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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.

Original publication

DOI

10.1038/ng.140

Type

Journal article

Journal

Nature genetics

Publication Date

06/2008

Volume

40

Pages

768 - 775

Addresses

MRC Epidemiology Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.

Keywords

Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, KORA, Nurses' Health Study, Diabetes Genetics Initiative, SardiNIA Study, Wellcome Trust Case Control Consortium, FUSION, Chromosomes, Human, Pair 18, Humans, Obesity, Genetic Predisposition to Disease, Body Weight, Proteins, Receptor, Melanocortin, Type 4, Body Mass Index, Case-Control Studies, Cohort Studies, Cross-Sectional Studies, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Alleles, Quantitative Trait Loci, Genome, Human, Adolescent, Adult, Aged, Middle Aged, Child, Female, Male, Adiposity, Meta-Analysis as Topic, Randomized Controlled Trials as Topic, Genetic Variation, Alpha-Ketoglutarate-Dependent Dioxygenase FTO