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 Timpson, John R.B. Perry, Xin Yuan, Robert A. Scott, Peter Henneman, Iris M. Heid, Jorge R. Kizer, Leo Pekka Lyytikäinen, Christian Fuchsberger, Toshiko Tanaka, Andrew P. Morris, Kerrin Small, Aaron Isaacs, Marian Beekman, Stefan Coassin, Kurt Lohman, Lu Qi, Stavroula KanoniJames S. Pankow, Hae Won Uh, Ying Wu, Aurelian Bidulescu, Laura J. Rasmussen-Torvik, Celia M.T. Greenwood, Martin Ladouceur, Jonna Grimsby, Alisa K. Manning, Ching Ti Liu, Jaspal Kooner, Vincent E. Mooser, Peter Vollenweider, Karen A. Kapur, John Chambers, Nicholas J. Wareham, Claudia Langenberg, Rune Frants, Ko Willems-VanDijk, Ben A. Oostra, Sara M. Willems, Claudia Lamina, Thomas W. Winkler, Bruce M. Psaty, Russell P. Tracy, Jennifer Brody, Ida Chen, Jorma Viikari, Mika Kähönen, Peter P. Pramstaller, David M. Evans, Beate St. Pourcain, Naveed Sattar, Andrew R. Wood, Stefania Bandinelli, Olga D. Carlson, Josephine M. Egan, Stefan Böhringer, Diana van Heemst, Lyudmyla Kedenko, Kati Kristiansson, Marja Liisa Nuotio, Britt Marie Loo, Tamara Harris, Melissa Garcia, Alka Kanaya, Margot Haun, Norman Klopp, H. Erich Wichmann, Panos Deloukas, Efi Katsareli, David J. Couper, Bruce B. Duncan, Margreet Kloppenburg, Linda S. Adair, Judith B. Borja, Jose C. Florez, Consortium MAGIC Consortium, Investigators GLGC Investigators, Consortium MuTHER Consortium, James G. Wilson, Solomon Musani, Xiuqing Guo, Toby Johnson, Robert Semple, Tanya M. Teslovich, Susan Redline, Sarah G. Buxbaum, Karen L. Mohlke, Ingrid Meulenbelt, Christie M. Ballantyne, George V. Dedoussis, Frank B. Hu, Yongmei Liu, Bernhard Paulweber, Timothy D. Spector, P. Eline Slagboom, Luigi Ferrucci, Antti Jula, Markus Perola, Olli Raitakari, Veikko Salomaa, Johan G. Eriksson, Timothy M. Frayling, Andrew A. Hicks, Terho Lehtimäki, George Davey Smith, David S. Siscovick, Florian Kronenberg, Cornelia van Duijn, Ruth J.F. Loos, Dawn M. Waterworth, James B. Meigs, 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, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J. Willer, Soumya Raychaudhuri, Steve A. McCarroll, Oliver M. Hofmann, Ayellet V. Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J. Bennett, Roza Blagieva, Eric Boerwinkle, Lori L. Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noël P. Burtt, Guillaume Charpentier, Peter S. Chines, Marilyn Cornelis, Gabe Crawford, Alex S.F. Doney, Katherine S. Elliott, Amanda L. Elliott, Michael R. Erdos, Caroline S. Fox, Christopher S. Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J. Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U. Jackson, Paul R.V. Johnson, Torben Jørgensen, Wen H.L. Kao, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M. Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A. Morken, Narisu Narisu, Peter Nilsson, Katharine R. Owen, Felicity Payne, Ann Kristin Petersen, Carl Platou, Christine Proenca, Inga Prokopenko, Wolfgang Rathmann, N. William Rayner, Neil R. Robertson, Ghislain Rocheleau, Michael Roden, Michael J. Sampson, Richa Saxena, Beverley M. Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Strassburger, Heather M. Stringham, Qi Sun, Amy J. Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M. van Dam, Timon W. van Haeften, Thijs van Herpt, Jana V. van Vliet-Ostaptchouk, G. Bragi Walters, Michael N. Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N. Bergman, Stephane Cauchi, Anna L. Gloyn, Ulf Gyllensten, Torben Hansen, Winston A. Hide, Graham A. Hitman, Albert Hofman, David J. Hunter, Kristian Hveem, Markku Laakso, Andrew D. Morris, Colin N.A. Palmer, Igor Rudan, Eric Sijbrands, Lincoln D. Stein, Jaakko Tuomilehto, Andre Uitterlinden, Mark Walker, Richard M. Watanabe, Goncalo R. Abecasis, Bernhard O. Boehm, Harry Campbell, Mark J. Daly, Andrew T. Hattersley, Oluf Pedersen, Inês Barroso, Leif Groop, Rob Sladek, Unnur Thorsteinsdottir, James F. Wilson, Thomas Illig, Philippe Froguel, Cornelia M. van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I. McCarthy, T. David, Nicole Soranzo, Eleanor Wheeler, Nicole L. Glazer, Nabila Bouatia-Naji, Reedik Mägi, Joshua Randall, Paul Elliott, Denis Rybin, Abbas Dehghan, Jouke Jan Hottenga, Anuj Goel, Taina Lajunen, Alex Doney, Christine Cavalcanti-Proença, Meena Kumari, Nicholas J. Timpson, Carina Zabena, Erik Ingelsson, Ping An, Jeffrey O'Connell, Jian’an Luan, Amanda Elliott, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Yavuz Ariyurek, Philip Barter, John P. Beilby, Yoav Ben-Shlomo, Sven Bergmann, Murielle Bochud, Amélie Bonnefond, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J. Bumpstead, Yii Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J.M. Coin, Matthew N. Cooper, Kijoung Song, Ian N.M. Day, Eco J.C. de Geus, Jerome Delplanque, Annette C. Fedson, Antje Fischer-Rosinsky, Nita G. Forouhi, Maria Grazia Franzosi, Pilar Galan, Mark O. Goodarzi, Jürgen Graessler, Scott Grundy, Rhian Gwilliam, Göran Hallmans, Naomi Hammond, Xijing Han, Anna Liisa Hartikainen, Caroline Hayward, Simon C. Heath, Serge Hercberg, David R. Hillman, Aroon D. Hingorani, Jennie Hui, Joe Hung, Marika Kaakinen, Jaakko Kaprio, Y. Antero Kesaniemi, Mika Kivimaki, Beatrice Knight, Seppo Koskinen, Peter Kovacs, Kirsten Ohm Kyvik, GMark Lathrop, Debbie A. Lawlor, Olivier Le Bacquer, Cécile Lecoeur, Yun Li, Robert Mahley, Massimo Mangino, María Teresa Martínez-Larrad, Jarred B. McAteer, Ruth McPherson, Christa Meisinger, David Melzer, David Meyre, Braxton D. Mitchell, Sutapa Mukherjee, Silvia Naitza, Matthew J. Neville, Marco Orrù, Ruth Pakyz, Giuseppe Paolisso, Cristian Pattaro, Daniel Pearson, John F. Peden, Nancy L. Pedersen, Andreas F.H. Pfeiffer, Irene Pichler, Ozren Polasek, Danielle Posthuma, Simon C. Potter, Anneli Pouta, Michael A. Province, Kenneth Rice, Samuli Ripatti, Fernando Rivadeneira, Olov Rolandsson, Annelli Sandbaek, Manjinder Sandhu, Serena Sanna, Avan Aihie Sayer, Paul Scheet, Udo Seedorf, Stephen J. Sharp, Beverley Shields, Gunnar Sigurðsson, Eric J.G. Sijbrands, Angela Silveira, Laila Simpson, Andrew Singleton, Nicholas L. Smith, Ulla Sovio, Amy Swift, Holly Syddall, Ann Christine Syvänen, Anke Tönjes, André G. Uitterlinden, Ko Willems van Dijk, Dhiraj Varma, Sophie Visvikis-Siest, Veronique Vitart, Nicole Vogelzangs, Gérard Waeber, Peter J. Wagner, Andrew Walley, GBragi Walters, Kim L. Ward, Hugh Watkins, Sarah H. Wild, Gonneke Willemsen, John W.G. Yarnell, Diana Zelenika, Björn Zethelius, Guangju Zhai, Jing Hua Zhao, M. Carola Zillikens, Ingrid B. Borecki, Pierre