Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: A multi-ethnic meta-analysis of 45,891 individuals

Zari Dastani, Marie France Hivert, Nicholas J. Timpson, Xin Yuan, Leo Pekka Lyytikäinen, Toshiko Tanaka, Andrew P. Morris, Aaron Isaacs, Kurt Lohman, Lu Qi, Stavroula Kanoni, James S. Pankow, Jonna Grimsby, Ching Ti Liu, Vincent E. Mooser, John Chambers, Nicholas J. Wareham, Claudia Langenberg, Rune Frants, Thomas W. WinklerBruce M. Psaty, Ida Chen, Jorma Viikari, Mika Kähönen, Peter P. Pramstaller, David M. Evans, Beate St. Pourcain, Andrew R. Wood, Stefania Bandinelli, Josephine M. Egan, Stefan Böhringer, Diana van Heemst, Marja Liisa Nuotio, Melissa Garcia, Margot Haun, Panos Deloukas, David J. Couper, Jose C. Florez, Consortium MAGIC Consortium, James G. Wilson, Xiuqing Guo, Toby Johnson, Tanya M. Teslovich, Ingrid Meulenbelt, George V. Dedoussis, Frank B. Hu, Yongmei Liu, Bernhard Paulweber, Timothy D. Spector, Timothy M. Frayling, George Davey Smith, David S. Siscovick, Florian Kronenberg, Cornelia van Duijn, Dawn M. Waterworth, James B. Meigs, J. Brent Richards, Benjamin F. Voight, Laura J. Scott, Valgerdur Steinthorsdottir, Christian Dina, Ryan P. Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S. Aulchenko, Gudmar Thorleifsson, Laura J. McCulloch, Teresa Ferreira, Soumya Raychaudhuri, Amanda J. Bennett, Roza Blagieva, Eric Boerwinkle, Kristina Bengtsson Boström, Suzannah Bumpstead, Noël P. Burtt, Peter S. Chines, Todd Green, Christopher J. Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Bo Isomaa, Anne U. Jackson, Augustine Kong, Man Li, Cecilia M. Lindgren, Michel Marre, Thomas Meitinger, Mario A. Morken, Katharine R. Owen, Felicity Payne, Christine Proenca, Inga Prokopenko, Michael Roden, Michael J. Sampson, Richa Saxena, Thomas Sparsø, Heather M. Stringham, Barbara Thorand, Rob M. van Dam, G. Bragi Walters, Michael N. Weedon, Stephane Cauchi, Albert Hofman, Andrew D. Morris, Eric J.G. Sijbrands, Lincoln D. Stein, Andre Uitterlinden, Richard M. Watanabe, Mark J. Daly, Leif Groop, Unnur Thorsteinsdottir, David Altshuler, Reedik Mägi, Denis Rybin, Anuj Goel, Erik Ingelsson, Jian’an Luan, Amanda Elliott, Praveen Sethupathy, Yavuz Ariyurek, Sven Bergmann, Amélie Bonnefond, Eric Brunner, Suzannah J. Bumpstead, Robert Clarke, Lachlan J.M. Coin, Ian N.M. Day, Eco J.C. de Geus, Jerome Delplanque, Nita G. Forouhi, Mark O. Goodarzi, Rhian Gwilliam, Naomi Hammond, Caroline Hayward, Simon C. Heath, Aroon D. Hingorani, Jennie Hui, Mika Kivimaki, Seppo Koskinen, Kirsten Ohm Kyvik, Debbie A. Lawlor, Yun Li, Massimo Mangino, María Teresa Martínez-Larrad, Jarred B. McAteer, Christa Meisinger, David Meyre, Braxton D. Mitchell, Silvia Naitza, Matthew J. Neville, Cristian Pattaro, Daniel Pearson, John F. Peden, Irene Pichler, Simon C. Potter, Samuli Ripatti, Fernando Rivadeneira, Olov Rolandsson, Manjinder Sandhu, Paul Scheet, Stephen J. Sharp, Gunnar Sigurðsson, Angela Silveira, Laila Simpson, Ulla Sovio, Amy Swift, Dhiraj Varma, Veronique Vitart, Peter J. Wagner, Hugh Watkins, Gonneke Willemsen, Jing Hua Zhao, Ingrid B. Borecki, Patrik K.E. Magnusson, David M. Nathan, Gordon H. Williams, Joachim Spranger, Fredrik Karpe, Manuel Serrano-Ríos, Lyle J. Palmer, Alan F. Wright, Michael Stumvoll, Jerome I. Rotter, Dorret I. Boomsma, Antonio Cao, Angelo Scuteri, David Schlessinger, Aimo Ruokonen, Marjo Riitta Jarvelin, Leena Peltonen, Kiran Musunuru, Christopher J. O’Donnell, James P. Pirruccello, Gina M. Peloso, Sally L. Ricketts, Xiaohui Li, Jong Young Lee, Kyunga Kim, Joshua D. Smith, Robert Y.L. Zee, John B. Whitfield, Ida Surakka, Juha Sinisalo, Juha Saharinen, Lynda M. Rose, Mark Rieder, Alex N. Parker, Christopher J. O’Donnell, David Masson, Nicholas G. Martin, Fabio Marroni, Robert Luben, Marja Liisa Lokki, Guillaume Lettre, Edward G. Lakatta, Inke R. König, Kay Tee Khaw, Lee M. Kaplan, A. Cecile W. Janssens, G. Kees Hovingh, Nicholas D. Hastie, Elena Gonzalez, Nelson B. Freimer, Jeanette Erdmann, Kenechi G. Ejebe, Serkalem Demissie, S. Matthijs Boekholdt, Mark Seielstad, Tien Y. Wong, Stacey B. Gabriel, Vilmundur Gudnason, Muredach P. Reilly, Heribert Schunkert, L. Adrienne Cupples

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381 Scopus citations

Abstract

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8- 1.2 ×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10−4). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10−3, n = 22,044), increased triglycerides (p = 2.6×10−14, n = 93,440), increased waist-to-hip ratio (p = 1.8×10−5, n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10−3, n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL- cholesterol concentrations (p = 4.5×10−13, n = 96,748) and decreased BMI (p = 1.4×10−4, n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

Original languageEnglish
Article numbere1002607
JournalPLoS Genetics
Volume8
Issue number3
DOIs
StatePublished - 29 Mar 2012
Externally publishedYes

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