Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals..pdf (772 kB)
Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals
journal contribution
posted on 2016-04-18, 11:49 authored by Z. Dastani, M. F. Hivert, N. Timpson, J. R. Perry, X. Yuan, R. A. Scott, P. Henneman, I. M. Heid, J. R. Kizer, L. P. Lyytikäinen, C. Fuchsberger, T. Tanaka, A. P. Morris, K. Small, A. Isaacs, M. Beekman, S. Coassin, K. Lohman, L. Qi, S. Kanoni, J. S. Pankow, H. W. Uh, Y. Wu, A. Bidulescu, L. J. Rasmussen-Torvik, C. M. Greenwood, M. Ladouceur, J. Grimsby, A. K. Manning, C. T. Liu, J. Kooner, V. E. Mooser, P. Vollenweider, K. A. Kapur, J. Chambers, N. J. Wareham, C. Langenberg, R. Frants, K. Willems-Vandijk, B. A. Oostra, S. M. Willems, C. Lamina, T. W. Winkler, B. M. Psaty, R. P. Tracy, J. Brody, I. Chen, J. Viikari, M. Kähönen, P. P. Pramstaller, D. M. Evans, B. St Pourcain, N. Sattar, A. R. Wood, S. Bandinelli, O. D. Carlson, J. M. Egan, S. Böhringer, D. van Heemst, L. Kedenko, K. Kristiansson, M. L. Nuotio, B. M. Loo, T. Harris, M. Garcia, A. Kanaya, M. Haun, N. Klopp, H. E. Wichmann, P. Deloukas, E. Katsareli, D. J. Couper, B. B. Duncan, M. Kloppenburg, L. S. Adair, J. B. Borja, DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, J. G. Wilson, S. Musani, X. Guo, T. Johnson, R. Semple, T. M. Teslovich, M. A. Allison, S. Redline, S. G. Buxbaum, K. L. Mohlke, I. Meulenbelt, C. M. Ballantyne, G. V. Dedoussis, F. B. Hu, Y. Liu, B. Paulweber, T. D. Spector, P. E. Slagboom, L. Ferrucci, A. Jula, M. Perola, O. Raitakari, J. C. Florez, V. Salomaa, J. G. Eriksson, T. M. Frayling, A. A. Hicks, T. Lehtimäki, G. D. Smith, D. S. Siscovick, F. Kronenberg, C. van Duijn, R. J. Loos, D. M. Waterworth, J. B. Meigs, J. Dupuis, J. B. Richards, B. F. Voight, L. J. Scott, V. Steinthorsdottir, C. Dina, R. P. Welch, E. Zeggini, C. Huth, Y. S. Aulchenko, G. Thorleifsson, L. J. McCulloch, T. Ferreira, H. Grallert, N. Amin, G. Wu, C. J. Willer, S. Raychaudhuri, S. A. McCarroll, O. M. Hofmann, A. V. Segrè, M. van Hoek, P. Navarro, K. Ardlie, B. Balkau, R. Benediktsson, A. J. Bennett, R. Blagieva, E. Boerwinkle, L. L. Bonnycastle, K. B. Boström, B. Bravenboer, S. Bumpstead, N. P. Burtt, G. Charpentier, P. S. Chines, M. Cornelis, G. Crawford, A. S. Doney, K. S. Elliott, A. L. Elliott, M. R. Erdos, C. S. Fox, C. S. Franklin, M. Ganser, C. Gieger, N. Grarup, T. Green, S. Griffin, C. J. Groves, C. Guiducci, S. Hadjadj, N. Hassanali, C. Herder, B. Isomaa, A. U. Jackson, P. R. Johnson, T. Jørgensen, W. H. Kao, A. Kong, P. Kraft, J. Kuusisto, T. Lauritzen, M. Li, A. Lieverse, C. M. Lindgren, V. Lyssenko, M. Marre, T. Meitinger, K. Midthjell, M. A. Morken, N. Narisu, P. Nilsson, K. R. Owen, F. Payne, A. K. Petersen, C. Platou, C. Proença, I. Prokopenko, W. Rathmann, N. W. Rayner, N. R. Robertson, G. Rocheleau, M. Roden, M. J. Sampson, R. Saxena, B. M. Shields, P. Shrader, G. Sigurdsson, T. Sparsø, K. Strassburger, H. M. Stringham, Q. Sun, A. J. Swift, B. Thorand, J. Tichet, T. Tuomi, R. M. van Dam, T. W. van Haeften, T. van Herpt, J. V. van Vliet-Ostaptchouk, G. B. Walters, M. N. Weedon, C. Wijmenga, J. Witteman, R. N. Bergman, S. Cauchi, F. S. Collins, A. L. Gloyn, U. Gyllensten, T. Hansen, W. A. Hide, G. A. Hitman, A. Hofman, D. J. Hunter, K. Hveem, M. Laakso, A. D. Morris, C. N. Palmer, I. Rudan, E. Sijbrands, L. D. Stein, J. Tuomilehto, A. Uitterlinden, M. Walker, R. M. Watanabe, G. R. Abecasis, B. O. Boehm, H. Campbell, M. J. Daly, A. T. Hattersley, O. Pedersen, I. Barroso, L. Groop, R. Sladek, U. Thorsteinsdottir, J. F. Wilson, T. Illig, P. Froguel, C. M. van Duijn, K. Stefansson, D. Altshuler, M. Boehnke, M. I. McCarthy, N. Soranzo, E. Wheeler, N. L. Glazer, N. Bouatia-Naji, R. Mägi, J. Randall, P. Elliott, D. Rybin, A. Dehghan, J. J. Hottenga, K. Song, A. Goel, T. Lajunen, A. Doney, C. Cavalcanti-Proença, M. Kumari, N. J. Timpson, C. Zabena, E. Ingelsson, P. An, J. O'Connell, J. Luan, A. Elliott, R. M. Roccasecca, F. Pattou, P. Sethupathy, Y. Ariyurek, P. Barter, J. P. Beilby, Y. Ben-Shlomo, S. Bergmann, M. Bochud, A. Bonnefond, K. Borch-Johnsen, Y. Böttcher, E. Brunner, S. J. Bumpstead, Y. D. Chen, P. Chines, R. Clarke, L. J. Coin, M. N. Cooper, L. Crisponi, I. N. Day, E. J. de