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Six new loci associated with body mass index highlight a neuronal influence on body weight regulation

2008; Nature Portfolio; Volume: 41; Issue: 1 Linguagem: Inglês

10.1038/ng.287

1546-1718

Cristen J. Willer, Elizabeth K. Speliotes, Ruth J. F. Loos, Shengxu Li, Cecilia M. Lindgren, Iris M. Heid, Sonja I. Berndt, Amanda L. Elliott, Anne Jackson, Claudia Lamina, Guillaume Lettre, Noha Lim, Helen N. Lyon, Steven A. McCarroll, Konstantinos Papadakis, Lu Qi, Joshua C. Randall, Rosa Maria Roccasecca, Serena Sanna, Paul Scheet, Michael N. Weedon, Eleanor Wheeler, Jing Hua Zhao, Leonie C. Jacobs, Inga Prokopenko, Nicole Soranzo, Toshiko Tanaka, Nicholas J. Timpson, Peter Almgren, Amanda J. Bennett, Richard N. Bergman, Sheila Bingham, Lori L. Bonnycastle, Matthew A. Brown, Noel L. P. Burtt, Peter S. Chines, Lachlan Coin, Francis S. Collins, John Connell, Cyrus Cooper, George Davey Smith, Elaine Dennison, Parimal Deodhar, Paul Elliott, Michael R. Erdos, Karol Estrada, David M. Evans, Lauren Gianniny, Christian Gieger, Christopher Gillson, Candace Guiducci, Rachel Hackett, David Hadley, Alistair S. Hall, Aki S. Havulinna, Johannes Hebebrand, Albert Hofman, Bo Isomaa, Kevin B. Jacobs, Toby Johnson, Pekka Jousilahti, Z Jovanović, Kay‐Tee Khaw, Peter Kraft, Mikko Kuokkanen, Johanna Kuusisto, Jaana Laitinen, Edward G. Lakatta, Jian’an Luan, Robert Luben, Massimo Mangino, Wendy L. McArdle, Thomas Meitinger, Antonella Mulas, Patricia B. Munroe, Narisu Narisu, Andy Ness, Kate Northstone, Stephen O’Rahilly, Carolin Purmann, Matthew G. Rees, Martin Ridderstråle, Susan M. Ring, Fernando Rivadeneira, A Ruokonen, Manjinder S. Sandhu, Jouko Saramies, Laura J. Scott, Angelo Scuteri, Kaisa Silander, Matthew Sims, Kijoung Song, Jonathan Stephens, Suzanne Stevens, Heather M. Stringham, Y. C. Loraine Tung, Timo T. Valle, Cornelia M. van Duijn, Karani S. Vimaleswaran, Péter Vollenweider, Gérard Waeber, Chris Wallace, Richard M. Watanabe, Dawn Waterworth, Nicholas A. Watkins, Jacqueline C.M. Witteman, Eleftheria Zeggini, Guangju Zhai, M. Carola Zillikens, David Altshuler, Mark J. Caulfield, Stephen J. Chanock, I. Sadaf Farooqi, Luigi Ferrucci, Jack M. Guralnik, Andrew T. Hattersley, Frank B. Hu, Marjo‐Riitta Järvelin, Markku Laakso, Vincent Mooser, Ken K. Ong, Willem H. Ouwehand, Veikko Salomaa, Mark M. Iles, Timothy D. Spector, Jaakko Tuomilehto, Jaakko Tuomilehto, Manuela Uda, André G. Uitterlinden, Nicholas J. Wareham, Panos Deloukas, Timothy M. Frayling, Per‐Henrik Groop, Richard B. Hayes, David J. Hunter, Karen L. Mohlke, Leena Peltonen, David Schlessinger, David P. Strachan, H-Erich Wichmann, Mark I. McCarthy, Michael Boehnke, Inês Barroso, Gonçalo R. Abecasis, Joel N. Hirschhorn,

Cancer-related molecular mechanisms research

Joel Hirschhorn and colleagues report results of a large-scale genome-wide association and replication study for obesity-related traits. The newly discovered loci are enriched for genes expressed in the central nervous system, and may thus contribute to weight gain by modulating food intake. Similar results are reported in a related study by Gudmar Thorleifsson and colleagues. Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 × 10−8): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.