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 Kanoni; James 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

doi:10.1371/journal.pgen.1002607

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

Research output: Contribution to journal › Article

272 Citations (Scopus)

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 language	English
Article number	e1002607
Journal	PloS Genetics
Volume	8
Issue number	3
DOIs	https://doi.org/10.1371/journal.pgen.1002607
Publication status	Published - 29 Mar 2012
Externally published	Yes

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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

Dastani, Zari ; Hivert, Marie France ; Timpson, Nicholas ; Perry, John R.B. ; Yuan, Xin ; Scott, Robert A. ; Henneman, Peter ; Heid, Iris M. ; Kizer, Jorge R. ; Lyytikäinen, Leo Pekka ; Fuchsberger, Christian ; Tanaka, Toshiko ; Morris, Andrew P. ; Small, Kerrin ; Isaacs, Aaron ; Beekman, Marian ; Coassin, Stefan ; Lohman, Kurt ; Qi, Lu ; Kanoni, Stavroula ; Pankow, James S. ; Uh, Hae Won ; Wu, Ying ; Bidulescu, Aurelian ; Rasmussen-Torvik, Laura J. ; Greenwood, Celia M.T. ; Ladouceur, Martin ; Grimsby, Jonna ; Manning, Alisa K. ; Liu, Ching Ti ; Kooner, Jaspal ; Mooser, Vincent E. ; Vollenweider, Peter ; Kapur, Karen A. ; Chambers, John ; Wareham, Nicholas J. ; Langenberg, Claudia ; Frants, Rune ; Willems-VanDijk, Ko ; Oostra, Ben A. ; Willems, Sara M. ; Lamina, Claudia ; Winkler, Thomas W. ; Psaty, Bruce M. ; Tracy, Russell P. ; Brody, Jennifer ; Chen, Ida ; Viikari, Jorma ; Kähönen, Mika ; Pramstaller, Peter P. ; Evans, David M. ; St. Pourcain, Beate ; Sattar, Naveed ; Wood, Andrew R. ; Bandinelli, Stefania ; Carlson, Olga D. ; Egan, Josephine M. ; Böhringer, Stefan ; van Heemst, Diana ; Kedenko, Lyudmyla ; Kristiansson, Kati ; Nuotio, Marja Liisa ; Loo, Britt Marie ; Harris, Tamara ; Garcia, Melissa ; Kanaya, Alka ; Haun, Margot ; Klopp, Norman ; Wichmann, H. Erich ; Deloukas, Panos ; Katsareli, Efi ; Couper, David J. ; Duncan, Bruce B. ; Kloppenburg, Margreet ; Adair, Linda S. ; Borja, Judith B. ; DIAGRAM+ Consortium ; MAGIC Consortium ; GLGC Investigators ; MuTHER Consortium ; Wilson, James G. ; Musani, Solomon ; Guo, Xiuqing ; Johnson, Toby ; Semple, Robert ; Teslovich, Tanya M. ; Redline, Susan ; Buxbaum, Sarah G. ; Mohlke, Karen L. ; Meulenbelt, Ingrid ; Ballantyne, Christie M. ; Dedoussis, George V. ; Hu, Frank B. ; Liu, Yongmei ; Paulweber, Bernhard ; Spector, Timothy D. ; Slagboom, P. Eline ; Ferrucci, Luigi ; Jula, Antti ; Perola, Markus ; Raitakari, Olli ; Florez, Jose C. ; Salomaa, Veikko ; Eriksson, Johan G. ; Frayling, Timothy M. ; Hicks, Andrew A. ; Lehtimäki, Terho ; Smith, George Davey ; Siscovick, David S. ; Kronenberg, Florian ; van Duijn, Cornelia ; Loos, Ruth J.F. ; Waterworth, Dawn M. ; Meigs, James B. ; Meigs, James B. ; Richards, J. Brent. / Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits : A multi-ethnic meta-analysis of 45,891 individuals. In: PloS Genetics. 2012 ; Vol. 8, No. 3.

