A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance

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

Research output: Contribution to journalArticle

401 Citations (Scopus)

Abstract

Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-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.

Original languageEnglish
Pages (from-to)659-669
Number of pages11
JournalNature Genetics
Volume44
Issue number6
DOIs
Publication statusPublished - Jun 2012

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Insulin Resistance
Fasting
Body Mass Index
Genome
Type 2 Diabetes Mellitus
Insulin
Genome-Wide Association Study
HDL Cholesterol
Meta-Analysis
Triglycerides
Joints
Glucose
Genes

ASJC Scopus subject areas

  • Genetics

Cite this

Manning, A. K., Hivert, M. F., Scott, R. A., Grimsby, J. L., Bouatia-Naji, N., Chen, H., ... Langenberg, C. (2012). A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance. Nature Genetics, 44(6), 659-669. https://doi.org/10.1038/ng.2274

A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance. / 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.; Corbató-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; Mark Lathrop, G.; 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; Wareham, Nicholas J.; McCarthy, Mark I.; Barroso, Ines; Watanabe, Richard M.; Florez, Jose C.; Dupuis, José; Meigs, James B.; Langenberg, Claudia.

In: Nature Genetics, Vol. 44, No. 6, 06.2012, p. 659-669.

Research output: Contribution to journalArticle

Manning, AK, Hivert, MF, Scott, RA, Grimsby, JL, Bouatia-Naji, N, Chen, H, Rybin, D, Liu, CT, Bielak, LF, Prokopenko, I, Amin, N, Barnes, D, Cadby, G, Hottenga, JJ, Ingelsson, E, Jackson, AU, Johnson, T, Kanoni, S, Ladenvall, C, Lagou, V, Lahti, J, Lecoeur, C, Liu, Y, Martinez-Larrad, MT, Montasser, ME, Navarro, P, Perry, JRB, Rasmussen-Torvik, LJ, Salo, P, Sattar, N, Shungin, D, Strawbridge, RJ, Tanaka, T, Van Duijn, CM, An, P, De Andrade, M, Andrews, JS, Aspelund, T, Atalay, M, Aulchenko, Y, Balkau, B, Bandinelli, S, Beckmann, JS, Beilby, JP, Bellis, C, Bergman, RN, Blangero, J, Boban, M, Boehnke, M, Boerwinkle, E, Bonnycastle, LL, Boomsma, DI, Borecki, IB, Böttcher, Y, Bouchard, C, Brunner, E, Budimir, D, Campbell, H, Carlson, O, Chines, PS, Clarke, R, Collins, FS, Corbató-Anchuelo, A, Couper, D, De Faire, U, Dedoussis, GV, Deloukas, P, Dimitriou, M, Egan, JM, Eiriksdottir, G, Erdos, MR, Eriksson, JG, Eury, E, Ferrucci, L, Ford, I, Forouhi, NG, Fox, CS, Franzosi, MG, Franks, PW, Frayling, TM, Froguel, P, Galan, P, De Geus, E, Gigante, B, Glazer, NL, Goel, A, Groop, L, Gudnason, V, Hallmans, G, Hamsten, A, Hansson, O, Harris, TB, Hayward, C, Heath, S, Hercberg, S, Hicks, AA, Hingorani, A, Hofman, A, Hui, J, Hung, J, Jarvelin, MR, Jhun, MA, Johnson, PCD, Jukema, JW, Jula, A, Kao, WH, Kaprio, J, Kardia, SLR, Keinanen-Kiukaanniemi, S, Kivimaki, M, Kolcic, I, Kovacs, P, Kumari, M, Kuusisto, J, Kyvik, KO, Laakso, M, Lakka, T, Lannfelt, L, Mark Lathrop, G, Launer, LJ, Leander, K, Li, G, Lind, L, Lindstrom, J, Lobbens, S, Loos, RJF, Luan, JA, Lyssenko, V, Mägi, R, Magnusson, PKE, Marmot, M, Meneton, P, Mohlke, KL, Mooser, V, Morken, MA, Miljkovic, I, Narisu, N, O'Connell, J, Ong, KK, Oostra, BA, Palmer, LJ, Palotie, A, Pankow, JS, Peden, JF, Pedersen, NL, Pehlic, M, Peltonen, L, Penninx, B, Pericic, M, Perola, M, Perusse, L, Peyser, PA, Polasek, O, Pramstaller, PP, Province, MA, Räikkönen, K, Rauramaa, R, Rehnberg, E, Rice, K, Rotter, JI, Rudan, I, Ruokonen, A, Saaristo, T, Sabater-Lleal, M, Salomaa, V, Savage, DB, Saxena, R, Schwarz, P, Seedorf, U, Sennblad, B, Serrano-Rios, M, Shuldiner, AR, Sijbrands, EJG, Siscovick, DS, Smit, JH, Small, KS, Smith, NL, Smith, AV, Stančáková, A, Stirrups, K, Stumvoll, M, Sun, YV, Swift, AJ, Tönjes, A, Tuomilehto, J, Trompet, S, Uitterlinden, AG, Uusitupa, M, Vikström, M, Vitart, V, Vohl, MC, Voight, BF, Vollenweider, P, Waeber, G, Waterworth, DM, Watkins, H, Wheeler, E, Widen, E, Wild, SH, Willems, SM, Willemsen, G, Wilson, JF, Witteman, JCM, Wright, AF, Yaghootkar, H, Zelenika, D, Zemunik, T, Zgaga, L, Wareham, NJ, McCarthy, MI, Barroso, I, Watanabe, RM, Florez, JC, Dupuis, J, Meigs, JB & Langenberg, C 2012, 'A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance', Nature Genetics, vol. 44, no. 6, pp. 659-669. https://doi.org/10.1038/ng.2274
