Dataset Information

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

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.

SUBMITTER: Loos RJ

PROVIDER: S-EPMC2669167 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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

Loos Ruth J F RJ Lindgren Cecilia M CM Li Shengxu S Wheeler Eleanor E Zhao Jing Hua JH Prokopenko Inga I Inouye Michael M Freathy Rachel M RM Attwood Antony P AP Beckmann Jacques S JS Berndt Sonja I SI Jacobs Kevin B KB Chanock Stephen J SJ Hayes Richard B RB Bergmann Sven S Bennett Amanda J AJ Bingham Sheila A SA Bochud Murielle M Brown Morris M Cauchi Stéphane S Connell John M JM Cooper Cyrus C Smith George Davey GD Day Ian I Dina Christian C De Subhajyoti S Dermitzakis Emmanouil T ET Doney Alex S F AS Elliott Katherine S KS Elliott Paul P Evans David M DM Sadaf Farooqi I I Froguel Philippe P Ghori Jilur J Groves Christopher J CJ Gwilliam Rhian R Hadley David D Hall Alistair S AS Hattersley Andrew T AT Hebebrand Johannes J Heid Iris M IM Lamina Claudia C Gieger Christian C Illig Thomas T Meitinger Thomas T Wichmann H-Erich HE Herrera Blanca B Hinney Anke A Hunt Sarah E SE Jarvelin Marjo-Riitta MR Johnson Toby T Jolley Jennifer D M JD Karpe Fredrik F Keniry Andrew A Khaw Kay-Tee KT Luben Robert N RN Mangino Massimo M Marchini Jonathan J McArdle Wendy L WL McGinnis Ralph R Meyre David D Munroe Patricia B PB Morris Andrew D AD Ness Andrew R AR Neville Matthew J MJ Nica Alexandra C AC Ong Ken K KK O'Rahilly Stephen S Owen Katharine R KR Palmer Colin N A CN Papadakis Konstantinos K Potter Simon S Pouta Anneli A Qi Lu L Randall Joshua C JC Rayner Nigel W NW Ring Susan M SM Sandhu Manjinder S MS Scherag André A Sims Matthew A MA Song Kijoung K Soranzo Nicole N Speliotes Elizabeth K EK Syddall Holly E HE Teichmann Sarah A SA Timpson Nicholas J NJ Tobias Jonathan H JH Uda Manuela M Vogel Carla I Ganz CI Wallace Chris C Waterworth Dawn M DM Weedon Michael N MN Willer Cristen J CJ Wraight Yuan Xin X Zeggini Eleftheria E Hirschhorn Joel N JN Strachan David P DP Ouwehand Willem H WH Caulfield Mark J MJ Samani Nilesh J NJ Frayling Timothy M TM Vollenweider Peter P Waeber Gerard G Mooser Vincent V Deloukas Panos P McCarthy Mark I MI Wareham Nicholas J NJ Barroso Inês I Jacobs Kevin B KB Chanock Stephen J SJ Hayes Richard B RB Lamina Claudia C Gieger Christian C Illig Thomas T Meitinger Thomas T Wichmann H-Erich HE Kraft Peter P Hankinson Susan E SE Hunter David J DJ Hu Frank B FB Lyon Helen N HN Voight Benjamin F BF Ridderstrale Martin M Groop Leif L Scheet Paul P Sanna Serena S Abecasis Goncalo R GR Albai Giuseppe G Nagaraja Ramaiah R Schlessinger David D Jackson Anne U AU Tuomilehto Jaakko J Collins Francis S FS Boehnke Michael M Mohlke Karen L KL

Nature genetics 20080504 6

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 ...[more]

PMID: 18454148

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Project description:BackgroundPrevious genome-wide association studies for type 2 diabetes susceptibility genes have confirmed that a common variant, rs9939609, in the fat mass and obesity associated (FTO) gene region is associated with body mass index (BMI) in European children and adults. A significant association of the same risk allele has been described in Asian adult populations, but the results are conflicting. In addition, no replication studies have been conducted in children and adolescents of Asian ancestry.MethodsA population-based survey was carried out among 3503 children and adolescents (6-18 years of age) in Beijing, China, including 1229 obese and 2274 non-obese subjects. We investigated the association of rs9939609 with BMI and the risk of obesity. In addition, we tested the association of rs9939609 with weight, height, waist circumference, waist-to-height ratio, fat mass percentage, birth weight, blood pressure and related metabolic traits.ResultsWe found significant associations of rs9939609 variant with weight, BMI, BMI standard deviation score (BMI-SDS), waist circumference, waist-to-height ratio, and fat mass percentage in children and adolescents (p for trend = 3.29 x 10-5, 1.39 x 10-6, 3.76 x 10-6, 2.26 x 10-5, 1.94 x 10-5, and 9.75 x 10-5, respectively). No significant associations were detected with height, birth weight, systolic and diastolic blood pressure and related metabolic traits such as total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol and fasting plasma glucose (all p > 0.05). Each additional copy of the rs9939609 A allele was associated with a BMI increase of 0.79 [95% Confidence interval (CI) 0.47 to 1.10] kg/m2, equivalent to 0.25 (95%CI 0.14 to 0.35) BMI-SDS units. This rs9939609 variant is significantly associated with the risk of obesity under an additive model [Odds ratio (OR) = 1.29, 95% CI 1.11 to 1.50] after adjusting for age and gender. Moreover, an interaction between the FTO rs9939609 genotype and physical activity (p < 0.001) was detected on BMI levels, the effect of rs9939609-A allele on BMI being (0.95 +/- 0.10), (0.77 +/- 0.08) and (0.67 +/- 0.05) kg/m2, for subjects who performed low, moderate and severe intensity physical activity.ConclusionThe FTO rs9939609 variant is strongly associated with BMI and the risk of obesity in a population of children and adolescents in Beijing, China.

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

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

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