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

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.",

author = "Zari Dastani and Hivert, {Marie France} and Nicholas Timpson and Perry, {John R.B.} and Xin Yuan and Scott, {Robert A.} and Peter Henneman and Heid, {Iris M.} and Kizer, {Jorge R.} and Lyytik{\"a}inen, {Leo Pekka} and Christian Fuchsberger and Toshiko Tanaka and Morris, {Andrew P.} and Kerrin Small and Aaron Isaacs and Marian Beekman and Stefan Coassin and Kurt Lohman and Lu Qi and Stavroula Kanoni and Pankow, {James S.} and Uh, {Hae Won} and Ying Wu and Aurelian Bidulescu and Rasmussen-Torvik, {Laura J.} and Greenwood, {Celia M.T.} and Martin Ladouceur and Jonna Grimsby and Manning, {Alisa K.} and Liu, {Ching Ti} and Jaspal Kooner and Mooser, {Vincent E.} and Peter Vollenweider and Kapur, {Karen A.} and John Chambers and Wareham, {Nicholas J.} and Claudia Langenberg and Rune Frants and Ko Willems-VanDijk and Oostra, {Ben A.} and Willems, {Sara M.} and Claudia Lamina and Winkler, {Thomas W.} and Psaty, {Bruce M.} and Tracy, {Russell P.} and Jennifer Brody and Ida Chen and Jorma Viikari and Mika K{\"a}h{\"o}nen and Pramstaller, {Peter P.} and Evans, {David M.} and {St. Pourcain}, Beate and Naveed Sattar and Wood, {Andrew R.} and Stefania Bandinelli and Carlson, {Olga D.} and Egan, {Josephine M.} and Stefan B{\"o}hringer and {van Heemst}, Diana and Lyudmyla Kedenko and Kati Kristiansson and Nuotio, {Marja Liisa} and Loo, {Britt Marie} and Tamara Harris and Melissa Garcia and Alka Kanaya and Margot Haun and Norman Klopp and Wichmann, {H. Erich} and Panos Deloukas and Efi Katsareli and Couper, {David J.} and Duncan, {Bruce B.} and Margreet Kloppenburg and Adair, {Linda S.} and Borja, {Judith B.} and {DIAGRAM+ Consortium} and {MAGIC Consortium} and {GLGC Investigators} and {MuTHER Consortium} and Wilson, {James G.} and Solomon Musani and Xiuqing Guo and Toby Johnson and Robert Semple and Teslovich, {Tanya M.} and Susan Redline and Buxbaum, {Sarah G.} and Mohlke, {Karen L.} and Ingrid Meulenbelt and Ballantyne, {Christie M.} and Dedoussis, {George V.} and Hu, {Frank B.} and Yongmei Liu and Bernhard Paulweber and Spector, {Timothy D.} and Slagboom, {P. Eline} and Luigi Ferrucci and Antti Jula and Markus Perola and Olli Raitakari and Florez, {Jose C.} and Veikko Salomaa and Eriksson, {Johan G.} and Frayling, {Timothy M.} and Hicks, {Andrew A.} and Terho Lehtim{\"a}ki and Smith, {George Davey} and Siscovick, {David S.} and Florian Kronenberg and {van Duijn}, Cornelia and Loos, {Ruth J.F.} and Waterworth, {Dawn M.} and Meigs, {James B.} and Meigs, {James B.} and Richards, {J. Brent} and Voight, {Benjamin F.} and Scott, {Laura J.} and Valgerdur Steinthorsdottir and Christian Dina and Welch, {Ryan P.} and Eleftheria Zeggini and Cornelia Huth and Aulchenko, {Yurii S.} and Gudmar Thorleifsson and McCulloch, {Laura J.} and Teresa Ferreira and Harald Grallert and Najaf Amin and Guanming Wu and Willer, {Cristen J.} and Soumya Raychaudhuri and McCarroll, {Steve A.} and Hofmann, {Oliver M.} and Segr{\`e}, {Ayellet V.} and {van Hoek}, Mandy and Pau Navarro and Kristin Ardlie and Beverley Balkau and Rafn Benediktsson and Bennett, {Amanda J.} and Roza Blagieva and Eric Boerwinkle and Bonnycastle, {Lori L.} and Bostr{\"o}m, {Kristina Bengtsson} and Bert Bravenboer and Suzannah Bumpstead and Burtt, {No{\"e}l P.} and Guillaume Charpentier and Chines, {Peter S.} and Marilyn Cornelis and Gabe Crawford and Doney, {Alex S.F.} and Elliott, {Katherine S.} and Elliott, {Amanda L.} and Erdos, {Michael R.} and Fox, {Caroline S.} and Franklin, {Christopher S.} and Martha Ganser and Christian Gieger and Niels Grarup and Todd Green and Simon Griffin and Groves, {Christopher J.} and Candace Guiducci and Samy Hadjadj and Neelam Hassanali and Christian Herder and Bo Isomaa and Jackson, {Anne U.} and Johnson, {Paul R.V.} and Torben J{\o}rgensen and Kao, {Wen H.L.} and Augustine Kong and Peter Kraft and Johanna Kuusisto and Torsten Lauritzen and Man Li and Aloysius Lieverse and Lindgren, {Cecilia M.} and Valeriya Lyssenko and Michel Marre and Thomas Meitinger and Kristian Midthjell and Morken, {Mario A.} and Narisu Narisu and Peter Nilsson and Owen, {Katharine R.} and Felicity Payne and Petersen, {Ann Kristin} and Carl Platou and Christine Proenca and Inga Prokopenko and Wolfgang Rathmann and Rayner, {N. William} and Robertson, {Neil R.} and Ghislain Rocheleau and Michael Roden and Sampson, {Michael J.} and Richa Saxena and Shields, {Beverley M.} and Peter Shrader and Gunnar Sigurdsson and Thomas Spars{\o} and Klaus Strassburger and Stringham, {Heather M.} and Qi Sun and Swift, {Amy J.} and Barbara Thorand and Jean Tichet and Tiinamaija Tuomi and {van Dam}, {Rob M.} and {van Haeften}, {Timon W.} and {van Herpt}, Thijs and {van Vliet-Ostaptchouk}, {Jana V.} and Walters, {G. Bragi} and Weedon, {Michael N.} and Cisca Wijmenga and Jacqueline Witteman and Bergman, {Richard N.} and Stephane Cauchi and Gloyn, {Anna L.} and Ulf Gyllensten and Torben Hansen and Hide, {Winston A.} and Hitman, {Graham A.} and Albert Hofman and Hunter, {David J.} and Kristian Hveem and Markku Laakso and Morris, {Andrew D.} and Palmer, {Colin N.A.} and Igor Rudan and Eric Sijbrands and Stein, {Lincoln D.} and Jaakko Tuomilehto and Andre Uitterlinden and Mark Walker and Watanabe, {Richard M.} and Abecasis, {Goncalo R.} and Boehm, {Bernhard O.} and Harry Campbell and Daly, {Mark J.} and Hattersley, {Andrew T.} and Oluf Pedersen and In{\^e}s Barroso and Leif Groop and Rob Sladek and Unnur Thorsteinsdottir and Wilson, {James F.} and Sutapa Mukherjee",

