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

TitleCommon variants near MC4R are associated with fat mass, weight and risk of obesity.
Publication TypeJournal Article
Year of Publication2008
AuthorsLoos, RJF, Lindgren, CM, Li, S, Wheeler, E, Zhao, JHua, Prokopenko, I, Inouye, M, Freathy, RM, Attwood, AP, Beckmann, JS, Berndt, SI, Jacobs, KB, Chanock, SJ, Hayes, RB, Bergmann, S, Bennett, AJ, Bingham, SA, Bochud, M, Brown, M, Cauchi, S, Connell, JM, Cooper, C, Smith, GDavey, Day, I, Dina, C, De, S, Dermitzakis, ET, Doney, ASF, Elliott, KS, Elliott, P, Evans, DM, I Farooqi, S, Froguel, P, Ghori, J, Groves, CJ, Gwilliam, R, Hadley, D, Hall, AS, Hattersley, AT, Hebebrand, J, Heid, IM, Lamina, C, Gieger, C, Illig, T, Meitinger, T, Wichmann, H-E, Herrera, B, Hinney, A, Hunt, SE, Jarvelin, M-R, Johnson, T, Jolley, JDM, Karpe, F, Keniry, A, Khaw, K-T, Luben, RN, Mangino, M, Marchini, J, McArdle, WL, McGinnis, R, Meyre, D, Munroe, PB, Morris, AD, Ness, AR, Neville, MJ, Nica, AC, Ong, KK, O'Rahilly, S, Owen, KR, Palmer, CNA, Papadakis, K, Potter, S, Pouta, A, Qi, L, Randall, JC, Rayner, NW, Ring, SM, Sandhu, MS, Scherag, A, Sims, MA, Song, K, Soranzo, N, Speliotes, EK, Syddall, HE, Teichmann, SA, Timpson, NJ, Tobias, JH, Uda, M, Vogel, CIGanz, Wallace, C, Waterworth, DM, Weedon, MN, Willer, CJ, Yuan, X, Zeggini, E, Hirschhorn, JN, Strachan, DP, Ouwehand, WH, Caulfield, MJ, Samani, NJ, Frayling, TM, Vollenweider, P, Waeber, G, Mooser, V, Deloukas, P, McCarthy, MI, Wareham, NJ, Barroso, I, Jacobs, KB, Chanock, SJ, Hayes, RB, Lamina, C, Gieger, C, Illig, T, Meitinger, T, Wichmann, H-E, Kraft, P, Hankinson, SE, Hunter, DJ, Hu, FB, Lyon, HN, Voight, BF, Ridderstrale, M, Groop, L, Scheet, P, Sanna, S, Abecasis, GR, Albai, G, Nagaraja, R, Schlessinger, D, Jackson, AU, Tuomilehto, J, Collins, FS, Boehnke, M, Mohlke, KL
Corporate Authors, , , , , ,
JournalNat Genet
Volume40
Issue6
Pagination768-75
Date Published2008 Jun
ISSN1546-1718
KeywordsAdiposity, Adolescent, Adult, Aged, Alleles, Body Mass Index, Body Weight, Case-Control Studies, Child, Chromosomes, Human, Pair 18, Cohort Studies, Cross-Sectional Studies, Female, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, Humans, Linkage Disequilibrium, Male, Meta-Analysis as Topic, Middle Aged, Obesity, Polymorphism, Single Nucleotide, Proteins, Quantitative Trait Loci, Randomized Controlled Trials as Topic, Receptor, Melanocortin, Type 4
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 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.

DOI10.1038/ng.140
Alternate JournalNat. Genet.
Citation Key10.1038/ng.140
PubMed ID18454148
PubMed Central IDPMC2669167
Grant List068545 / / Wellcome Trust / United Kingdom
076113 / / Wellcome Trust / United Kingdom
077016 / / Wellcome Trust / United Kingdom
079557 / / Wellcome Trust / United Kingdom
084713 / / Wellcome Trust / United Kingdom
090532 / / Wellcome Trust / United Kingdom
DHCS/07/07/008 / / Department of Health / United Kingdom
F32 DK079466 / DK / NIDDK NIH HHS / United States
F32 DK079466-01 / DK / NIDDK NIH HHS / United States
G0000934 / / Medical Research Council / United Kingdom
G0000934(68341) / / Medical Research Council / United Kingdom
G0400874 / / Medical Research Council / United Kingdom
G0401527 / / Medical Research Council / United Kingdom
G0600331 / / Medical Research Council / United Kingdom
G0600705 / / Medical Research Council / United Kingdom
G0601261 / / Medical Research Council / United Kingdom
G0701863 / / Medical Research Council / United Kingdom
G9521010 / / Medical Research Council / United Kingdom
G9521010(63660) / / Medical Research Council / United Kingdom
G9824984 / / Medical Research Council / United Kingdom
G9828345 / / Medical Research Council / United Kingdom
K23 DK080145 / DK / NIDDK NIH HHS / United States
K23 DK080145-01 / DK / NIDDK NIH HHS / United States
MC_QA137934 / / Medical Research Council / United Kingdom
MC_U105161047 / / Medical Research Council / United Kingdom
MC_U105630924 / / Medical Research Council / United Kingdom
MC_U106179472 / / Medical Research Council / United Kingdom
MC_U106188470 / / Medical Research Council / United Kingdom
MC_U147585824 / / Medical Research Council / United Kingdom
MC_UP_A620_1014 / / Medical Research Council / United Kingdom
P30 DK040561 / DK / NIDDK NIH HHS / United States
P30 DK040561-13 / DK / NIDDK NIH HHS / United States
R01 DK072193 / DK / NIDDK NIH HHS / United States
T32 DK007191 / DK / NIDDK NIH HHS / United States
U.1475.00.002.00001.01 (85824) / / Medical Research Council / United Kingdom
/ / British Heart Foundation / United Kingdom
/ / Cancer Research UK / United Kingdom
/ / Medical Research Council / United Kingdom
/ / Wellcome Trust / United Kingdom