A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance by Manning Alisa K, Hivert Marie-France, Scott Robert A, Grimsby Jonna L, Bouatia-Naji Nabila, Chen Han, Rybin Denis, Liu Ching-Ti, Bielak Lawrence F, Prokopenko Inga, Amin Najaf, Barnes Daniel, Cadby Gemma, Hottenga Jouke-Jan, Ingelsson Erik, Jackson Anne U, Johnson Toby, Kanoni Stavroula, Ladenvall Claes, Lagou Vasiliki, Lahti Jari, Lecoeur Cecile, Liu Yongmei, Martinez-Larrad Maria Teresa, Montasser May E, Navarro Pau, Perry John R B, Rasmussen-Torvik Laura J, Salo Perttu, Sattar Naveed, Shungin Dmitry, Strawbridge Rona J, Tanaka Toshiko, van Duijn Cornelia M, An Ping, de Andrade Mariza, Andrews Jeanette S, Aspelund Thor, Atalay Mustafa, Aulchenko Yurii, Balkau Beverley, Bandinelli Stefania, Beckmann Jacques S, Beilby John P, Bellis Claire, Bergman Richard N, Blangero John, Boban Mladen, Boehnke Michael, Boerwinkle Eric, Bonnycastle Lori L, Boomsma Dorret I, Borecki Ingrid B, Böttcher Yvonne, Bouchard Claude, Brunner Eric, Budimir Danijela, Campbell Harry, Carlson Olga, Chines Peter S, Clarke Robert, Collins Francis S, Corbatón-Anchuelo Arturo, Couper David, de Faire Ulf, Dedoussis George V, Deloukas Panos, Dimitriou Maria, Egan Josephine M, Eiriksdottir Gudny, Erdos Michael R, Eriksson Johan G, Eury Elodie, Ferrucci Luigi, Ford Ian, Forouhi Nita G, Fox Caroline S, Franzosi Maria Grazia, Franks Paul W, Frayling Timothy M, Froguel Philippe, Galan Pilar, de Geus Eco, Gigante Bruna, Glazer Nicole L, Goel Anuj, Groop Leif, Gudnason Vilmundur, Hallmans Göran, Hamsten Anders, Hansson Ola, Harris Tamara B, Hayward Caroline, Heath Simon, Hercberg Serge, Hicks Andrew A, Hingorani Aroon, Hofman Albert, Hui Jennie, Hung Joseph, Jarvelin Marjo-Riitta, Jhun Min A, Johnson Paul C D, Jukema J Wouter, Jula Antti, Kao W H, Kaprio Jaakko, Kardia Sharon L R, Keinanen-Kiukaanniemi Sirkka, Kivimaki Mika, Kolcic Ivana, Kovacs Peter, Kumari Meena, Kuusisto Johanna, Kyvik Kirsten Ohm, Laakso Markku, Lakka Timo, Lannfelt Lars, Lathrop G Mark, Launer Lenore J, Leander Karin, Li Guo, Lind Lars, Lindstrom Jaana, Lobbens Stéphane, Loos Ruth J F, Luan Jian'an, Lyssenko Valeriya, Mägi Reedik, Magnusson Patrik K E, Marmot Michael, Meneton Pierre, Mohlke Karen L, Mooser Vincent, Morken Mario A, Miljkovic Iva, Narisu Narisu, O'Connell Jeff, Ong Ken K, Oostra Ben A, Palmer Lyle J, Palotie Aarno, Pankow James S, Peden John F, Pedersen Nancy L, Pehlic Marina, Peltonen Leena, Penninx Brenda, Pericic Marijana, Perola Markus, Perusse Louis, Peyser Patricia A, Polasek Ozren, Pramstaller Peter P, Province Michael A, Räikkönen Katri, Rauramaa Rainer, Rehnberg Emil, Rice Ken, Rotter Jerome I, Rudan Igor, Ruokonen Aimo, Saaristo Timo, Sabater-Lleal Maria, Salomaa Veikko, Savage David B, Saxena Richa, Schwarz Peter, Seedorf Udo, Sennblad Bengt, Serrano-Rios Manuel, Shuldiner Alan R, Sijbrands Eric J G, Siscovick David S, Smit Johannes H, Small Kerrin S, Smith Nicholas L, Smith Albert Vernon, Stančáková Alena, Stirrups Kathleen, Stumvoll Michael, Sun Yan V, Swift Amy J, Tönjes Anke, Tuomilehto Jaakko, Trompet Stella, Uitterlinden Andre G, Uusitupa Matti, Vikström Max, Vitart Veronique, Vohl Marie-Claude, Voight Benjamin F, Vollenweider Peter, Waeber Gerard, Waterworth Dawn M, Watkins Hugh, Wheeler Eleanor, Widen Elisabeth, Wild Sarah H, Willems Sara M, Willemsen Gonneke, Wilson James F, Witteman Jacqueline C M, Wright Alan F, Yaghootkar Hanieh, Zelenika Diana, Zemunik Tatijana, Zgaga Lina, DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, The Multiple Tissue Human Expression Resource (MUTHER) Consortium, Wareham Nicholas J, McCarthy Mark I, Barroso Ines, Watanabe Richard M, Florez Jose C, Dupuis Josée, Meigs James B, Langenberg Claudia in Nature genetics (2012). PubMed

Abstract

Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and beta-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.

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