year = "2012",

month = mar,

day = "29",

doi = "10.1371/journal.pgen.1002607",

language = "English",

volume = "8",

journal = "PloS Genetics",

issn = "1553-7390",

number = "3",

}

Dastani, Z, Hivert, MF, Timpson, N, Perry, JRB, Yuan, X, Scott, RA, Henneman, P, Heid, IM, Kizer, JR, Lyytikäinen, LP, Fuchsberger, C, Tanaka, T, Morris, AP, Small, K, Isaacs, A, Beekman, M, Coassin, S, Lohman, K, Qi, L, Kanoni, S, Pankow, JS, Uh, HW, Wu, Y, Bidulescu, A, Rasmussen-Torvik, LJ, Greenwood, CMT, Ladouceur, M, Grimsby, J, Manning, AK, Liu, CT, Kooner, J, Mooser, VE, Vollenweider, P, Kapur, KA, Chambers, J, Wareham, NJ, Langenberg, C, Frants, R, Willems-VanDijk, K, Oostra, BA, Willems, SM, Lamina, C, Winkler, TW, Psaty, BM, Tracy, RP, Brody, J, Chen, I, Viikari, J, Kähönen, M, Pramstaller, PP, Evans, DM, St. Pourcain, B, Sattar, N, Wood, AR, Bandinelli, S, Carlson, OD, Egan, JM, Böhringer, S, van Heemst, D, Kedenko, L, Kristiansson, K, Nuotio, ML, Loo, BM, Harris, T, Garcia, M, Kanaya, A, Haun, M, Klopp, N, Wichmann, HE, Deloukas, P, Katsareli, E, Couper, DJ, Duncan, BB, Kloppenburg, M, Adair, LS, Borja, JB, DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, Wilson, JG, Musani, S, Guo, X, Johnson, T, Semple, R, Teslovich, TM, Redline, S, Buxbaum, SG, Mohlke, KL, Meulenbelt, I, Ballantyne, CM, Dedoussis, GV, Hu, FB, Liu, Y, Paulweber, B, Spector, TD, Slagboom, PE, Ferrucci, L, Jula, A, Perola, M, Raitakari, O, Florez, JC, Salomaa, V, Eriksson, JG, Frayling, TM, Hicks, AA, Lehtimäki, T, Smith, GD, Siscovick, DS, Kronenberg, F, van Duijn, C, Loos, RJF, Waterworth, DM, Meigs, JB, Meigs, JB & Richards, JB 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, vol. 8, no. 3, e1002607. https://doi.org/10.1371/journal.pgen.1002607

