TY - JOUR T1 - Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. JF - Nat Genet Y1 - 2012 A1 - Scott, Robert A A1 - Lagou, Vasiliki A1 - Welch, Ryan P A1 - Wheeler, Eleanor A1 - Montasser, May E A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Strawbridge, Rona J A1 - Rehnberg, Emil A1 - Gustafsson, Stefan A1 - Kanoni, Stavroula A1 - Rasmussen-Torvik, Laura J A1 - Yengo, Loic A1 - Lecoeur, Cécile A1 - Shungin, Dmitry A1 - Sanna, Serena A1 - Sidore, Carlo A1 - Johnson, Paul C D A1 - Jukema, J Wouter A1 - Johnson, Toby A1 - Mahajan, Anubha A1 - Verweij, Niek A1 - Thorleifsson, Gudmar A1 - Hottenga, Jouke-Jan A1 - Shah, Sonia A1 - Smith, Albert V A1 - Sennblad, Bengt A1 - Gieger, Christian A1 - Salo, Perttu A1 - Perola, Markus A1 - Timpson, Nicholas J A1 - Evans, David M A1 - Pourcain, Beate St A1 - Wu, Ying A1 - Andrews, Jeanette S A1 - Hui, Jennie A1 - Bielak, Lawrence F A1 - Zhao, Wei A1 - Horikoshi, Momoko A1 - Navarro, Pau A1 - Isaacs, Aaron A1 - O'Connell, Jeffrey R A1 - Stirrups, Kathleen A1 - Vitart, Veronique A1 - Hayward, Caroline A1 - Esko, Tõnu A1 - Mihailov, Evelin A1 - Fraser, Ross M A1 - Fall, Tove A1 - Voight, Benjamin F A1 - Raychaudhuri, Soumya A1 - Chen, Han A1 - Lindgren, Cecilia M A1 - Morris, Andrew P A1 - Rayner, Nigel W A1 - Robertson, Neil A1 - Rybin, Denis A1 - Liu, Ching-Ti A1 - Beckmann, Jacques S A1 - Willems, Sara M A1 - Chines, Peter S A1 - Jackson, Anne U A1 - Kang, Hyun Min A1 - Stringham, Heather M A1 - Song, Kijoung A1 - Tanaka, Toshiko A1 - Peden, John F A1 - Goel, Anuj A1 - Hicks, Andrew A A1 - An, Ping A1 - Müller-Nurasyid, Martina A1 - Franco-Cereceda, Anders A1 - Folkersen, Lasse A1 - Marullo, Letizia A1 - Jansen, Hanneke A1 - Oldehinkel, Albertine J A1 - Bruinenberg, Marcel A1 - Pankow, James S A1 - North, Kari E A1 - Forouhi, Nita G A1 - Loos, Ruth J F A1 - Edkins, Sarah A1 - Varga, Tibor V A1 - Hallmans, Göran A1 - Oksa, Heikki A1 - Antonella, Mulas A1 - Nagaraja, Ramaiah A1 - Trompet, Stella A1 - Ford, Ian A1 - Bakker, Stephan J L A1 - Kong, Augustine A1 - Kumari, Meena A1 - Gigante, Bruna A1 - Herder, Christian A1 - Munroe, Patricia B A1 - Caulfield, Mark A1 - Antti, Jula A1 - Mangino, Massimo A1 - Small, Kerrin A1 - Miljkovic, Iva A1 - Liu, Yongmei A1 - Atalay, Mustafa A1 - Kiess, Wieland A1 - James, Alan L A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Palmer, Colin N A A1 - Doney, Alex S F A1 - Willemsen, Gonneke A1 - Smit, Johannes H A1 - Campbell, Susan A1 - Polasek, Ozren A1 - Bonnycastle, Lori L A1 - Hercberg, Serge A1 - Dimitriou, Maria A1 - Bolton, Jennifer L A1 - Fowkes, Gerard R A1 - Kovacs, Peter A1 - Lindström, Jaana A1 - Zemunik, Tatijana A1 - Bandinelli, Stefania A1 - Wild, Sarah H A1 - Basart, Hanneke V A1 - Rathmann, Wolfgang A1 - Grallert, Harald A1 - Maerz, Winfried A1 - Kleber, Marcus E A1 - Boehm, Bernhard O A1 - Peters, Annette A1 - Pramstaller, Peter P A1 - Province, Michael A A1 - Borecki, Ingrid B A1 - Hastie, Nicholas D A1 - Rudan, Igor A1 - Campbell, Harry A1 - Watkins, Hugh A1 - Farrall, Martin A1 - Stumvoll, Michael A1 - Ferrucci, Luigi A1 - Waterworth, Dawn M A1 - Bergman, Richard N A1 - Collins, Francis S A1 - Tuomilehto, Jaakko A1 - Watanabe, Richard M A1 - de Geus, Eco J C A1 - Penninx, Brenda W A1 - Hofman, Albert A1 - Oostra, Ben A A1 - Psaty, Bruce M A1 - Vollenweider, Peter A1 - Wilson, James F A1 - Wright, Alan F A1 - Hovingh, G Kees A1 - Metspalu, Andres A1 - Uusitupa, Matti A1 - Magnusson, Patrik K E A1 - Kyvik, Kirsten O A1 - Kaprio, Jaakko A1 - Price, Jackie F A1 - Dedoussis, George V A1 - Deloukas, Panos A1 - Meneton, Pierre A1 - Lind, Lars A1 - Boehnke, Michael A1 - Shuldiner, Alan R A1 - van Duijn, Cornelia M A1 - Morris, Andrew D A1 - Toenjes, Anke A1 - Peyser, Patricia A A1 - Beilby, John P A1 - Körner, Antje A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Bornstein, Stefan R A1 - Schwarz, Peter E H A1 - Lakka, Timo A A1 - Rauramaa, Rainer A1 - Adair, Linda S A1 - Smith, George Davey A1 - Spector, Tim D A1 - Illig, Thomas A1 - de Faire, Ulf A1 - Hamsten, Anders A1 - Gudnason, Vilmundur A1 - Kivimaki, Mika A1 - Hingorani, Aroon A1 - Keinanen-Kiukaanniemi, Sirkka M A1 - Saaristo, Timo E A1 - Boomsma, Dorret I A1 - Stefansson, Kari A1 - van der Harst, Pim A1 - Dupuis, Josée A1 - Pedersen, Nancy L A1 - Sattar, Naveed A1 - Harris, Tamara B A1 - Cucca, Francesco A1 - Ripatti, Samuli A1 - Salomaa, Veikko A1 - Mohlke, Karen L A1 - Balkau, Beverley A1 - Froguel, Philippe A1 - Pouta, Anneli A1 - Jarvelin, Marjo-Riitta A1 - Wareham, Nicholas J A1 - Bouatia-Naji, Nabila A1 - McCarthy, Mark I A1 - Franks, Paul W A1 - Meigs, James B A1 - Teslovich, Tanya M A1 - Florez, Jose C A1 - Langenberg, Claudia A1 - Ingelsson, Erik A1 - Prokopenko, Inga A1 - Barroso, Inês KW - Adult KW - Animals KW - Blood Glucose KW - Fasting KW - Female KW - Gene Frequency KW - Genome-Wide Association Study KW - Humans KW - Insulin KW - Male KW - Metabolic Networks and Pathways KW - Mice KW - Osmolar Concentration KW - Quantitative Trait Loci AB -

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.

