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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.

  • Author(s): Dastani, Zari
  • Hivert, Marie-France
  • Timpson, Nicholas
  • Perry, John RB
  • 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 MT
  • 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
  • Allison, Matthew A
  • 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 JF
  • Waterworth, Dawn M
  • Meigs, James B
  • Dupuis, Josee
  • Richards, J Brent
  • Voight, Benjamin F
  • Scott, Laura J
  • Steinthorsdottir, Valgerdur
  • Dina, Christian
  • Welch, Ryan P
  • Zeggini, Eleftheria
  • Huth, Cornelia
  • Aulchenko, Yurii S
  • Thorleifsson, Gudmar
  • McCulloch, Laura J
  • Ferreira, Teresa
  • Grallert, Harald
  • Amin, Najaf
  • Wu, Guanming
  • Willer, Cristen J
  • Raychaudhuri, Soumya
  • McCarroll, Steve A
  • Hofmann, Oliver M
  • Segrè, Ayellet V
  • van Hoek, Mandy
  • Navarro, Pau
  • Ardlie, Kristin
  • Balkau, Beverley
  • Benediktsson, Rafn
  • Bennett, Amanda J
  • Blagieva, Roza
  • Boerwinkle, Eric
  • Bonnycastle, Lori L
  • Boström, Kristina Bengtsson
  • Bravenboer, Bert
  • Bumpstead, Suzannah
  • Burtt, Noël P
  • Charpentier, Guillaume
  • Chines, Peter S
  • Cornelis, Marilyn
  • Crawford, Gabe
  • Doney, Alex SF
  • Elliott, Katherine S
  • Elliott, Amanda L
  • Erdos, Michael R
  • Fox, Caroline S
  • Franklin, Christopher S
  • Ganser, Martha
  • Gieger, Christian
  • Grarup, Niels
  • Green, Todd
  • Griffin, Simon
  • Groves, Christopher J
  • Guiducci, Candace
  • Hadjadj, Samy
  • Hassanali, Neelam
  • Herder, Christian
  • Isomaa, Bo
  • Jackson, Anne U
  • Johnson, Paul RV
  • Jørgensen, Torben
  • Kao, Wen HL
  • Kong, Augustine
  • Kraft, Peter
  • Kuusisto, Johanna
  • Lauritzen, Torsten
  • Li, Man
  • Lieverse, Aloysius
  • Lindgren, Cecilia M
  • Lyssenko, Valeriya
  • Marre, Michel
  • Meitinger, Thomas
  • Midthjell, Kristian
  • Morken, Mario A
  • Narisu, Narisu
  • Nilsson, Peter
  • Owen, Katharine R
  • Payne, Felicity
  • Petersen, Ann-Kristin
  • Platou, Carl
  • Proença, Christine
  • Prokopenko, Inga
  • Rathmann, Wolfgang
  • Rayner, N William
  • Robertson, Neil R
  • Rocheleau, Ghislain
  • Roden, Michael
  • Sampson, Michael J
  • Saxena, Richa
  • Shields, Beverley M
  • Shrader, Peter
  • Sigurdsson, Gunnar
  • Sparsø, Thomas
  • Strassburger, Klaus
  • Stringham, Heather M
  • Sun, Qi
  • Swift, Amy J
  • Thorand, Barbara
  • Tichet, Jean
  • Tuomi, Tiinamaija
  • van Dam, Rob M
  • van Haeften, Timon W
  • van Herpt, Thijs
  • van Vliet-Ostaptchouk, Jana V
  • Walters, G Bragi
  • Weedon, Michael N
  • Wijmenga, Cisca
  • Witteman, Jacqueline
  • Bergman, Richard N
  • Cauchi, Stephane
  • Collins, Francis S
  • Gloyn, Anna L
  • Gyllensten, Ulf
  • Hansen, Torben
  • Hide, Winston A
  • Hitman, Graham A
  • Hofman, Albert
  • Hunter, David J
  • Hveem, Kristian
  • Laakso, Markku
  • Morris, Andrew D
  • Palmer, Colin NA
  • Rudan, Igor
  • Sijbrands, Eric
  • Stein, Lincoln D
  • Tuomilehto, Jaakko
  • Uitterlinden, Andre
  • Walker, Mark
  • Watanabe, Richard M
  • Abecasis, Goncalo R
  • Boehm, Bernhard O
  • Campbell, Harry
  • Daly, Mark J