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits : A multi-ethnic meta-analysis of 45,891 individuals. / Dastani, Zari; Hivert, Marie France; Timpson, Nicholas; Perry, John R.B.; Yuan, Xin; Scott, Robert A.; Henneman, Peter; Heid, Iris M.; Kizer, Jorge R.; Lyytikäinen, Leo Pekka; Fuchsberger, Christian; Tanaka, Toshiko; Morris, Andrew P.; Small, Kerrin; Isaacs, Aaron; Beekman, Marian; Coassin, Stefan; Lohman, Kurt; Qi, Lu; Kanoni, Stavroula; Pankow, James S.; Uh, Hae Won; Wu, Ying; Bidulescu, Aurelian; Rasmussen-Torvik, Laura J.; Greenwood, Celia M.T.; Ladouceur, Martin; Grimsby, Jonna; Manning, Alisa K.; Liu, Ching Ti; Kooner, Jaspal; Mooser, Vincent E.; Vollenweider, Peter; Kapur, Karen A.; Chambers, John; Wareham, Nicholas J.; Langenberg, Claudia; Frants, Rune; Willems-VanDijk, Ko; Oostra, Ben A.; Willems, Sara M.; Lamina, Claudia; Winkler, Thomas W.; Psaty, Bruce M.; Tracy, Russell P.; Brody, Jennifer; Chen, Ida; Viikari, Jorma; Kähönen, Mika; Pramstaller, Peter P.; Evans, David M.; St. Pourcain, Beate; Sattar, Naveed; Wood, Andrew R.; Bandinelli, Stefania; Carlson, Olga D.; Egan, Josephine M.; Böhringer, Stefan; van Heemst, Diana; Kedenko, Lyudmyla; Kristiansson, Kati; Nuotio, Marja Liisa; Loo, Britt Marie; Harris, Tamara; Garcia, Melissa; Kanaya, Alka; Haun, Margot; Klopp, Norman; Wichmann, H. Erich; Deloukas, Panos; Katsareli, Efi; Couper, David J.; Duncan, Bruce B.; Kloppenburg, Margreet; Adair, Linda S.; Borja, Judith B.; DIAGRAM+ Consortium; MAGIC Consortium; GLGC Investigators; MuTHER Consortium; Wilson, James G.; Musani, Solomon; Guo, Xiuqing; Johnson, Toby; Semple, Robert; Teslovich, Tanya M.; Redline, Susan; Buxbaum, Sarah G.; Mohlke, Karen L.; Meulenbelt, Ingrid; Ballantyne, Christie M.; Dedoussis, George V.; Hu, Frank B.; Liu, Yongmei; Paulweber, Bernhard; Spector, Timothy D.; Slagboom, P. Eline; Ferrucci, Luigi; Jula, Antti; Perola, Markus; Raitakari, Olli; Florez, Jose C.; Salomaa, Veikko; Eriksson, Johan G.; Frayling, Timothy M.; Hicks, Andrew A.; Lehtimäki, Terho; Smith, George Davey; Siscovick, David S.; Kronenberg, Florian; van Duijn, Cornelia; Loos, Ruth J.F.; Waterworth, Dawn M.; Meigs, James B.; Meigs, James B.; Richards, J. Brent.

In: PloS Genetics, Vol. 8, No. 3, e1002607, 29.03.2012.

Research output: Contribution to journal › Article

TY - JOUR

T1 - Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits

T2 - A multi-ethnic meta-analysis of 45,891 individuals

AU - Dastani, Zari

AU - Hivert, Marie France

AU - Timpson, Nicholas

AU - Perry, John R.B.

AU - Yuan, Xin

AU - Scott, Robert A.

AU - Henneman, Peter

AU - Heid, Iris M.

AU - Kizer, Jorge R.

AU - Lyytikäinen, Leo Pekka

AU - Fuchsberger, Christian

AU - Tanaka, Toshiko

AU - Morris, Andrew P.

AU - Small, Kerrin

AU - Isaacs, Aaron

AU - Beekman, Marian

AU - Coassin, Stefan

AU - Lohman, Kurt

AU - Qi, Lu

AU - Kanoni, Stavroula

AU - Pankow, James S.

AU - Uh, Hae Won

AU - Wu, Ying

AU - Bidulescu, Aurelian

AU - Rasmussen-Torvik, Laura J.

AU - Greenwood, Celia M.T.

AU - Ladouceur, Martin

AU - Grimsby, Jonna

AU - Manning, Alisa K.

AU - Liu, Ching Ti

AU - Kooner, Jaspal

AU - Mooser, Vincent E.

AU - Vollenweider, Peter

AU - Kapur, Karen A.

AU - Chambers, John

AU - Wareham, Nicholas J.

AU - Langenberg, Claudia

AU - Frants, Rune

AU - Willems-VanDijk, Ko

AU - Oostra, Ben A.

AU - Willems, Sara M.

AU - Lamina, Claudia

AU - Winkler, Thomas W.

AU - Psaty, Bruce M.

AU - Tracy, Russell P.

AU - Brody, Jennifer

AU - Chen, Ida

AU - Viikari, Jorma

AU - Kähönen, Mika

AU - Pramstaller, Peter P.

AU - Evans, David M.

AU - St. Pourcain, Beate

AU - Sattar, Naveed

AU - Wood, Andrew R.

AU - Bandinelli, Stefania

AU - Carlson, Olga D.

AU - Egan, Josephine M.

AU - Böhringer, Stefan

AU - van Heemst, Diana

AU - Kedenko, Lyudmyla

AU - Kristiansson, Kati

AU - Nuotio, Marja Liisa

AU - Loo, Britt Marie

AU - Harris, Tamara

AU - Garcia, Melissa

AU - Kanaya, Alka

AU - Haun, Margot

AU - Klopp, Norman

AU - Wichmann, H. Erich

AU - Deloukas, Panos

AU - Katsareli, Efi

AU - Couper, David J.

AU - Duncan, Bruce B.

AU - Kloppenburg, Margreet

AU - Adair, Linda S.

AU - Borja, Judith B.

AU - DIAGRAM+ Consortium

AU - MAGIC Consortium

AU - GLGC Investigators

AU - MuTHER Consortium

AU - Wilson, James G.

AU - Musani, Solomon

AU - Guo, Xiuqing

AU - Johnson, Toby

AU - Semple, Robert

AU - Teslovich, Tanya M.

AU - Redline, Susan

AU - Buxbaum, Sarah G.

AU - Mohlke, Karen L.

AU - Meulenbelt, Ingrid

AU - Ballantyne, Christie M.

AU - Dedoussis, George V.

AU - Hu, Frank B.

AU - Liu, Yongmei

AU - Paulweber, Bernhard

AU - Spector, Timothy D.

AU - Slagboom, P. Eline

AU - Ferrucci, Luigi

AU - Jula, Antti

AU - Perola, Markus

AU - Raitakari, Olli

AU - Florez, Jose C.

AU - Salomaa, Veikko

AU - Eriksson, Johan G.

AU - Frayling, Timothy M.

AU - Hicks, Andrew A.

AU - Lehtimäki, Terho

AU - Smith, George Davey

AU - Siscovick, David S.

AU - Kronenberg, Florian

AU - van Duijn, Cornelia

AU - Loos, Ruth J.F.

AU - Waterworth, Dawn M.

AU - Meigs, James B.

AU - Richards, J. Brent

AU - Voight, Benjamin F.

AU - Scott, Laura J.

AU - Steinthorsdottir, Valgerdur

AU - Dina, Christian

AU - Welch, Ryan P.

AU - Zeggini, Eleftheria

AU - Huth, Cornelia

AU - Aulchenko, Yurii S.

