
Christian
C
Hinney
Anke
A
Vatin
Vincent
V
Scherag
Susann
S
Vogel
Carla I G
CI
Müller
Timo D
TD
Grallert
Harald
H
Wichmann
H-Erich
HE
Balkau
Beverley
B
Heude
Barbara
B
Jarvelin
Marjo-Riitta
MR
Hartikainen
Anna-Liisa
AL
Levy-Marchal
Claire
C
Weill
Jacques
J
Delplanque
Jérôme
J
Körner
Antje
A
Kiess
Wieland
W
Kovacs
Peter
P
Rayner
Nigel W
NW
Prokopenko
Inga
I
McCarthy
Mark I
MI
Schäfer
Helmut
H
Jarick
Ivonne
I
Boeing
Heiner
H
Fisher
Eva
E
Reinehr
Thomas
T
Heinrich
Joachim
J
Rzehak
Peter
P
Berdel
Dietrich
D
Borte
Michael
M
Biebermann
Heike
H
Krude
Heiko
H
Rosskopf
Dieter
D
Rimmbach
Christian
C
Rief
Winfried
W
Fromme
Tobias
T
Klingenspor
Martin
M
Schürmann
Annette
A
Schulz
Nadja
N
Nöthen
Markus M
MM
Mühleisen
Thomas W
TW
Erbel
Raimund
R
Jöckel
Karl-Heinz
KH
Moebus
Susanne
S
Boes
Tanja
T
Illig
Thomas
T
Froguel
Philippe
P
Hebebrand
Johannes
J
Meyre
David
D
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000483:Alleles; D015992:Body Mass Index; D001835:Body Weight / Q000235:genetics*; D002648:Child; D005602:France / Q000453:epidemiology; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D005858:Germany / Q000453:epidemiology; D006801:Humans; D009765:Obesity / Q000453:epidemiology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide