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, Consortium DIAGRAM+ Consortium, Consortium MAGIC Consortium, Investigators GLGC Investigators, Consortium MuTHER Consortium, James G. Wilson, Solomon Musani, Xiuqing Guo, Toby Johnson, Robert Semple, Tanya M. Teslovich, Matthew A. Allison, 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, Jose C. Florez, 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, Josee Dupuis, J. Brent Richards, Benjamin F. Voight, Laura J. Scott, Valgerdur Steinthorsdottir, Andrew P. Morris, 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, Claudia Langenberg, Oliver M. Hofmann, Josée Dupuis, Lu Qi, 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, David J. Couper, 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, Norman Klopp, 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, John R B Perry, 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, Francis S. Collins, Anna L. Gloyn, Ulf Gyllensten, Torben Hansen, Winston A. Hide, Graham A. Hitman, Albert Hofman, David J. Hunter, Kristian Hveem, Markku Laakso, Karen L. Mohlke, Andrew D. Morris, Colin N A Palmer, Peter P. Pramstaller, Igor Rudan, Eric Sijbrands, Lincoln D. Stein, Jaakko Tuomilehto, Andre Uitterlinden, Mark Walker, Nicholas J. Wareham, Richard M. Watanabe, Goncalo R. Abecasis, Bernhard O. Boehm, Harry Campbell, Mark J. Daly, Andrew T. Hattersley, Frank B. Hu, James B. Meigs, James S. Pankow, Oluf Pedersen, H. Erich Wichmann, Inês Barroso, Jose C. Florez, Timothy M. Frayling, 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, Josée Dupuis, Claudia Langenberg, Inga Prokopenko, Richa Saxena, Nicole Soranzo, Anne U. Jackson, Eleanor Wheeler, Nicole L. Glazer, Nabila Bouatia-Naji, Anna L. Gloyn, Cecilia M. Lindgren, Reedik Mägi, Andrew P. Morris, Joshua Randall, Toby Johnson, Paul Elliott, Denis Rybin, Gudmar Thorleifsson, Valgerdur Steinthorsdottir, Peter Henneman, Harald Grallert, Abbas Dehghan, Jouke Jan Hottenga, Christopher S. Franklin, Pau Navarro, Kijoung Song, Anuj Goel, John R B Perry, Josephine M. Egan, Taina Lajunen, Niels Grarup, Thomas Sparsø, Alex Doney, Benjamin F. Voight, Heather M. Stringham, Man Li, Stavroula Kanoni, Peter Shrader, Christine Cavalcanti-Proença, Meena Kumari, Lu Qi, Nicholas J. Timpson, Christian Gieger, Carina Zabena, Ghislain Rocheleau, Erik Ingelsson, Ping An, Jeffrey O’Connell, Jian’an Luan, Amanda Elliott, Steven A. McCarroll, Felicity Payne, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Kristin Ardlie, Yavuz Ariyurek, Beverley Balkau, Philip Barter, John P. Beilby, Yoav Ben-Shlomo, Rafn Benediktsson, Amanda J. Bennett, Sven Bergmann, Murielle Bochud, Eric Boerwinkle, Amélie Bonnefond, Lori L. Bonnycastle, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J. Bumpstead, Guillaume Charpentier, Yii Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J M Coin, Matthew N. Cooper, Marilyn Cornelis, Gabe Crawford, Laura Crisponi, Ian N M Day, Eco J C de Geus, Jerome Delplanque, Christian Dina, Michael R. Erdos, Annette C. Fedson, Antje Fischer-Rosinsky, Nita G. Forouhi, Caroline S. Fox, Rune Frants, Maria Grazia Franzosi, Pilar Galan, Mark O. Goodarzi, Jürgen Graessler, Christopher J. Groves, Scott Grundy, Rhian Gwilliam, Ulf Gyllensten, Samy Hadjadj, Göran Hallmans, Naomi Hammond, Xijing Han, Anna Liisa Hartikainen, Neelam Hassanali, Caroline Hayward, Simon C. 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Frayling, Luigi Ferrucci, Augustine Kong, Unnur Thorsteinsdottir, Kari Stefansson, Cornelia M. van Duijn, Yurii S. Aulchenko, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo Riitta Jarvelin, Dawn M. Waterworth, Peter Vollenweider, Leena Peltonen, Vincent Mooser, Goncalo R. Abecasis, Nicholas J. Wareham, Robert Sladek, Philippe Froguel, Richard M. Watanabe, James B. Meigs, Leif Groop, Michael Boehnke, Mark I. McCarthy, Jose C. Florez, Inês Barroso, Tanya M. Teslovich, Kiran Musunuru, Albert V. Smith, Andrew C. Edmondson, Ioannis M. Stylianou, Masahiro Koseki, James P. Pirruccello, Samuli Ripatti, Daniel I. Chasman, Cristen J. Willer, Christopher T. Johansen, Sigrid W. Fouchier, Aaron Isaacs, Gina M. Peloso, Maja Barbalic, Sally L. Ricketts, Joshua C. Bis, Yurii S. Aulchenko, Gudmar Thorleifsson, Mary F. 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Kees Hovingh, Jouke Jan Hottenga, Albert Hofman, Andrew A. Hicks, Christian Hengstenberg, Iris M. Heid, Caroline Hayward, Aki S. Havulinna, Nicholas D. Hastie, Tamara B. Harris, Talin Haritunians, Alistair S. Hall, Ulf Gyllensten, Candace Guiducci, Leif C. Groop, Elena Gonzalez, Christian Gieger, Nelson B. Freimer, Luigi Ferrucci, Jeanette Erdmann, Paul Elliott, Kenechi G. Ejebe, Angela Döring, Anna F. Dominiczak, Serkalem Demissie, Panagiotis Deloukas, Eco J C de Geus, Ulf de Faire, Gabriel Crawford, Francis S. Collins, Yii Der I Chen, Mark J. Caulfield, Harry Campbell, Noel P. Burtt, Lori L. Bonnycastle, Dorret I. Boomsma, S. Matthijs Boekholdt, Richard N. Bergman, Inês Barroso, Stefania Bandinelli, Christie M. Ballantyne, Themistocles L. Assimes, Thomas Quertermous, David Altshuler, Mark Seielstad, Tien Y. Wong, E. Shyong Tai, Alan B. Feranil, Christopher W. Kuzawa, Linda S. Adair, Herman A. Taylor, Ingrid B. Borecki, Stacey B. Gabriel, James G. Wilson, Hilma Holm, Unnur Thorsteinsdottir, Vilmundur Gudnason, Ronald M. Krauss, Karen L. Mohlke, Jose M. Ordovas, Patricia B. Munroe, Jaspal S. Kooner, Alan R. Tall, Robert A. Hegele, John J P Kastelein, Eric E. Schadt, Jerome I. Rotter, Eric Boerwinkle, David P. Strachan, Vincent Mooser, Kari Stefansson, Muredach P. Reilly, Nilesh J. Samani, Heribert Schunkert, L. Adrienne Cupples, Manjinder S. Sandhu, PaulM Ridker

Research output: Contribution to journalArticlepeer-review

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−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
Publication statusPublished - 2012

ASJC Scopus subject areas

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

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