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DOI 10.1038/ng.140

Медицинская библиотека · Nature genetics · 2008

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

Loos Ruth J F, Lindgren Cecilia M, Li Shengxu, Wheeler Eleanor, Zhao Jing Hua, Prokopenko Inga, Inouye Michael, Freathy Rachel M, Attwood Antony P, Beckmann Jacques S, Berndt Sonja I, Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Jacobs Kevin B, Chanock Stephen J, Hayes Richard B, Bergmann Sven, Bennett Amanda J, Bingham Sheila A, Bochud Murielle, Brown Morris, Cauchi Stéphane, Connell John M, Cooper Cyrus, Smith George Davey, Day Ian, Dina Christian, De Subhajyoti, Dermitzakis Emmanouil T, Doney Alex S F, Elliott Katherine S, Elliott Paul, Evans David M, Sadaf Farooqi I, Froguel Philippe, Ghori Jilur, Groves Christopher J, Gwilliam Rhian, Hadley David, Hall Alistair S, Hattersley Andrew T, Hebebrand Johannes, Heid Iris M, KORA, Lamina Claudia, Gieger Christian, Illig Thomas, Meitinger Thomas, Wichmann H-Erich, Herrera Blanca, Hinney Anke, Hunt Sarah E, Jarvelin Marjo-Riitta, Johnson Toby, Jolley Jennifer D M, Karpe Fredrik, Keniry Andrew, Khaw Kay-Tee, Luben Robert N, Mangino Massimo, Marchini Jonathan, McArdle Wendy L, McGinnis Ralph, Meyre David, Munroe Patricia B, Morris Andrew D, Ness Andrew R, Neville Matthew J, Nica Alexandra C, Ong Ken K, O'Rahilly Stephen, Owen Katharine R, Palmer Colin N A, Papadakis Konstantinos, Potter Simon, Pouta Anneli, Qi Lu, Nurses' Health Study, Randall Joshua C, Rayner Nigel W, Ring Susan M, Sandhu Manjinder S, Scherag André, Sims Matthew A, Song Kijoung, Soranzo Nicole, Speliotes Elizabeth K, Diabetes Genetics Initiative, Syddall Holly E, Teichmann Sarah A, Timpson Nicholas J, Tobias Jonathan H, Uda Manuela, SardiNIA Study, Vogel Carla I Ganz, Wallace Chris, Waterworth Dawn M, Weedon Michael N, Wellcome Trust Case Control Consortium, Willer Cristen J, FUSION, Wraight, Yuan Xin, Zeggini Eleftheria, Hirschhorn Joel N, Strachan David P, Ouwehand Willem H, Caulfield Mark J, Samani Nilesh J, Frayling Timothy M, Vollenweider Peter, Waeber Gerard, Mooser Vincent, Deloukas Panos, McCarthy Mark I, Wareham Nicholas J, Barroso Inês, Jacobs Kevin B, Chanock Stephen J, Hayes Richard B, Lamina Claudia, Gieger Christian, Illig Thomas, Meitinger Thomas, Wichmann H-Erich, Kraft Peter, Hankinson Susan E, Hunter David J, Hu Frank B, Lyon Helen N, Voight Benjamin F, Ridderstrale Martin, Groop Leif, Scheet Paul, Sanna Serena, Abecasis Goncalo R, Albai Giuseppe, Nagaraja Ramaiah, Schlessinger David, Jackson Anne U, Tuomilehto Jaakko, Collins Francis S, Boehnke Michael, Mohlke Karen L

СтатьяМногоцентровое исследованиеПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПеревод в очереди

Аннотация

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.