VL - 44 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22885924?dopt=Abstract ER - TY - JOUR T1 - Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals. JF - PLoS Genet Y1 - 2012 A1 - Dastani, Zari A1 - Hivert, Marie-France A1 - Timpson, Nicholas A1 - Perry, John R B A1 - Yuan, Xin A1 - Scott, Robert A A1 - Henneman, Peter A1 - Heid, Iris M A1 - Kizer, Jorge R A1 - Lyytikäinen, Leo-Pekka A1 - Fuchsberger, Christian A1 - Tanaka, Toshiko A1 - Morris, Andrew P A1 - Small, Kerrin A1 - Isaacs, Aaron A1 - Beekman, Marian A1 - Coassin, Stefan A1 - Lohman, Kurt A1 - Qi, Lu A1 - Kanoni, Stavroula A1 - Pankow, James S A1 - Uh, Hae-Won A1 - Wu, Ying A1 - Bidulescu, Aurelian A1 - Rasmussen-Torvik, Laura J A1 - Greenwood, Celia M T A1 - Ladouceur, Martin A1 - Grimsby, Jonna A1 - Manning, Alisa K A1 - Liu, Ching-Ti A1 - Kooner, Jaspal A1 - Mooser, Vincent E A1 - Vollenweider, Peter A1 - Kapur, Karen A A1 - Chambers, John A1 - Wareham, Nicholas J A1 - Langenberg, Claudia A1 - Frants, Rune A1 - Willems-Vandijk, Ko A1 - Oostra, Ben A A1 - Willems, Sara M A1 - Lamina, Claudia A1 - Winkler, Thomas W A1 - Psaty, Bruce M A1 - Tracy, Russell P A1 - Brody, Jennifer A1 - Chen, Ida A1 - Viikari, Jorma A1 - Kähönen, Mika A1 - Pramstaller, Peter P A1 - Evans, David M A1 - St Pourcain, Beate A1 - Sattar, Naveed A1 - Wood, Andrew R A1 - Bandinelli, Stefania A1 - Carlson, Olga D A1 - Egan, Josephine M A1 - Böhringer, Stefan A1 - van Heemst, Diana A1 - Kedenko, Lyudmyla A1 - Kristiansson, Kati A1 - Nuotio, Marja-Liisa A1 - Loo, Britt-Marie A1 - Harris, Tamara A1 - Garcia, Melissa A1 - Kanaya, Alka A1 - Haun, Margot A1 - Klopp, Norman A1 - Wichmann, H-Erich A1 - Deloukas, Panos A1 - Katsareli, Efi A1 - Couper, David J A1 - Duncan, Bruce B A1 - Kloppenburg, Margreet A1 - Adair, Linda S A1 - Borja, Judith B A1 - Wilson, James G A1 - Musani, Solomon A1 - Guo, Xiuqing A1 - Johnson, Toby A1 - Semple, Robert A1 - Teslovich, Tanya M A1 - Allison, Matthew A A1 - Redline, Susan A1 - Buxbaum, Sarah G A1 - Mohlke, Karen L A1 - Meulenbelt, Ingrid A1 - Ballantyne, Christie M A1 - Dedoussis, George V A1 - Hu, Frank B A1 - Liu, Yongmei A1 - Paulweber, Bernhard A1 - Spector, Timothy D A1 - Slagboom, P Eline A1 - Ferrucci, Luigi A1 - Jula, Antti A1 - Perola, Markus A1 - Raitakari, Olli A1 - Florez, Jose C A1 - Salomaa, Veikko A1 - Eriksson, Johan G A1 - Frayling, Timothy M A1 - Hicks, Andrew A A1 - Lehtimäki, Terho A1 - Smith, George Davey A1 - Siscovick, David S A1 - Kronenberg, Florian A1 - van Duijn, Cornelia A1 - Loos, Ruth J F A1 - Waterworth, Dawn M A1 - Meigs, James B A1 - Dupuis, Josée A1 - Richards, J Brent A1 - Voight, Benjamin F A1 - Scott, Laura J A1 - Steinthorsdottir, Valgerdur A1 - Dina, Christian A1 - Welch, Ryan P A1 - Zeggini, Eleftheria A1 - Huth, Cornelia A1 - Aulchenko, Yurii S A1 - Thorleifsson, Gudmar A1 - McCulloch, Laura J A1 - Ferreira, Teresa A1 - Grallert, Harald A1 - Amin, Najaf A1 - Wu, Guanming A1 - Willer, Cristen J A1 - Raychaudhuri, Soumya A1 - McCarroll, Steve A A1 - Hofmann, Oliver M A1 - Segrè, Ayellet V A1 - van Hoek, Mandy A1 - Navarro, Pau A1 - Ardlie, Kristin A1 - Balkau, Beverley A1 - Benediktsson, Rafn A1 - Bennett, Amanda J A1 - Blagieva, Roza A1 - Boerwinkle, Eric A1 - Bonnycastle, Lori L A1 - Boström, Kristina Bengtsson A1 - Bravenboer, Bert A1 - Bumpstead, Suzannah A1 - Burtt, Noel P A1 - Charpentier, Guillaume A1 - Chines, Peter S A1 - Cornelis, Marilyn A1 - Crawford, Gabe A1 - Doney, Alex S F A1 - Elliott, Katherine S A1 - Elliott, Amanda L A1 - Erdos, Michael R A1 - Fox, Caroline S A1 - Franklin, Christopher S A1 - Ganser, Martha A1 - Gieger, Christian A1 - Grarup, Niels A1 - Green, Todd A1 - Griffin, Simon A1 - Groves, Christopher J A1 - Guiducci, Candace A1 - Hadjadj, Samy A1 - Hassanali, Neelam A1 - Herder, Christian A1 - Isomaa, Bo A1 - Jackson, Anne U A1 - Johnson, Paul R V A1 - Jørgensen, Torben A1 - Kao, Wen H L A1 - Kong, Augustine A1 - Kraft, Peter A1 - Kuusisto, Johanna A1 - Lauritzen, Torsten A1 - Li, Man A1 - Lieverse, Aloysius A1 - Lindgren, Cecilia M A1 - Lyssenko, Valeriya A1 - Marre, Michel A1 - Meitinger, Thomas A1 - Midthjell, Kristian A1 - Morken, Mario A A1 - Narisu, Narisu A1 - Nilsson, Peter A1 - Owen, Katharine R A1 - Payne, Felicity A1 - Petersen, Ann-Kristin A1 - Platou, Carl A1 - Proença, Christine A1 - Prokopenko, Inga A1 - Rathmann, Wolfgang A1 - Rayner, N William A1 - Robertson, Neil R A1 - Rocheleau, Ghislain A1 - Roden, Michael A1 - Sampson, Michael J A1 - Saxena, Richa A1 - Shields, Beverley M A1 - Shrader, Peter A1 - Sigurdsson, Gunnar A1 - Sparsø, Thomas A1 - Strassburger, Klaus A1 - Stringham, Heather M A1 - Sun, Qi A1 - Swift, Amy J A1 - Thorand, Barbara A1 - Tichet, Jean A1 - Tuomi, Tiinamaija A1 - van Dam, Rob M A1 - van Haeften, Timon W A1 - van Herpt, Thijs A1 - van Vliet-Ostaptchouk, Jana V A1 - Walters, G Bragi A1 - Weedon, Michael N A1 - Wijmenga, Cisca A1 - Witteman, Jacqueline A1 - Bergman, Richard N A1 - Cauchi, Stephane A1 - Collins, Francis S A1 - Gloyn, Anna L A1 - Gyllensten, Ulf A1 - Hansen, Torben A1 - Hide, Winston A A1 - Hitman, Graham A A1 - Hofman, Albert A1 - Hunter, David J A1 - Hveem, Kristian A1 - Laakso, Markku A1 - Morris, Andrew D A1 - Palmer, Colin N A A1 - Rudan, Igor A1 - Sijbrands, Eric A1 - Stein, Lincoln D A1 - Tuomilehto, Jaakko A1 - Uitterlinden, Andre A1 - Walker, Mark A1 - Watanabe, Richard M A1 - Abecasis, Goncalo R A1 - Boehm, Bernhard O A1 - Campbell, Harry A1 - Daly, Mark J A1 - Hattersley, Andrew T A1 - Pedersen, Oluf A1 - Barroso, Inês A1 - Groop, Leif A1 - Sladek, Rob A1 - Thorsteinsdottir, Unnur A1 - Wilson, James F A1 - Illig, Thomas A1 - Froguel, Philippe A1 - van Duijn, Cornelia M A1 - Stefansson, Kari A1 - Altshuler, David A1 - Boehnke, Michael A1 - McCarthy, Mark I A1 - Soranzo, Nicole A1 - Wheeler, Eleanor A1 - Glazer, Nicole L A1 - Bouatia-Naji, Nabila A1 - Mägi, Reedik A1 - Randall, Joshua A1 - Elliott, Paul A1 - Rybin, Denis A1 - Dehghan, Abbas A1 - Hottenga, Jouke Jan A1 - Song, Kijoung A1 - Goel, Anuj A1 - Lajunen, Taina A1 - Doney, Alex A1 - Cavalcanti-Proença, Christine A1 - Kumari, Meena A1 - Timpson, Nicholas J A1 - Zabena, Carina A1 - Ingelsson, Erik A1 - An, Ping A1 - O'Connell, Jeffrey A1 - Luan, Jian'an A1 - Elliott, Amanda A1 - McCarroll, Steven A A1 - Roccasecca, Rosa Maria A1 - Pattou, François A1 - Sethupathy, Praveen A1 - Ariyurek, Yavuz A1 - Barter, Philip A1 - Beilby, John P A1 - Ben-Shlomo, Yoav A1 - Bergmann, Sven A1 - Bochud, Murielle A1 - Bonnefond, Amélie A1 - Borch-Johnsen, Knut A1 - Böttcher, Yvonne A1 - Brunner, Eric A1 - Bumpstead, Suzannah J A1 - Chen, Yii-Der Ida A1 - Chines, Peter A1 - Clarke, Robert A1 - Coin, Lachlan J M A1 - Cooper, Matthew N A1 - Crisponi, Laura A1 - Day, Ian N M A1 - de Geus, Eco J C A1 - Delplanque, Jerome A1 - Fedson, Annette C A1 - Fischer-Rosinsky, Antje A1 - Forouhi, Nita G A1 - Franzosi, Maria Grazia A1 - Galan, Pilar A1 - Goodarzi, Mark O A1 - Graessler, Jürgen A1 - Grundy, Scott A1 - Gwilliam, Rhian A1 - Hallmans, Göran A1 - Hammond, Naomi A1 - Han, Xijing A1 - Hartikainen, Anna-Liisa A1 - Hayward, Caroline A1 - Heath, Simon C A1 - Hercberg, Serge A1 - Hillman, David R A1 - Hingorani, Aroon D A1 - Hui, Jennie A1 - Hung, Joe A1 - Kaakinen, Marika A1 - Kaprio, Jaakko A1 - Kesaniemi, Y Antero A1 - Kivimaki, Mika A1 - Knight, Beatrice A1 - Koskinen, Seppo A1 - Kovacs, Peter A1 - Kyvik, Kirsten Ohm A1 - Lathrop, G Mark A1 - Lawlor, Debbie A A1 - Le Bacquer, Olivier A1 - Lecoeur, Cécile A1 - Li, Yun A1 - Mahley, Robert A1 - Mangino, Massimo A1 - Martínez-Larrad, María Teresa A1 - McAteer, Jarred B A1 - McPherson, Ruth A1 - Meisinger, Christa A1 - Melzer, David A1 - Meyre, David A1 - Mitchell, Braxton D A1 - Mukherjee, Sutapa A1 - Naitza, Silvia A1 - Neville, Matthew J A1 - Orrù, Marco A1 - Pakyz, Ruth A1 - Paolisso, Giuseppe A1 - Pattaro, Cristian A1 - Pearson, Daniel A1 - Peden, John F A1 - Pedersen, Nancy L A1 - Pfeiffer, Andreas F H A1 - Pichler, Irene A1 - Polasek, Ozren A1 - Posthuma, Danielle A1 - Potter, Simon C A1 - Pouta, Anneli A1 - Province, Michael A A1 - Rayner, Nigel W A1 - Rice, Kenneth A1 - Ripatti, Samuli A1 - Rivadeneira, Fernando A1 - Rolandsson, Olov A1 - Sandbaek, Annelli A1 - Sandhu, Manjinder A1 - Sanna, Serena A1 - Sayer, Avan Aihie A1 - Scheet, Paul A1 - Seedorf, Udo A1 - Sharp, Stephen J A1 - Shields, Beverley A1 - Sigurðsson, Gunnar A1 - Sijbrands, Eric J G A1 - Silveira, Angela A1 - Simpson, Laila A1 - Singleton, Andrew A1 - Smith, Nicholas L A1 - Sovio, Ulla A1 - Swift, Amy A1 - Syddall, Holly A1 - Syvänen, Ann-Christine A1 - Tönjes, Anke A1 - Uitterlinden, André G A1 - van Dijk, Ko Willems A1 - Varma, Dhiraj A1 - Visvikis-Siest, Sophie A1 - Vitart, Veronique A1 - Vogelzangs, Nicole A1 - Waeber, Gérard A1 - Wagner, Peter J A1 - Walley, Andrew A1 - Ward, Kim L A1 - Watkins, Hugh A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Witteman, Jaqueline C M A1 - Yarnell, John W G A1 - Zelenika, Diana A1 - Zethelius, Björn A1 - Zhai, Guangju A1 - Zhao, Jing Hua A1 - Zillikens, M Carola A1 - Borecki, Ingrid B A1 - Meneton, Pierre A1 - Magnusson, Patrik K E A1 - Nathan, David M A1 - Williams, Gordon H A1 - Silander, Kaisa A1 - Bornstein, Stefan R A1 - Schwarz, Peter A1 - Spranger, Joachim A1 - Karpe, Fredrik A1 - Shuldiner, Alan R A1 - Cooper, Cyrus A1 - Serrano-Ríos, Manuel A1 - Lind, Lars A1 - Palmer, Lyle J A1 - Hu, Frank B A1 - Franks, Paul W A1 - Ebrahim, Shah A1 - Marmot, Michael A1 - Kao, W H Linda A1 - Pramstaller, Peter Paul A1 - Wright, Alan F A1 - Stumvoll, Michael A1 - Hamsten, Anders A1 - Buchanan, Thomas A A1 - Valle, Timo T A1 - Rotter, Jerome I A1 - Penninx, Brenda W J H A1 - Boomsma, Dorret I A1 - Cao, Antonio A1 - Scuteri, Angelo A1 - Schlessinger, David A1 - Uda, Manuela A1 - Ruokonen, Aimo A1 - Jarvelin, Marjo-Riitta A1 - Peltonen, Leena A1 - Mooser, Vincent A1 - Sladek, Robert A1 - Musunuru, Kiran A1 - Smith, Albert V A1 - Edmondson, Andrew C A1 - Stylianou, Ioannis M A1 - Koseki, Masahiro A1 - Pirruccello, James P A1 - Chasman, Daniel I A1 - Johansen, Christopher T A1 - Fouchier, Sigrid W A1 - Peloso, Gina M A1 - Barbalic, Maja A1 - Ricketts, Sally L A1 - Bis, Joshua C A1 - Feitosa, Mary F A1 - Orho-Melander, Marju A1 - Melander, Olle A1 - Li, Xiaohui A1 - Li, Mingyao A1 - Cho, Yoon Shin A1 - Go, Min Jin A1 - Kim, Young Jin A1 - Lee, Jong-Young A1 - Park, Taesung A1 - Kim, Kyunga A1 - Sim, Xueling A1 - Ong, Rick Twee-Hee A1 - Croteau-Chonka, Damien C A1 - Lange, Leslie A A1 - Smith, Joshua D A1 - Ziegler, Andreas A1 - Zhang, Weihua A1 - Zee, Robert Y L A1 - Whitfield, John B A1 - Thompson, John R A1 - Surakka, Ida A1 - Spector, Tim D A1 - Smit, Johannes H A1 - Sinisalo, Juha A1 - Scott, James A1 - Saharinen, Juha A1 - Sabatti, Chiara A1 - Rose, Lynda M A1 - Roberts, Robert A1 - Rieder, Mark A1 - Parker, Alex N A1 - Paré, Guillaume A1 - O'Donnell, Christopher J A1 - Nieminen, Markku S A1 - Nickerson, Deborah A A1 - Montgomery, Grant W A1 - McArdle, Wendy A1 - Masson, David A1 - Martin, Nicholas G A1 - Marroni, Fabio A1 - Lucas, Gavin A1 - Luben, Robert A1 - Lokki, Marja-Liisa A1 - Lettre, Guillaume A1 - Launer, Lenore J A1 - Lakatta, Edward G A1 - Laaksonen, Reijo A1 - Kyvik, Kirsten O A1 - König, Inke R A1 - Khaw, Kay-Tee A1 - Kaplan, Lee M A1 - Johansson, Asa A1 - Janssens, A Cecile J W A1 - Igl, Wilmar A1 - Hovingh, G Kees A1 - Hengstenberg, Christian A1 - Havulinna, Aki S A1 - Hastie, Nicholas D A1 - Harris, Tamara B A1 - Haritunians, Talin A1 - Hall, Alistair S A1 - Groop, Leif C A1 - Gonzalez, Elena A1 - Freimer, Nelson B A1 - Erdmann, Jeanette A1 - Ejebe, Kenechi G A1 - Döring, Angela A1 - Dominiczak, Anna F A1 - Demissie, Serkalem A1 - Deloukas, Panagiotis A1 - de Faire, Ulf A1 - Crawford, Gabriel A1 - Chen, Yii-der I A1 - Caulfield, Mark J A1 - Boekholdt, S Matthijs A1 - Assimes, Themistocles L A1 - Quertermous, Thomas A1 - Seielstad, Mark A1 - Wong, Tien Y A1 - Tai, E-Shyong A1 - Feranil, Alan B A1 - Kuzawa, Christopher W A1 - Taylor, Herman A A1 - Gabriel, Stacey B A1 - Holm, Hilma A1 - Gudnason, Vilmundur A1 - Krauss, Ronald M A1 - Ordovas, Jose M A1 - Munroe, Patricia B A1 - Kooner, Jaspal S A1 - Tall, Alan R A1 - Hegele, Robert A A1 - Kastelein, John J P A1 - Schadt, Eric E A1 - Strachan, David P A1 - Reilly, Muredach P A1 - Samani, Nilesh J A1 - Schunkert, Heribert A1 - Cupples, L Adrienne A1 - Sandhu, Manjinder S A1 - Ridker, Paul M A1 - Rader, Daniel J A1 - Kathiresan, Sekar KW - Adiponectin KW - African Americans KW - Asian Continental Ancestry Group KW - Cholesterol, HDL KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Female KW - Gene Expression KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glucose Tolerance Test KW - Humans KW - Insulin Resistance KW - Male KW - Metabolic Networks and Pathways KW - Polymorphism, Single Nucleotide KW - Waist-Hip Ratio 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.