Meneton, Patrik K.E. Magnusson, David M. Nathan, Gordon H. Williams, Kaisa Silander, Stefan R. Bornstein, Peter Schwarz, Joachim Spranger, Fredrik Karpe, Alan R. Shuldiner, Cyrus Cooper, Manuel Serrano-Ríos, Lars Lind, Lyle J. Palmer, Paul W. Franks, Michael Marmot, Alan F. Wright, Michael Stumvoll, Anders Hamsten, Thomas A. Buchanan, Timo T. Valle, Jerome I. Rotter, Brenda W.J.H. Penninx, Dorret I. Boomsma, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo Riitta Jarvelin, Leena Peltonen, Vincent Mooser, Kiran Musunuru, James P. Pirruccello, Daniel I. Chasman, Robert Y.L. Zee, Christopher J. O’Donnell, Paul M. Ridker, Masahiro Koseki, James P. Pirruccello, Christopher T. Johansen, Sigrid W. Fouchier, Daniel I. Chasman, Maja Barbalic, Sally L. Ricketts, Joshua C. Bis, Mary F. Feitosa, Marju Orho-Melander, Olle Melander, Xiaohui Li, Yoon Shin Cho, Min Jin Go, Young Jin Kim, Jong Young Lee, Taesung Park, Kyunga Kim, Xueling Sim, Rick Twee Hee Ong, Damien C. Croteau-Chonka, Leslie A. Lange, Joshua D. Smith, Andreas Ziegler, Weihua Zhang, Robert Y.L. Zee, Jacqueline C.M. Witteman, John B. Whitfield, John R. Thompson, Ida Surakka, Johannes H. Smit, Juha Sinisalo, James Scott, Juha Saharinen, Chiara Sabatti, Lynda M. Rose, Robert Roberts, Mark Rieder, Alex N. Parker, Guillaume Pare, Christopher J. O’Donnell, Markku S. Nieminen, Deborah A. Nickerson, Grant W. Montgomery, Wendy McArdle, David Masson, Nicholas G. Martin, Fabio Marroni, Gavin Lucas, Robert Luben, Marja Liisa Lokki, Guillaume Lettre, Lenore J. Launer, Edward G. Lakatta, Reijo Laaksonen, Inke R. König, Kay Tee Khaw, Lee M. Kaplan, Åsa Johansson, A. Cecile W. Janssens, Wilmar Igl, G. Kees Hovingh, Christian Hengstenberg, Aki S. Havulinna, Nicholas D. Hastie, Tamara B. Harris, Talin Haritunians, Alistair S. Hall, Leif C. Groop, Elena Gonzalez, Nelson B. Freimer, Jeanette Erdmann, Kenechi G. Ejebe, Angela Döring, Anna F. Dominiczak, Serkalem Demissie, Ulf de Faire, Mark J. Caulfield, S. Matthijs Boekholdt, Themistocles L. Assimes, Thomas Quertermous, Mark Seielstad, Tien Y. Wong, E. Shyong Tai, Alan B. Feranil, Christopher W. Kuzawa, Stacey B. Gabriel, Hilma Holm, Vilmundur Gudnason, Herman A. Taylor, Ronald M. Krauss, Jose M. Ordovas, Jaspal S. Kooner, Alan R. Tall, Robert A. Hegele, John J.P. Kastelein, Eric E. Schadt, David P. Strachan, Muredach P. Reilly, Nilesh J. Samani, Heribert Schunkert, L. Adrienne Cupples, Manjinder S. Sandhu, Paul M. Ridker, Patricia B. Munroe

Research output: Contribution to journalArticle

269 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 (US)
Article numbere1002607
JournalPLoS genetics
Volume8
Issue number3
DOIs
StatePublished - Mar 29 2012

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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    Dastani, Z., Hivert, M. F., Timpson, N., Perry, J. R. B., Yuan, X., Scott, R. A., Henneman, P., Heid, I. M., Kizer, J. R., Lyytikäinen, L. P., Fuchsberger, C., Tanaka, T., Morris, A. P., Small, K., Isaacs, A., Beekman, M., Coassin, S., Lohman, K., Qi, L., ... Munroe, P. B. (2012). Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: A multi-ethnic meta-analysis of 45,891 individuals. PLoS genetics, 8(3), [e1002607]. https://doi.org/10.1371/journal.pgen.1002607