Geus, J. Delplanque, A. C. Fedson, A. Fischer-Rosinsky, N. G. Forouhi, M. G. Franzosi, P. Galan, M. O. Goodarzi, J. Graessler, S. Grundy, R. Gwilliam, G. Hallmans, N. Hammond, X. Han, A. L. Hartikainen, C. Hayward, S. C. Heath, S. Hercberg, D. R. Hillman, A. D. Hingorani, J. Hui, J. Hung, M. Kaakinen, J. Kaprio, Y. A. Kesaniemi, M. Kivimaki, B. Knight, S. Koskinen, P. Kovacs, K. O. Kyvik, G. M. Lathrop, D. A. Lawlor, O. Le Bacquer, C. Lecoeur, Y. Li, R. Mahley, M. Mangino, M. T. Martínez-Larrad, J. B. McAteer, R. McPherson, C. Meisinger, D. Melzer, D. Meyre, B. D. Mitchell, S. Mukherjee, S. Naitza, M. J. Neville, M. Orrù, R. Pakyz, G. Paolisso, C. Pattaro, D. Pearson, J. F. Peden, N. L. Pedersen, A. F. Pfeiffer, I. Pichler, O. Polasek, D. Posthuma, S. C. Potter, A. Pouta, M. A. Province, K. Rice, S. Ripatti, F. Rivadeneira, O. Rolandsson, A. Sandbaek, M. Sandhu, S. Sanna, A. A. Sayer, P. Scheet, U. Seedorf, S. J. Sharp, B. Shields, G. Sigurðsson, E. J. Sijbrands, A. Silveira, L. Simpson, A. Singleton, N. L. Smith, U. Sovio, A. Swift, H. Syddall, A. C. Syvänen, A. Tönjes, A. G. Uitterlinden, K. W. van Dijk, D. Varma, S. Visvikis-Siest, V. Vitart, N. Vogelzangs, G. Waeber, P. J. Wagner, A. Walley, K. L. Ward, H. Watkins, S. H. Wild, G. Willemsen, J. C. Witteman, J. W. Yarnell, D. Zelenika, B. Zethelius, G. Zhai, J. H. Zhao, M. C. Zillikens, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, I. B. Borecki, P. Meneton, P. K. Magnusson, D. M. Nathan, G. H. Williams, K. Silander, S. R. Bornstein, P. Schwarz, J. Spranger, F. Karpe, A. R. Shuldiner, C. Cooper, M. Serrano-Ríos, L. Lind, L. J. Palmer, P. W. Franks, S. Ebrahim, M. Marmot, A. F. Wright, M. Stumvoll, A. Hamsten, Procardis Consortium, T. A. Buchanan, T. T. Valle, J. I. Rotter, B. W. Penninx, D. I. Boomsma, A. Cao, A. Scuteri, D. Schlessinger, M. Uda, A. Ruokonen, M. R. Jarvelin, L. Peltonen, V. Mooser, MAGIC investigators, GLGC Consortium, K. Musunuru, A. V. Smith, A. C. Edmondson, I. M. Stylianou, M. Koseki, J. P. Pirruccello, D. I. Chasman, C. T. Johansen, S. W. Fouchier, G. M. Peloso, M. Barbalic, S. L. Ricketts, J. C. Bis, M. F. Feitosa, M. Orho-Melander, O. Melander, X. Li, Y. S. Cho, M. J. Go, Y. J. Kim, J. Y. Lee, T. Park, K. Kim, X. Sim, R. T. Ong, D. C. Croteau-Chonka, L. A. Lange, J. D. Smith, A. Ziegler, W. Zhang, R. Y. Zee, J. B. Whitfield, J. R. Thompson, I. Surakka, J. H. Smit, J. Sinisalo, J. Scott, J. Saharinen, C. Sabatti, L. M. Rose, R. Roberts, M. Rieder, A. N. Parker, G. Pare, C. J. O'Donnell, M. S. Nieminen, D. A. Nickerson, G. W. Montgomery, W. McArdle, D. Masson, N. G. Martin, F. Marroni, G. LucasCirculating 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.
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PLoS Genetics, 2012, 8 (3), e1002607Author affiliation
/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cardiovascular SciencesVersion
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PLoS GeneticsPublisher
Public Library of Scienceissn
1553-7390eissn
1553-7404Acceptance date
2012-02-03Copyright date
2012Available date
2016-04-18Publisher DOI
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http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1002607Language
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AdiponectinAfrican AmericansAsian Continental Ancestry GroupCholesterol, HDLDiabetes Mellitus, Type 2European Continental Ancestry GroupFemaleGene ExpressionGenetic Predisposition to DiseaseGenome-Wide Association StudyGlucose Tolerance TestHumansInsulin ResistanceMaleMetabolic Networks and PathwaysPolymorphism, Single NucleotideWaist-Hip Ratio
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