VL - 8 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22479202?dopt=Abstract ER - TY - JOUR T1 - Common variants associated with plasma triglycerides and risk for coronary artery disease. JF - Nat Genet Y1 - 2013 A1 - Do, Ron A1 - Willer, Cristen J A1 - Schmidt, Ellen M A1 - Sengupta, Sebanti A1 - Gao, Chi A1 - Peloso, Gina M A1 - Gustafsson, Stefan A1 - Kanoni, Stavroula A1 - Ganna, Andrea A1 - Chen, Jin A1 - Buchkovich, Martin L A1 - Mora, Samia A1 - Beckmann, Jacques S A1 - Bragg-Gresham, Jennifer L A1 - Chang, Hsing-Yi A1 - Demirkan, Ayse A1 - Den Hertog, Heleen M A1 - Donnelly, Louise A A1 - Ehret, Georg B A1 - Esko, Tõnu A1 - Feitosa, Mary F A1 - Ferreira, Teresa A1 - Fischer, Krista A1 - Fontanillas, Pierre A1 - Fraser, Ross M A1 - Freitag, Daniel F A1 - Gurdasani, Deepti A1 - Heikkilä, Kauko A1 - Hyppönen, Elina A1 - Isaacs, Aaron A1 - Jackson, Anne U A1 - Johansson, Asa A1 - Johnson, Toby A1 - Kaakinen, Marika A1 - Kettunen, Johannes A1 - Kleber, Marcus E A1 - Li, Xiaohui A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Magnusson, Patrik K E A1 - Mangino, Massimo A1 - Mihailov, Evelin A1 - Montasser, May E A1 - Müller-Nurasyid, Martina A1 - Nolte, Ilja M A1 - O'Connell, Jeffrey R A1 - Palmer, Cameron D A1 - Perola, Markus A1 - Petersen, Ann-Kristin A1 - Sanna, Serena A1 - Saxena, Richa A1 - Service, Susan K A1 - Shah, Sonia A1 - Shungin, Dmitry A1 - Sidore, Carlo A1 - Song, Ci A1 - Strawbridge, Rona J A1 - Surakka, Ida A1 - Tanaka, Toshiko A1 - Teslovich, Tanya M A1 - Thorleifsson, Gudmar A1 - van den Herik, Evita G A1 - Voight, Benjamin F A1 - Volcik, Kelly A A1 - Waite, Lindsay L A1 - Wong, Andrew A1 - Wu, Ying A1 - Zhang, Weihua A1 - Absher, Devin A1 - Asiki, Gershim A1 - Barroso, Inês A1 - Been, Latonya F A1 - Bolton, Jennifer L A1 - Bonnycastle, Lori L A1 - Brambilla, Paolo A1 - Burnett, Mary S A1 - Cesana, Giancarlo A1 - Dimitriou, Maria A1 - Doney, Alex S F A1 - Döring, Angela A1 - Elliott, Paul A1 - Epstein, Stephen E A1 - Eyjolfsson, Gudmundur Ingi A1 - Gigante, Bruna A1 - Goodarzi, Mark O A1 - Grallert, Harald A1 - Gravito, Martha L A1 - Groves, Christopher J A1 - Hallmans, Göran A1 - Hartikainen, Anna-Liisa A1 - Hayward, Caroline A1 - Hernandez, Dena A1 - Hicks, Andrew A A1 - Holm, Hilma A1 - Hung, Yi-Jen A1 - Illig, Thomas A1 - Jones, Michelle R A1 - Kaleebu, Pontiano A1 - Kastelein, John J P A1 - Khaw, Kay-Tee A1 - Kim, Eric A1 - Klopp, Norman A1 - Komulainen, Pirjo A1 - Kumari, Meena A1 - Langenberg, Claudia A1 - Lehtimäki, Terho A1 - Lin, Shih-Yi A1 - Lindström, Jaana A1 - Loos, Ruth J F A1 - Mach, François A1 - McArdle, Wendy L A1 - Meisinger, Christa A1 - Mitchell, Braxton D A1 - Müller, Gabrielle A1 - Nagaraja, Ramaiah A1 - Narisu, Narisu A1 - Nieminen, Tuomo V M A1 - Nsubuga, Rebecca N A1 - Olafsson, Isleifur A1 - Ong, Ken K A1 - Palotie, Aarno A1 - Papamarkou, Theodore A1 - Pomilla, Cristina A1 - Pouta, Anneli A1 - Rader, Daniel J A1 - Reilly, Muredach P A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rudan, Igor A1 - Ruokonen, Aimo A1 - Samani, Nilesh A1 - Scharnagl, Hubert A1 - Seeley, Janet A1 - Silander, Kaisa A1 - Stančáková, Alena A1 - Stirrups, Kathleen A1 - Swift, Amy J A1 - Tiret, Laurence A1 - Uitterlinden, André G A1 - van Pelt, L Joost A1 - Vedantam, Sailaja A1 - Wainwright, Nicholas A1 - Wijmenga, Cisca A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Wilsgaard, Tom A1 - Wilson, James F A1 - Young, Elizabeth H A1 - Zhao, Jing Hua A1 - Adair, Linda S A1 - Arveiler, Dominique A1 - Assimes, Themistocles L A1 - Bandinelli, Stefania A1 - Bennett, Franklyn A1 - Bochud, Murielle A1 - Boehm, Bernhard O A1 - Boomsma, Dorret I A1 - Borecki, Ingrid B A1 - Bornstein, Stefan R A1 - Bovet, Pascal A1 - Burnier, Michel A1 - Campbell, Harry A1 - Chakravarti, Aravinda A1 - Chambers, John C A1 - Chen, Yii-Der Ida A1 - Collins, Francis S A1 - Cooper, Richard S A1 - Danesh, John A1 - Dedoussis, George A1 - de Faire, Ulf A1 - Feranil, Alan B A1 - Ferrieres, Jean A1 - Ferrucci, Luigi A1 - Freimer, Nelson B A1 - Gieger, Christian A1 - Groop, Leif C A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hingorani, Aroon A1 - Hirschhorn, Joel N A1 - Hofman, Albert A1 - Hovingh, G Kees A1 - Hsiung, Chao Agnes A1 - Humphries, Steve E A1 - Hunt, Steven C A1 - Hveem, Kristian A1 - Iribarren, Carlos A1 - Jarvelin, Marjo-Riitta A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kaprio, Jaakko A1 - Kesäniemi, Antero A1 - Kivimaki, Mika A1 - Kooner, Jaspal S A1 - Koudstaal, Peter J A1 - Krauss, Ronald M A1 - Kuh, Diana A1 - Kuusisto, Johanna A1 - Kyvik, Kirsten O A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Martin, Nicholas G A1 - März, Winfried A1 - McCarthy, Mark I A1 - McKenzie, Colin A A1 - Meneton, Pierre A1 - Metspalu, Andres A1 - Moilanen, Leena A1 - Morris, Andrew D A1 - Munroe, Patricia B A1 - Njølstad, Inger A1 - Pedersen, Nancy L A1 - Power, Chris A1 - Pramstaller, Peter P A1 - Price, Jackie F A1 - Psaty, Bruce M A1 - Quertermous, Thomas A1 - Rauramaa, Rainer A1 - Saleheen, Danish A1 - Salomaa, Veikko A1 - Sanghera, Dharambir K A1 - Saramies, Jouko A1 - Schwarz, Peter E H A1 - Sheu, Wayne H-H A1 - Shuldiner, Alan R A1 - Siegbahn, Agneta A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Strachan, David P A1 - Tayo, Bamidele O A1 - Tremoli, Elena A1 - Tuomilehto, Jaakko A1 - Uusitupa, Matti A1 - van Duijn, Cornelia M A1 - Vollenweider, Peter A1 - Wallentin, Lars A1 - Wareham, Nicholas J A1 - Whitfield, John B A1 - Wolffenbuttel, Bruce H R A1 - Altshuler, David A1 - Ordovas, Jose M A1 - Boerwinkle, Eric A1 - Palmer, Colin N A A1 - Thorsteinsdottir, Unnur A1 - Chasman, Daniel I A1 - Rotter, Jerome I A1 - Franks, Paul W A1 - Ripatti, Samuli A1 - Cupples, L Adrienne A1 - Sandhu, Manjinder S A1 - Rich, Stephen S A1 - Boehnke, Michael A1 - Deloukas, Panos A1 - Mohlke, Karen L A1 - Ingelsson, Erik A1 - Abecasis, Goncalo R A1 - Daly, Mark J A1 - Neale, Benjamin M A1 - Kathiresan, Sekar KW - Biological Transport KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Coronary Artery Disease KW - Humans KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Triglycerides AB -

