TY - JOUR
T1 - Common variants near MC4R are associated with fat mass, weight and risk of obesity
AU - The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial
AU - KORA
AU - Nurses' Health Study
AU - Diabetes Genetics Initiative
AU - The SardiNIA Study
AU - The Wellcome Trust Case Control Consortium
AU - FUSION
AU - Loos, Ruth J.F.
AU - Lindgren, Cecilia M.
AU - Li, Shengxu
AU - Wheeler, Eleanor
AU - Hua Zhao, Jing
AU - Prokopenko, Inga
AU - Inouye, Michael
AU - Freathy, Rachel M.
AU - Attwood, Antony P.
AU - Beckmann, Jacques S.
AU - Berndt, Sonja I.
AU - Bergmann, Sven
AU - Bennett, Amanda J.
AU - Bingham, Sheila A.
AU - Bochud, Murielle
AU - Brown, Morris
AU - Cauchi, Stéphane
AU - Connell, John M.
AU - Cooper, Cyrus
AU - Davey Smith, George
AU - Day, Ian
AU - Dina, Christian
AU - De, Subhajyoti
AU - Dermitzakis, Emmanouil T.
AU - Doney, Alex S.F.
AU - Elliott, Katherine S.
AU - Elliott, Paul
AU - Evans, David M.
AU - Sadaf Farooqi, I.
AU - Froguel, Philippe
AU - Ghori, Jilur
AU - Groves, Christopher J.
AU - Gwilliam, Rhian
AU - Hadley, David
AU - Hall, Alistair S.
AU - Hattersley, Andrew T.
AU - Hebebrand, Johannes
AU - Heid, Iris M.
AU - Herrera, Blanca
AU - Hinney, Anke
AU - Hunt, Sarah E.
AU - Jarvelin, Marjo Riitta
AU - Johnson, Toby
AU - Jolley, Jennifer D.M.
AU - Karpe, Fredrik
AU - Keniry, Andrew
AU - Khaw, Kay Tee
AU - Luben, Robert N.
AU - Mangino, Massimo
AU - Scheet, Paul
N1 - Funding Information:
We acknowledge support of the UK Medical Research Council, the Wellcome Trust, Diabetes UK, Cancer Research United Kingdom, BDA Research, UK National Health Service Research and Development, the European Commission, the Academy of Finland, the British Heart Foundation, the National Institutes of Health, the Novartis Institutes for BioMedical Research, GlaxoSmithKline and the German National Genome Research Net. Personal support was provided by NIDDK (E.K.S., H.N.L., J.N.H., F.S.C.), the Wellcome Trust (A.T.H., E.Z.), Diabetes UK (R.M.F.), the Throne-Holst Foundation (C.M.L.), the Vandervell Foundation (M.N.W.), American Diabetes Association (C.J.W.), Unilever Corporate Research (S.L.) and the British Heart foundation (N.J.S).
PY - 2008/6/1
Y1 - 2008/6/1
N2 - To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 × 10-6) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 × 10 -15) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 × 10-8). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 × 10-11). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 × 10-4). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.
AB - To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 × 10-6) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 × 10 -15) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 × 10-8). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 × 10-11). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 × 10-4). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.
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U2 - 10.1038/ng.140
DO - 10.1038/ng.140
M3 - Article
C2 - 18454148
AN - SCOPUS:44349142294
SN - 1061-4036
VL - 40
SP - 768
EP - 775
JO - Nature Genetics
JF - Nature Genetics
IS - 6
ER -