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

Loos, Ruth J. F., Evans, David M., Wellcome Trust Case Control Consortium, Brown, Matthew A. and Bradbury, Linda A. (2008) Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nature Genetics, 40 6: 768-775. doi:10.1038/ng.140


Author Loos, Ruth J. F.
Evans, David M.
Wellcome Trust Case Control Consortium
Brown, Matthew A.
Bradbury, Linda A.
Title Common variants near MC4R are associated with fat mass, weight and risk of obesity
Formatted title
Common variants near MC4R are associated with fat mass, weight and risk of obesity
Journal name Nature Genetics   Check publisher's open access policy
ISSN 1061-4036
1546-1718
Publication date 2008-06
Sub-type Article (original research)
DOI 10.1038/ng.140
Open Access Status
Volume 40
Issue 6
Start page 768
End page 775
Total pages 8
Editor Myles Axton
Place of publication New York, U.S.A.
Publisher Nature America
Language eng
Subject 1103 Clinical Sciences
Formatted abstract
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.
Keyword Genome-wide Association
Melacortin-4 Receptor Gene
Early-onset obesity
Frameshift mutation
Adult obesity
Expression
Deficiency
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
UQ Diamantina Institute Publications
 
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