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 | |
| Publication status | Published - 29 Mar 2012 |
| Externally published | Yes |
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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 › Review article › peer-review
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 - 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
AU - Bumpstead, Suzannah
AU - Burtt, Noël P.
AU - Charpentier, Guillaume
AU - Chines, Peter S.
AU - Cornelis, Marilyn
AU - Crawford, Gabe
AU - Doney, Alex S.F.
AU - Elliott, Katherine S.
AU - Elliott, Amanda L.
AU - Erdos, Michael R.
AU - Fox, Caroline S.
AU - Franklin, Christopher S.
AU - Ganser, Martha
AU - Gieger, Christian
AU - Grarup, Niels
AU - Green, Todd
AU - Griffin, Simon
AU - Groves, Christopher J.
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 - Review article
C2 - 22479202
AN - SCOPUS:84859238629
VL - 8
JO - PloS Genetics
JF - PloS Genetics
SN - 1553-7390
IS - 3
M1 - e1002607
ER -