Для цитирования: Loos Ruth J F, Lindgren Cecilia M, Li Shengxu, Wheeler Eleanor, Zhao Jing Hua, Prokopenko Inga, Inouye Michael, Freathy Rachel M, Attwood Antony P, Beckmann Jacques S, Berndt Sonja I, Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Jacobs Kevin B, Chanock Stephen J, Hayes Richard B, Bergmann Sven, Bennett Amanda J, Bingham Sheila A, Bochud Murielle, Brown Morris, Cauchi Stéphane, Connell John M, Cooper Cyrus, Smith George Davey, Day Ian, Dina Christian, De Subhajyoti, Dermitzakis Emmanouil T, Doney Alex S F, Elliott Katherine S, Elliott Paul, Evans David M, Sadaf Farooqi I, Froguel Philippe, Ghori Jilur, Groves Christopher J, Gwilliam Rhian, Hadley David, Hall Alistair S, Hattersley Andrew T, Hebebrand Johannes, Heid Iris M, KORA, Lamina Claudia, Gieger Christian, Illig Thomas, Meitinger Thomas, Wichmann H-Erich, Herrera Blanca, Hinney Anke, Hunt Sarah E, Jarvelin Marjo-Riitta, Johnson Toby, Jolley Jennifer D M, Karpe Fredrik, Keniry Andrew, Khaw Kay-Tee, Luben Robert N, Mangino Massimo, Marchini Jonathan, McArdle Wendy L, McGinnis Ralph, Meyre David, Munroe Patricia B, Morris Andrew D, Ness Andrew R, Neville Matthew J, Nica Alexandra C, Ong Ken K, O'Rahilly Stephen, Owen Katharine R, Palmer Colin N A, Papadakis Konstantinos, Potter Simon, Pouta Anneli, Qi Lu, Nurses' Health Study, Randall Joshua C, Rayner Nigel W, Ring Susan M, Sandhu Manjinder S, Scherag André, Sims Matthew A, Song Kijoung, Soranzo Nicole, Speliotes Elizabeth K, Diabetes Genetics Initiative, Syddall Holly E, Teichmann Sarah A, Timpson Nicholas J, Tobias Jonathan H, Uda Manuela, SardiNIA Study, Vogel Carla I Ganz, Wallace Chris, Waterworth Dawn M, Weedon Michael N, Wellcome Trust Case Control Consortium, Willer Cristen J, FUSION, Wraight, Yuan Xin, Zeggini Eleftheria, Hirschhorn Joel N, Strachan David P, Ouwehand Willem H, Caulfield Mark J, Samani Nilesh J, Frayling Timothy M, Vollenweider Peter, Waeber Gerard, Mooser Vincent, Deloukas Panos, McCarthy Mark I, Wareham Nicholas J, Barroso Inês, Jacobs Kevin B, Chanock Stephen J, Hayes Richard B, Lamina Claudia, Gieger Christian, Illig Thomas, Meitinger Thomas, Wichmann H-Erich, Kraft Peter, Hankinson Susan E, Hunter David J, Hu Frank B, Lyon Helen N, Voight Benjamin F, Ridderstrale Martin, Groop Leif, Scheet Paul, Sanna Serena, Abecasis Goncalo R, Albai Giuseppe, Nagaraja Ramaiah, Schlessinger David, Jackson Anne U, Tuomilehto Jaakko, Collins Francis S, Boehnke Michael, Mohlke Karen L. Common variants near MC4R are associated with fat mass, weight and risk of obesity.. Nature genetics. 2008. DOI: 10.1038/ng.140.

Предметные рубрики MeSH

AdiposityAdolescentAdultAgedAllelesAlpha-Ketoglutarate-Dependent Dioxygenase FTOBody Mass IndexBody WeightCase-Control StudiesChildChromosomes, Human, Pair 18Cohort StudiesCross-Sectional StudiesFemaleGenetic Predisposition to DiseaseGenetic VariationGenome, HumanHumansLinkage DisequilibriumMaleMeta-Analysis as TopicMiddle AgedObesityPolymorphism, Single NucleotideProteinsQuantitative Trait LociRandomized Controlled Trials as TopicReceptor, Melanocortin, Type 4
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