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

VL - 45 IS - 11 ER - TY - JOUR T1 - Discovery and refinement of loci associated with lipid levels. JF - Nat Genet Y1 - 2013 A1 - Willer, Cristen J A1 - Schmidt, Ellen M A1 - Sengupta, Sebanti A1 - Peloso, Gina M A1 - Gustafsson, Stefan A1 - Kanoni, Stavroula A1 - Ganna, Andrea A1 - Chen, Jin A1 - Buchkovich, Martin L A1 - Mora, Samia A1 - Beckmann, Jacques S A1 - Bragg-Gresham, Jennifer L A1 - Chang, Hsing-Yi A1 - Demirkan, Ayse A1 - Den Hertog, Heleen M A1 - Do, Ron A1 - Donnelly, Louise A A1 - Ehret, Georg B A1 - Esko, Tõnu A1 - Feitosa, Mary F A1 - Ferreira, Teresa A1 - Fischer, Krista A1 - Fontanillas, Pierre A1 - Fraser, Ross M A1 - Freitag, Daniel F A1 - Gurdasani, Deepti A1 - Heikkilä, Kauko A1 - Hyppönen, Elina A1 - Isaacs, Aaron A1 - Jackson, Anne U A1 - Johansson, Asa A1 - Johnson, Toby A1 - Kaakinen, Marika A1 - Kettunen, Johannes A1 - Kleber, Marcus E A1 - Li, Xiaohui A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Magnusson, Patrik K E A1 - Mangino, Massimo A1 - Mihailov, Evelin A1 - Montasser, May E A1 - Müller-Nurasyid, Martina A1 - Nolte, Ilja M A1 - O'Connell, Jeffrey R A1 - Palmer, Cameron D A1 - Perola, Markus A1 - Petersen, Ann-Kristin A1 - Sanna, Serena A1 - Saxena, Richa A1 - Service, Susan K A1 - Shah, Sonia A1 - Shungin, Dmitry A1 - Sidore, Carlo A1 - Song, Ci A1 - Strawbridge, Rona J A1 - Surakka, Ida A1 - Tanaka, Toshiko A1 - Teslovich, Tanya M A1 - Thorleifsson, Gudmar A1 - van den Herik, Evita G A1 - Voight, Benjamin F A1 - Volcik, Kelly A A1 - Waite, Lindsay L A1 - Wong, Andrew A1 - Wu, Ying A1 - Zhang, Weihua A1 - Absher, Devin A1 - Asiki, Gershim A1 - Barroso, Inês A1 - Been, Latonya F A1 - Bolton, Jennifer L A1 - Bonnycastle, Lori L A1 - Brambilla, Paolo A1 - Burnett, Mary S A1 - Cesana, Giancarlo A1 - Dimitriou, Maria A1 - Doney, Alex S F A1 - Döring, Angela A1 - Elliott, Paul A1 - Epstein, Stephen E A1 - Ingi Eyjolfsson, Gudmundur A1 - Gigante, Bruna A1 - Goodarzi, Mark O A1 - Grallert, Harald A1 - Gravito, Martha L A1 - Groves, Christopher J A1 - Hallmans, Göran A1 - Hartikainen, Anna-Liisa A1 - Hayward, Caroline A1 - Hernandez, Dena A1 - Hicks, Andrew A A1 - Holm, Hilma A1 - Hung, Yi-Jen A1 - Illig, Thomas A1 - Jones, Michelle R A1 - Kaleebu, Pontiano A1 - Kastelein, John J P A1 - Khaw, Kay-Tee A1 - Kim, Eric A1 - Klopp, Norman A1 - Komulainen, Pirjo A1 - Kumari, Meena A1 - Langenberg, Claudia A1 - Lehtimäki, Terho A1 - Lin, Shih-Yi A1 - Lindström, Jaana A1 - Loos, Ruth J F A1 - Mach, François A1 - McArdle, Wendy L A1 - Meisinger, Christa A1 - Mitchell, Braxton D A1 - Müller, Gabrielle A1 - Nagaraja, Ramaiah A1 - Narisu, Narisu A1 - Nieminen, Tuomo V M A1 - Nsubuga, Rebecca N A1 - Olafsson, Isleifur A1 - Ong, Ken K A1 - Palotie, Aarno A1 - Papamarkou, Theodore A1 - Pomilla, Cristina A1 - Pouta, Anneli A1 - Rader, Daniel J A1 - Reilly, Muredach P A1 - Ridker, Paul M A1 - Rivadeneira, Fernando A1 - Rudan, Igor A1 - Ruokonen, Aimo A1 - Samani, Nilesh A1 - Scharnagl, Hubert A1 - Seeley, Janet A1 - Silander, Kaisa A1 - Stančáková, Alena A1 - Stirrups, Kathleen A1 - Swift, Amy J A1 - Tiret, Laurence A1 - Uitterlinden, André G A1 - van Pelt, L Joost A1 - Vedantam, Sailaja A1 - Wainwright, Nicholas A1 - Wijmenga, Cisca A1 - Wild, Sarah H A1 - Willemsen, Gonneke A1 - Wilsgaard, Tom A1 - Wilson, James F A1 - Young, Elizabeth H A1 - Zhao, Jing Hua A1 - Adair, Linda S A1 - Arveiler, Dominique A1 - Assimes, Themistocles L A1 - Bandinelli, Stefania A1 - Bennett, Franklyn A1 - Bochud, Murielle A1 - Boehm, Bernhard O A1 - Boomsma, Dorret I A1 - Borecki, Ingrid B A1 - Bornstein, Stefan R A1 - Bovet, Pascal A1 - Burnier, Michel A1 - Campbell, Harry A1 - Chakravarti, Aravinda A1 - Chambers, John C A1 - Chen, Yii-Der Ida A1 - Collins, Francis S A1 - Cooper, Richard S A1 - Danesh, John A1 - Dedoussis, George A1 - de Faire, Ulf A1 - Feranil, Alan B A1 - Ferrieres, Jean A1 - Ferrucci, Luigi A1 - Freimer, Nelson B A1 - Gieger, Christian A1 - Groop, Leif C A1 - Gudnason, Vilmundur A1 - Gyllensten, Ulf A1 - Hamsten, Anders A1 - Harris, Tamara B A1 - Hingorani, Aroon A1 - Hirschhorn, Joel N A1 - Hofman, Albert A1 - Hovingh, G Kees A1 - Hsiung, Chao Agnes A1 - Humphries, Steve E A1 - Hunt, Steven C A1 - Hveem, Kristian A1 - Iribarren, Carlos A1 - Jarvelin, Marjo-Riitta A1 - Jula, Antti A1 - Kähönen, Mika A1 - Kaprio, Jaakko A1 - Kesäniemi, Antero A1 - Kivimaki, Mika A1 - Kooner, Jaspal S A1 - Koudstaal, Peter J A1 - Krauss, Ronald M A1 - Kuh, Diana A1 - Kuusisto, Johanna A1 - Kyvik, Kirsten O A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lind, Lars A1 - Lindgren, Cecilia M A1 - Martin, Nicholas G A1 - März, Winfried A1 - McCarthy, Mark I A1 - McKenzie, Colin A A1 - Meneton, Pierre A1 - Metspalu, Andres A1 - Moilanen, Leena A1 - Morris, Andrew D A1 - Munroe, Patricia B A1 - Njølstad, Inger A1 - Pedersen, Nancy L A1 - Power, Chris A1 - Pramstaller, Peter P A1 - Price, Jackie F A1 - Psaty, Bruce M A1 - Quertermous, Thomas A1 - Rauramaa, Rainer A1 - Saleheen, Danish A1 - Salomaa, Veikko A1 - Sanghera, Dharambir K A1 - Saramies, Jouko A1 - Schwarz, Peter E H A1 - Sheu, Wayne H-H A1 - Shuldiner, Alan R A1 - Siegbahn, Agneta A1 - Spector, Tim D A1 - Stefansson, Kari A1 - Strachan, David P A1 - Tayo, Bamidele O A1 - Tremoli, Elena A1 - Tuomilehto, Jaakko A1 - Uusitupa, Matti A1 - van Duijn, Cornelia M A1 - Vollenweider, Peter A1 - Wallentin, Lars A1 - Wareham, Nicholas J A1 - Whitfield, John B A1 - Wolffenbuttel, Bruce H R A1 - Ordovas, Jose M A1 - Boerwinkle, Eric A1 - Palmer, Colin N A A1 - Thorsteinsdottir, Unnur A1 - Chasman, Daniel I A1 - Rotter, Jerome I A1 - Franks, Paul W A1 - Ripatti, Samuli A1 - Cupples, L Adrienne A1 - Sandhu, Manjinder S A1 - Rich, Stephen S A1 - Boehnke, Michael A1 - Deloukas, Panos A1 - Kathiresan, Sekar A1 - Mohlke, Karen L A1 - Ingelsson, Erik A1 - Abecasis, Goncalo R KW - African Continental Ancestry Group KW - Asian Continental Ancestry Group KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Coronary Artery Disease KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Lipids KW - Triglycerides AB -

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

VL - 45 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24097068?dopt=Abstract ER - TY - JOUR T1 - Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins. JF - Nat Commun Y1 - 2014 A1 - Postmus, Iris A1 - Trompet, Stella A1 - Deshmukh, Harshal A A1 - Barnes, Michael R A1 - Li, Xiaohui A1 - Warren, Helen R A1 - Chasman, Daniel I A1 - Zhou, Kaixin A1 - Arsenault, Benoit J A1 - Donnelly, Louise A A1 - Wiggins, Kerri L A1 - Avery, Christy L A1 - Griffin, Paula A1 - Feng, QiPing A1 - Taylor, Kent D A1 - Li, Guo A1 - Evans, Daniel S A1 - Smith, Albert V A1 - de Keyser, Catherine E A1 - Johnson, Andrew D A1 - de Craen, Anton J M A1 - Stott, David J A1 - Buckley, Brendan M A1 - Ford, Ian A1 - Westendorp, Rudi G J A1 - Slagboom, P Eline A1 - Sattar, Naveed A1 - Munroe, Patricia B A1 - Sever, Peter A1 - Poulter, Neil A1 - Stanton, Alice A1 - Shields, Denis C A1 - O'Brien, Eoin A1 - Shaw-Hawkins, Sue A1 - Chen, Y-D Ida A1 - Nickerson, Deborah A A1 - Smith, Joshua D A1 - Dubé, Marie Pierre A1 - Boekholdt, S Matthijs A1 - Hovingh, G Kees A1 - Kastelein, John J P A1 - McKeigue, Paul M A1 - Betteridge, John A1 - Neil, Andrew A1 - Durrington, Paul N A1 - Doney, Alex A1 - Carr, Fiona A1 - Morris, Andrew A1 - McCarthy, Mark I A1 - Groop, Leif A1 - Ahlqvist, Emma A1 - Bis, Joshua C A1 - Rice, Kenneth A1 - Smith, Nicholas L A1 - Lumley, Thomas A1 - Whitsel, Eric A A1 - Stürmer, Til A1 - Boerwinkle, Eric A1 - Ngwa, Julius S A1 - O'Donnell, Christopher J A1 - Vasan, Ramachandran S A1 - Wei, Wei-Qi A1 - Wilke, Russell A A1 - Liu, Ching-Ti A1 - Sun, Fangui A1 - Guo, Xiuqing A1 - Heckbert, Susan R A1 - Post, Wendy A1 - Sotoodehnia, Nona A1 - Arnold, Alice M A1 - Stafford, Jeanette M A1 - Ding, Jingzhong A1 - Herrington, David M A1 - Kritchevsky, Stephen B A1 - Eiriksdottir, Gudny A1 - Launer, Leonore J A1 - Harris, Tamara B A1 - Chu, Audrey Y A1 - Giulianini, Franco A1 - MacFadyen, Jean G A1 - Barratt, Bryan J A1 - Nyberg, Fredrik A1 - Stricker, Bruno H A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Emilsson, Valur A1 - Franco, Oscar H A1 - Ridker, Paul M A1 - Gudnason, Vilmundur A1 - Liu, Yongmei A1 - Denny, Joshua C A1 - Ballantyne, Christie M A1 - Rotter, Jerome I A1 - Adrienne Cupples, L A1 - Psaty, Bruce M A1 - Palmer, Colin N A A1 - Tardif, Jean-Claude A1 - Colhoun, Helen M A1 - Hitman, Graham A1 - Krauss, Ronald M A1 - Wouter Jukema, J A1 - Caulfield, Mark J KW - Cholesterol, LDL KW - Genome-Wide Association Study KW - Humans KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors KW - Pharmacogenetics KW - Polymorphism, Single Nucleotide AB -