AU - Thorleifsson, Gudmar

AU - McCulloch, Laura J.

AU - Ferreira, Teresa

AU - Grallert, Harald

AU - Amin, Najaf

AU - Wu, Guanming

AU - Willer, Cristen J.

AU - Raychaudhuri, Soumya

AU - McCarroll, Steve A.

AU - Hofmann, Oliver M.

AU - Segrè, Ayellet V.

AU - van Hoek, Mandy

AU - Navarro, Pau

AU - Ardlie, Kristin

AU - Balkau, Beverley

AU - Benediktsson, Rafn

AU - Bennett, Amanda J.

AU - Blagieva, Roza

AU - Boerwinkle, Eric

AU - Bonnycastle, Lori L.

AU - Boström, Kristina Bengtsson

AU - Bravenboer, Bert

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AU - Charpentier, Guillaume

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AU - Guiducci, Candace

AU - Hadjadj, Samy

AU - Hassanali, Neelam

AU - Herder, Christian

AU - Isomaa, Bo

AU - Jackson, Anne U.

AU - Johnson, Paul R.V.

AU - Jørgensen, Torben

AU - Kao, Wen H.L.

AU - Kong, Augustine

AU - Kraft, Peter

AU - Kuusisto, Johanna

AU - Lauritzen, Torsten

AU - Li, Man

AU - Lieverse, Aloysius

AU - Lindgren, Cecilia M.

AU - Lyssenko, Valeriya

AU - Marre, Michel

AU - Meitinger, Thomas

AU - Midthjell, Kristian

AU - Morken, Mario A.

AU - Narisu, Narisu

AU - Nilsson, Peter

AU - Owen, Katharine R.

AU - Payne, Felicity

AU - Petersen, Ann Kristin

AU - Platou, Carl

AU - Proenca, Christine

AU - Prokopenko, Inga

AU - Rathmann, Wolfgang

AU - Rayner, N. William

AU - Robertson, Neil R.

AU - Rocheleau, Ghislain

AU - Roden, Michael

AU - Sampson, Michael J.

AU - Saxena, Richa

AU - Shields, Beverley M.

AU - Shrader, Peter

AU - Sigurdsson, Gunnar

AU - Sparsø, Thomas

AU - Strassburger, Klaus

AU - Stringham, Heather M.

AU - Sun, Qi

AU - Swift, Amy J.

AU - Thorand, Barbara

AU - Tichet, Jean

AU - Tuomi, Tiinamaija

AU - van Dam, Rob M.

AU - van Haeften, Timon W.

AU - van Herpt, Thijs

AU - van Vliet-Ostaptchouk, Jana V.

AU - Walters, G. Bragi

AU - Weedon, Michael N.

AU - Wijmenga, Cisca

AU - Witteman, Jacqueline

AU - Bergman, Richard N.

AU - Cauchi, Stephane

AU - Gloyn, Anna L.

AU - Gyllensten, Ulf

AU - Hansen, Torben

AU - Hide, Winston A.

AU - Hitman, Graham A.

AU - Hofman, Albert

AU - Hunter, David J.

AU - Hveem, Kristian

AU - Laakso, Markku

AU - Morris, Andrew D.

AU - Palmer, Colin N.A.

AU - Rudan, Igor

AU - Sijbrands, Eric

AU - Stein, Lincoln D.

AU - Tuomilehto, Jaakko

AU - Uitterlinden, Andre

AU - Walker, Mark

AU - Watanabe, Richard M.

AU - Abecasis, Goncalo R.

AU - Boehm, Bernhard O.

AU - Campbell, Harry

AU - Daly, Mark J.

AU - Hattersley, Andrew T.

AU - Pedersen, Oluf

AU - Barroso, Inês

AU - Groop, Leif

AU - Sladek, Rob

AU - Thorsteinsdottir, Unnur

AU - Wilson, James F.

AU - Mukherjee, Sutapa

PY - 2012/3/29

Y1 - 2012/3/29

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84859238629&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1002607

DO - 10.1371/journal.pgen.1002607

M3 - Article

C2 - 22479202

AN - SCOPUS:84859238629

VL - 8

JO - PloS Genetics

JF - PloS Genetics

SN - 1553-7390

IS - 3

M1 - e1002607

ER -