  • Hattersley, Andrew T
  • Pedersen, Oluf
  • Barroso, Inês
  • Groop, Leif
  • Sladek, Rob
  • Thorsteinsdottir, Unnur
  • Wilson, James F
  • Illig, Thomas
  • Froguel, Philippe
  • van Duijn, Cornelia M
  • Stefansson, Kari
  • Altshuler, David
  • Boehnke, Michael
  • McCarthy, Mark I
  • Soranzo, Nicole
  • Wheeler, Eleanor
  • Glazer, Nicole L
  • Bouatia-Naji, Nabila
  • Mägi, Reedik
  • Randall, Joshua
  • Elliott, Paul
  • Rybin, Denis
  • Dehghan, Abbas
  • Hottenga, Jouke Jan
  • Song, Kijoung
  • Goel, Anuj
  • Lajunen, Taina
  • Doney, Alex
  • Cavalcanti-Proença, Christine
  • Kumari, Meena
  • Timpson, Nicholas J
  • Zabena, Carina
  • Ingelsson, Erik
  • An, Ping
  • O'Connell, Jeffrey
  • Luan, Jian'an
  • Elliott, Amanda
  • McCarroll, Steven A
  • Roccasecca, Rosa Maria
  • Pattou, François
  • Sethupathy, Praveen
  • Ariyurek, Yavuz
  • Barter, Philip
  • Beilby, John P
  • Ben-Shlomo, Yoav
  • Bergmann, Sven
  • Bochud, Murielle
  • Bonnefond, Amélie
  • Borch-Johnsen, Knut
  • Böttcher, Yvonne
  • Brunner, Eric
  • Bumpstead, Suzannah J
  • Chen, Yii-Der Ida
  • Chines, Peter
  • Clarke, Robert
  • Coin, Lachlan JM
  • Cooper, Matthew N
  • Crisponi, Laura
  • Day, Ian NM
  • de Geus, Eco JC
  • Delplanque, Jerome
  • Fedson, Annette C
  • Fischer-Rosinsky, Antje
  • Forouhi, Nita G
  • Franzosi, Maria Grazia
  • Galan, Pilar
  • Goodarzi, Mark O
  • Graessler, Jürgen
  • Grundy, Scott
  • Gwilliam, Rhian
  • Hallmans, Göran
  • Hammond, Naomi
  • Han, Xijing
  • Hartikainen, Anna-Liisa
  • Hayward, Caroline
  • Heath, Simon C
  • Hercberg, Serge
  • Hillman, David R
  • Hingorani, Aroon D
  • Hui, Jennie
  • Hung, Joe
  • Kaakinen, Marika
  • Kaprio, Jaakko
  • Kesaniemi, Y Antero
  • Kivimaki, Mika
  • Knight, Beatrice
  • Koskinen, Seppo
  • Kovacs, Peter
  • Kyvik, Kirsten Ohm
  • Lathrop, G Mark
  • Lawlor, Debbie A
  • Le Bacquer, Olivier
  • Lecoeur, Cécile
  • Li, Yun
  • Mahley, Robert
  • Mangino, Massimo
  • Martínez-Larrad, María Teresa
  • McAteer, Jarred B
  • McPherson, Ruth
  • Meisinger, Christa
  • Melzer, David
  • Meyre, David
  • Mitchell, Braxton D
  • Mukherjee, Sutapa
  • Naitza, Silvia
  • Neville, Matthew J
  • Orrù, Marco
  • Pakyz, Ruth
  • Paolisso, Giuseppe
  • Pattaro, Cristian
  • Pearson, Daniel
  • Peden, John F
  • Pedersen, Nancy L
  • Pfeiffer, Andreas FH
  • Pichler, Irene
  • Polasek, Ozren
  • Posthuma, Danielle
  • Potter, Simon C
  • Pouta, Anneli
  • Province, Michael A
  • Rayner, Nigel W
  • Rice, Kenneth
  • Ripatti, Samuli
  • Rivadeneira, Fernando
  • Rolandsson, Olov
  • Sandbaek, Annelli
  • Sandhu, Manjinder
  • Sanna, Serena
  • Sayer, Avan Aihie
  • Scheet, Paul
  • Seedorf, Udo
  • Sharp, Stephen J
  • Shields, Beverley
  • Sigurðsson, Gunnar
  • Sijbrands, Eric JG
  • Silveira, Angela
  • Simpson, Laila
  • Singleton, Andrew
  • Smith, Nicholas L
  • Sovio, Ulla
  • Swift, Amy
  • Syddall, Holly
  • Syvänen, Ann-Christine
  • Tönjes, Anke
  • Uitterlinden, André G
  • van Dijk, Ko Willems
  • Varma, Dhiraj
  • Visvikis-Siest, Sophie
  • Vitart, Veronique
  • Vogelzangs, Nicole
  • Waeber, Gérard
  • Wagner, Peter J
  • Walley, Andrew
  • Ward, Kim L
  • Watkins, Hugh