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

VL - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25350695?dopt=Abstract ER - TY - JOUR T1 - Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. JF - Nature Y1 - 2015 A1 - Do, Ron A1 - Stitziel, Nathan O A1 - Won, Hong-Hee A1 - Jørgensen, Anders Berg A1 - Duga, Stefano A1 - Angelica Merlini, Pier A1 - Kiezun, Adam A1 - Farrall, Martin A1 - Goel, Anuj A1 - Zuk, Or A1 - Guella, Illaria A1 - Asselta, Rosanna A1 - Lange, Leslie A A1 - Peloso, Gina M A1 - Auer, Paul L A1 - Girelli, Domenico A1 - Martinelli, Nicola A1 - Farlow, Deborah N A1 - DePristo, Mark A A1 - Roberts, Robert A1 - Stewart, Alexander F R A1 - Saleheen, Danish A1 - Danesh, John A1 - Epstein, Stephen E A1 - Sivapalaratnam, Suthesh A1 - Hovingh, G Kees A1 - Kastelein, John J A1 - Samani, Nilesh J A1 - Schunkert, Heribert A1 - Erdmann, Jeanette A1 - Shah, Svati H A1 - Kraus, William E A1 - Davies, Robert A1 - Nikpay, Majid A1 - Johansen, Christopher T A1 - Wang, Jian A1 - Hegele, Robert A A1 - Hechter, Eliana A1 - März, Winfried A1 - Kleber, Marcus E A1 - Huang, Jie A1 - Johnson, Andrew D A1 - Li, Mingyao A1 - Burke, Greg L A1 - Gross, Myron A1 - Liu, Yongmei A1 - Assimes, Themistocles L A1 - Heiss, Gerardo A1 - Lange, Ethan M A1 - Folsom, Aaron R A1 - Taylor, Herman A A1 - Olivieri, Oliviero A1 - Hamsten, Anders A1 - Clarke, Robert A1 - Reilly, Dermot F A1 - Yin, Wu A1 - Rivas, Manuel A A1 - Donnelly, Peter A1 - Rossouw, Jacques E A1 - Psaty, Bruce M A1 - Herrington, David M A1 - Wilson, James G A1 - Rich, Stephen S A1 - Bamshad, Michael J A1 - Tracy, Russell P A1 - Cupples, L Adrienne A1 - Rader, Daniel J A1 - Reilly, Muredach P A1 - Spertus, John A A1 - Cresci, Sharon A1 - Hartiala, Jaana A1 - Tang, W H Wilson A1 - Hazen, Stanley L A1 - Allayee, Hooman A1 - Reiner, Alex P A1 - Carlson, Christopher S A1 - Kooperberg, Charles A1 - Jackson, Rebecca D A1 - Boerwinkle, Eric A1 - Lander, Eric S A1 - Schwartz, Stephen M A1 - Siscovick, David S A1 - McPherson, Ruth A1 - Tybjaerg-Hansen, Anne A1 - Abecasis, Goncalo R A1 - Watkins, Hugh A1 - Nickerson, Deborah A A1 - Ardissino, Diego A1 - Sunyaev, Shamil R A1 - O'Donnell, Christopher J A1 - Altshuler, David A1 - Gabriel, Stacey A1 - Kathiresan, Sekar KW - Age Factors KW - Age of Onset KW - Alleles KW - Apolipoproteins A KW - Case-Control Studies KW - Cholesterol, LDL KW - Coronary Artery Disease KW - Exome KW - Female KW - Genetic Predisposition to Disease KW - Genetics, Population KW - Heterozygote KW - Humans KW - Male KW - Middle Aged KW - Mutation KW - Myocardial Infarction KW - National Heart, Lung, and Blood Institute (U.S.) KW - Receptors, LDL KW - Triglycerides KW - United States AB -

Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.

VL - 518 IS - 7537 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25487149?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of genome-wide association studies of HDL cholesterol response to statins. JF - J Med Genet Y1 - 2016 A1 - Postmus, Iris A1 - Warren, Helen R A1 - Trompet, Stella A1 - Arsenault, Benoit J A1 - Avery, Christy L A1 - Bis, Joshua C A1 - Chasman, Daniel I A1 - de Keyser, Catherine E A1 - Deshmukh, Harshal A A1 - Evans, Daniel S A1 - Feng, QiPing A1 - Li, Xiaohui A1 - Smit, Roelof A J A1 - Smith, Albert V A1 - Sun, Fangui A1 - Taylor, Kent D A1 - Arnold, Alice M A1 - Barnes, Michael R A1 - Barratt, Bryan J A1 - Betteridge, John A1 - Boekholdt, S Matthijs A1 - Boerwinkle, Eric A1 - Buckley, Brendan M A1 - Chen, Y-D Ida A1 - de Craen, Anton J M A1 - Cummings, Steven R A1 - Denny, Joshua C A1 - Dubé, Marie Pierre A1 - Durrington, Paul N A1 - Eiriksdottir, Gudny A1 - Ford, Ian A1 - Guo, Xiuqing A1 - Harris, Tamara B A1 - Heckbert, Susan R A1 - Hofman, Albert A1 - Hovingh, G Kees A1 - Kastelein, John J P A1 - Launer, Leonore J A1 - Liu, Ching-Ti A1 - Liu, Yongmei A1 - Lumley, Thomas A1 - McKeigue, Paul M A1 - Munroe, Patricia B A1 - Neil, Andrew A1 - Nickerson, Deborah A A1 - Nyberg, Fredrik A1 - O'Brien, Eoin A1 - O'Donnell, Christopher J A1 - Post, Wendy A1 - Poulter, Neil A1 - Vasan, Ramachandran S A1 - Rice, Kenneth A1 - Rich, Stephen S A1 - Rivadeneira, Fernando A1 - Sattar, Naveed A1 - Sever, Peter A1 - Shaw-Hawkins, Sue A1 - Shields, Denis C A1 - Slagboom, P Eline A1 - Smith, Nicholas L A1 - Smith, Joshua D A1 - Sotoodehnia, Nona A1 - Stanton, Alice A1 - Stott, David J A1 - Stricker, Bruno H A1 - Stürmer, Til A1 - Uitterlinden, André G A1 - Wei, Wei-Qi A1 - Westendorp, Rudi G J A1 - Whitsel, Eric A A1 - Wiggins, Kerri L A1 - Wilke, Russell A A1 - Ballantyne, Christie M A1 - Colhoun, Helen M A1 - Cupples, L Adrienne A1 - Franco, Oscar H A1 - Gudnason, Vilmundur A1 - Hitman, Graham A1 - Palmer, Colin N A A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Stafford, Jeanette M A1 - Stein, Charles M A1 - Tardif, Jean-Claude A1 - Caulfield, Mark J A1 - Jukema, J Wouter A1 - Rotter, Jerome I A1 - Krauss, Ronald M AB -

BACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation.

