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Common variants near MC4R are associated with fat mass, weight and risk of obesity

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Author

  • Ruth J. F. Loos
  • Cecilia M. Lindgren
  • Shengxu Li
  • Eleanor Wheeler
  • Jing Hua Zhao
  • Inga Prokopenko
  • Michael Inouye
  • Rachel M. Freathy
  • Antony P. Attwood
  • Jacques S. Beckmann
  • Sonja I. Berndt
  • Sven Bergmann
  • Amanda J. Bennett
  • Sheila A. Bingham
  • Murielle Bochud
  • Morris Brown
  • Stephane Cauchi
  • John M. Connell
  • Cyrus Cooper
  • George Davey Smith
  • Ian Day
  • Christian Dina
  • Subhajyoti De
  • Emmanouil T. Dermitzakis
  • Alex S. F. Doney
  • Katherine S. Elliott
  • Paul Elliott
  • David M. Evans
  • I. Sadaf Farooqi
  • Philippe Froguel
  • Jilur Ghori
  • Christopher J. Groves
  • Rhian Gwilliam
  • David Hadley
  • Alistair S. Hall
  • Andrew T. Hattersley
  • Johannes Hebebrand
  • Iris M. Heid
  • Blanca Herrera
  • Anke Hinney
  • Sarah E. Hunt
  • Marjo-Riitta Jarvelin
  • Toby Johnson
  • Jennifer D. M. Jolley
  • Fredrik Karpe
  • Andrew Keniry
  • Kay-Tee Khaw
  • Robert N. Luben
  • Martin Ridderstråle
  • Leif Groop
Show all

Summary, in English

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 x 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 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 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 x 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.

Department/s

Publishing year

2008

Language

English

Pages

768-775

Publication/Series

Nature Genetics

Volume

40

Issue

6

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Endocrinology and Diabetes
  • Nutrition and Dietetics

Status

Published

Research group

  • Diabetes - Clinical Obesity
  • Genomics, Diabetes and Endocrinology

ISBN/ISSN/Other

  • ISSN: 1546-1718