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, DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, 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, 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, James B. Meigs, J. Brent Richards

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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
Publication statusPublished - 29 Mar 2012
Externally publishedYes

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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., ... Richards, J. 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