  • Wild, Sarah H
  • Willemsen, Gonneke
  • Witteman, Jaqueline CM
  • Yarnell, John WG
  • Zelenika, Diana
  • Zethelius, Björn
  • Zhai, Guangju
  • Zhao, Jing Hua
  • Zillikens, M Carola
  • DIAGRAM Consortium
  • GIANT Consortium
  • Global B Pgen Consortium
  • Borecki, Ingrid B
  • Meneton, Pierre
  • Magnusson, Patrik KE
  • Nathan, David M
  • Williams, Gordon H
  • Silander, Kaisa
  • Bornstein, Stefan R
  • Schwarz, Peter
  • Spranger, Joachim
  • Karpe, Fredrik
  • Shuldiner, Alan R
  • Cooper, Cyrus
  • Serrano-Ríos, Manuel
  • Lind, Lars
  • Palmer, Lyle J
  • Hu, Frank B
  • Franks, Paul W
  • Ebrahim, Shah
  • Marmot, Michael
  • Kao, WH Linda
  • Pramstaller, Peter Paul
  • Wright, Alan F
  • Stumvoll, Michael
  • Hamsten, Anders
  • Procardis Consortium
  • Buchanan, Thomas A
  • Valle, Timo T
  • Rotter, Jerome I
  • Penninx, Brenda WJH
  • Boomsma, Dorret I
  • Cao, Antonio
  • Scuteri, Angelo
  • Schlessinger, David
  • Uda, Manuela
  • Ruokonen, Aimo
  • Jarvelin, Marjo-Riitta
  • Peltonen, Leena
  • Mooser, Vincent
  • Sladek, Robert
  • MAGIC investigators
  • GLGC Consortium
  • Musunuru, Kiran
  • Smith, Albert V
  • Edmondson, Andrew C
  • Stylianou, Ioannis M
  • Koseki, Masahiro
  • Pirruccello, James P
  • Chasman, Daniel I
  • Johansen, Christopher T
  • Fouchier, Sigrid W
  • Peloso, Gina M
  • Barbalic, Maja
  • Ricketts, Sally L
  • Bis, Joshua C
  • Feitosa, Mary F
  • Orho-Melander, Marju
  • Melander, Olle
  • Li, Xiaohui
  • Li, Mingyao
  • Cho, Yoon Shin
  • Go, Min Jin
  • Kim, Young Jin
  • Lee, Jong-Young
  • Park, Taesung
  • Kim, Kyunga
  • Sim, Xueling
  • Ong, Rick Twee-Hee
  • Croteau-Chonka, Damien C
  • Lange, Leslie A
  • Smith, Joshua D
  • Ziegler, Andreas
  • Zhang, Weihua
  • Zee, Robert YL
  • Whitfield, John B
  • Thompson, John R
  • Surakka, Ida
  • Spector, Tim D
  • Smit, Johannes H
  • Sinisalo, Juha
  • Scott, James
  • Saharinen, Juha
  • Sabatti, Chiara
  • Rose, Lynda M
  • Roberts, Robert
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  • McArdle, Wendy
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  • Luben, Robert
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  • Lettre, Guillaume
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  • Kyvik, Kirsten O
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  • Kaplan, Lee M
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  • Janssens, A Cecile JW
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  • Döring, Angela
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  • Demissie, Serkalem
  • Deloukas, Panagiotis
  • de Faire, Ulf
  • Crawford, Gabriel
  • Chen, Yii-der I
  • Caulfield, Mark J
  • Boekholdt, S Matthijs
  • Assimes, Themistocles L
  • Quertermous, Thomas
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  • Taylor, Herman A
  • Gabriel, Stacey B
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  • Gudnason, Vilmundur
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  • Hegele, Robert A
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  • Kathiresan, Sekar
  • et al.
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.

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