METHODS AND RESULTS: We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1×10(-4) from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5×10(-8)) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment.

CONCLUSIONS: Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.

VL - 53 IS - 12 ER - TY - JOUR T1 - Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis. JF - PLoS Med Y1 - 2017 A1 - Wheeler, Eleanor A1 - Leong, Aaron A1 - Liu, Ching-Ti A1 - Hivert, Marie-France A1 - Strawbridge, Rona J A1 - Podmore, Clara A1 - Li, Man A1 - Yao, Jie A1 - Sim, Xueling A1 - Hong, Jaeyoung A1 - Chu, Audrey Y A1 - Zhang, Weihua A1 - Wang, Xu A1 - Chen, Peng A1 - Maruthur, Nisa M A1 - Porneala, Bianca C A1 - Sharp, Stephen J A1 - Jia, Yucheng A1 - Kabagambe, Edmond K A1 - Chang, Li-Ching A1 - Chen, Wei-Min A1 - Elks, Cathy E A1 - Evans, Daniel S A1 - Fan, Qiao A1 - Giulianini, Franco A1 - Go, Min Jin A1 - Hottenga, Jouke-Jan A1 - Hu, Yao A1 - Jackson, Anne U A1 - Kanoni, Stavroula A1 - Kim, Young Jin A1 - Kleber, Marcus E A1 - Ladenvall, Claes A1 - Lecoeur, Cécile A1 - Lim, Sing-Hui A1 - Lu, Yingchang A1 - Mahajan, Anubha A1 - Marzi, Carola A1 - Nalls, Mike A A1 - Navarro, Pau A1 - Nolte, Ilja M A1 - Rose, Lynda M A1 - Rybin, Denis V A1 - Sanna, Serena A1 - Shi, Yuan A1 - Stram, Daniel O A1 - Takeuchi, Fumihiko A1 - Tan, Shu Pei A1 - van der Most, Peter J A1 - van Vliet-Ostaptchouk, Jana V A1 - Wong, Andrew A1 - Yengo, Loic A1 - Zhao, Wanting A1 - Goel, Anuj A1 - Martinez Larrad, Maria Teresa A1 - Radke, Dörte A1 - Salo, Perttu A1 - Tanaka, Toshiko A1 - van Iperen, Erik P A A1 - Abecasis, Goncalo A1 - Afaq, Saima A1 - Alizadeh, Behrooz Z A1 - Bertoni, Alain G A1 - Bonnefond, Amélie A1 - Böttcher, Yvonne A1 - Bottinger, Erwin P A1 - Campbell, Harry A1 - Carlson, Olga D A1 - Chen, Chien-Hsiun A1 - Cho, Yoon Shin A1 - Garvey, W Timothy A1 - Gieger, Christian A1 - Goodarzi, Mark O A1 - Grallert, Harald A1 - Hamsten, Anders A1 - Hartman, Catharina A A1 - Herder, Christian A1 - Hsiung, Chao Agnes A1 - Huang, Jie A1 - Igase, Michiya A1 - Isono, Masato A1 - Katsuya, Tomohiro A1 - Khor, Chiea-Chuen A1 - Kiess, Wieland A1 - Kohara, Katsuhiko A1 - Kovacs, Peter A1 - Lee, Juyoung A1 - Lee, Wen-Jane A1 - Lehne, Benjamin A1 - Li, Huaixing A1 - Liu, Jianjun A1 - Lobbens, Stephane A1 - Luan, Jian'an A1 - Lyssenko, Valeriya A1 - Meitinger, Thomas A1 - Miki, Tetsuro A1 - Miljkovic, Iva A1 - Moon, Sanghoon A1 - Mulas, Antonella A1 - Müller, Gabriele A1 - Müller-Nurasyid, Martina A1 - Nagaraja, Ramaiah A1 - Nauck, Matthias A1 - Pankow, James S A1 - Polasek, Ozren A1 - Prokopenko, Inga A1 - Ramos, Paula S A1 - Rasmussen-Torvik, Laura A1 - Rathmann, Wolfgang A1 - Rich, Stephen S A1 - Robertson, Neil R A1 - Roden, Michael A1 - Roussel, Ronan A1 - Rudan, Igor A1 - Scott, Robert A A1 - Scott, William R A1 - Sennblad, Bengt A1 - Siscovick, David S A1 - Strauch, Konstantin A1 - Sun, Liang A1 - Swertz, Morris A1 - Tajuddin, Salman M A1 - Taylor, Kent D A1 - Teo, Yik-Ying A1 - Tham, Yih Chung A1 - Tönjes, Anke A1 - Wareham, Nicholas J A1 - Willemsen, Gonneke A1 - Wilsgaard, Tom A1 - Hingorani, Aroon D A1 - Egan, Josephine A1 - Ferrucci, Luigi A1 - Hovingh, G Kees A1 - Jula, Antti A1 - Kivimaki, Mika A1 - Kumari, Meena A1 - Njølstad, Inger A1 - Palmer, Colin N A A1 - Serrano Ríos, Manuel A1 - Stumvoll, Michael A1 - Watkins, Hugh A1 - Aung, Tin A1 - Blüher, Matthias A1 - Boehnke, Michael A1 - Boomsma, Dorret I A1 - Bornstein, Stefan R A1 - Chambers, John C A1 - Chasman, Daniel I A1 - Chen, Yii-Der Ida A1 - Chen, Yduan-Tsong A1 - Cheng, Ching-Yu A1 - Cucca, Francesco A1 - de Geus, Eco J C A1 - Deloukas, Panos A1 - Evans, Michele K A1 - Fornage, Myriam A1 - Friedlander, Yechiel A1 - Froguel, Philippe A1 - Groop, Leif A1 - Gross, Myron D A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Heng, Chew-Kiat A1 - Ingelsson, Erik A1 - Kato, Norihiro A1 - Kim, Bong-Jo A1 - Koh, Woon-Puay A1 - Kooner, Jaspal S A1 - Körner, Antje A1 - Kuh, Diana A1 - Kuusisto, Johanna A1 - Laakso, Markku A1 - Lin, Xu A1 - Liu, Yongmei A1 - Loos, Ruth J F A1 - Magnusson, Patrik K E A1 - März, Winfried A1 - McCarthy, Mark I A1 - Oldehinkel, Albertine J A1 - Ong, Ken K A1 - Pedersen, Nancy L A1 - Pereira, Mark A A1 - Peters, Annette A1 - Ridker, Paul M A1 - Sabanayagam, Charumathi A1 - Sale, Michele A1 - Saleheen, Danish A1 - Saltevo, Juha A1 - Schwarz, Peter Eh A1 - Sheu, Wayne H H A1 - Snieder, Harold A1 - Spector, Timothy D A1 - Tabara, Yasuharu A1 - Tuomilehto, Jaakko A1 - van Dam, Rob M A1 - Wilson, James G A1 - Wilson, James F A1 - Wolffenbuttel, Bruce H R A1 - Wong, Tien Yin A1 - Wu, Jer-Yuarn A1 - Yuan, Jian-Min A1 - Zonderman, Alan B A1 - Soranzo, Nicole A1 - Guo, Xiuqing A1 - Roberts, David J A1 - Florez, Jose C A1 - Sladek, Robert A1 - Dupuis, Josée A1 - Morris, Andrew P A1 - Tai, E-Shyong A1 - Selvin, Elizabeth A1 - Rotter, Jerome I A1 - Langenberg, Claudia A1 - Barroso, Inês A1 - Meigs, James B KW - Diabetes Mellitus, Type 2 KW - Genetic Variation KW - Genome-Wide Association Study KW - Glycated Hemoglobin A KW - Humans KW - Phenotype KW - Risk AB -

BACKGROUND: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.

METHODS & FINDINGS: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 × 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55-0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.

CONCLUSIONS: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

VL - 14 IS - 9 ER -