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. ; Corbató-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 ; Mark Lathrop, G. ; 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 ; Wareham, Nicholas J. ; McCarthy, Mark I. ; Barroso, Ines ; Watanabe, Richard M. ; Florez, Jose C. ; Dupuis, José ; Meigs, James B. ; Langenberg, Claudia. / A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance. In: Nature Genetics. 2012 ; Vol. 44, No. 6. pp. 659-669.
@article{975f0c38bba44eb896566398c4183ffe,
title = "A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance",
abstract = "Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-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.",
author = "Manning, {Alisa K.} and Hivert, {Marie France} and Scott, {Robert A.} and Grimsby, {Jonna L.} and Nabila Bouatia-Naji and Han Chen and Denis Rybin and Liu, {Ching Ti} and Bielak, {Lawrence F.} and Inga Prokopenko and Najaf Amin and Daniel Barnes and Gemma Cadby and Hottenga, {Jouke Jan} and Erik Ingelsson and Jackson, {Anne U.} and Toby Johnson and Stavroula Kanoni and Claes Ladenvall and Vasiliki Lagou and Jari Lahti and Cecile Lecoeur and Yongmei Liu and Martinez-Larrad, {Maria Teresa} and Montasser, {May E.} and Pau Navarro and Perry, {John R B} and Rasmussen-Torvik, {Laura J.} and Perttu Salo and Naveed Sattar and Dmitry Shungin and Strawbridge, {Rona J.} and Toshiko Tanaka and {Van Duijn}, {Cornelia M.} and Ping An and {De Andrade}, Mariza and Andrews, {Jeanette S.} and Thor Aspelund and Mustafa Atalay and Yurii Aulchenko and Beverley Balkau and Stefania Bandinelli and Beckmann, {Jacques S.} and Beilby, {John P.} and Claire Bellis and Bergman, {Richard N.} and John Blangero and Mladen Boban and Michael Boehnke and Eric Boerwinkle and Bonnycastle, {Lori L.} and Boomsma, {Dorret I.} and Borecki, {Ingrid B.} and Yvonne B{\"o}ttcher and Claude Bouchard and Eric Brunner and Danijela Budimir and Harry Campbell and Olga Carlson and Chines, {Peter S.} and Robert Clarke and Collins, {Francis S.} and Arturo Corbat{\'o}-Anchuelo and David Couper and {De Faire}, Ulf and Dedoussis, {George V.} and Panos Deloukas and Maria Dimitriou and Egan, {Josephine M.} and Gudny Eiriksdottir and Erdos, {Michael R.} and Eriksson, {Johan G.} and Elodie Eury and Luigi Ferrucci and Ian Ford and Forouhi, {Nita G.} and Fox, {Caroline S.} and Franzosi, {Maria Grazia} and Franks, {Paul W.} and Frayling, {Timothy M.} and Philippe Froguel and Pilar Galan and {De Geus}, Eco and Bruna Gigante and Glazer, {Nicole L.} and Anuj Goel and Leif Groop and Vilmundur Gudnason and G{\"o}ran Hallmans and Anders Hamsten and Ola Hansson and Harris, {Tamara B.} and Caroline Hayward and Simon Heath and Serge Hercberg and Hicks, {Andrew A.} and Aroon Hingorani and Albert Hofman and Jennie Hui and Joseph Hung and Jarvelin, {Marjo Riitta} and Jhun, {Min A.} and Johnson, {Paul C D} and Jukema, {J. Wouter} and Antti Jula and Kao, {W. H.} and Jaakko Kaprio and Kardia, {Sharon L R} and Sirkka Keinanen-Kiukaanniemi and Mika Kivimaki and Ivana Kolcic and Peter Kovacs and Meena Kumari and Johanna Kuusisto and Kyvik, {Kirsten Ohm} and Markku Laakso and Timo Lakka and Lars Lannfelt and {Mark Lathrop}, G. and Launer, {Lenore J.} and Karin Leander and Guo Li and Lars Lind and Jaana Lindstrom and St{\'e}phane Lobbens and Loos, {Ruth J F} and Jian'An Luan and Valeriya Lyssenko and Reedik M{\"a}gi and Magnusson, {Patrik K E} and Michael Marmot and Pierre Meneton and Mohlke, {Karen L.} and Vincent Mooser and Morken, {Mario A.} and Iva Miljkovic and Narisu Narisu and Jeff O'Connell and Ong, {Ken K.} and Oostra, {Ben A.} and Palmer, {Lyle J.} and Aarno Palotie and Pankow, {James S.} and Peden, {John F.} and Pedersen, {Nancy L.} and Marina Pehlic and Leena Peltonen and Brenda Penninx and Marijana Pericic and Markus Perola and Louis Perusse and Peyser, {Patricia A.} and Ozren Polasek and Pramstaller, {Peter P.} and Province, {Michael A.} and Katri R{\"a}ikk{\"o}nen and Rainer Rauramaa and Emil Rehnberg and Ken Rice and Rotter, {Jerome I.} and Igor Rudan and Aimo Ruokonen and Timo Saaristo and Maria Sabater-Lleal and Veikko Salomaa and Savage, {David B.} and Richa Saxena and Peter Schwarz and Udo Seedorf and Bengt Sennblad and Manuel Serrano-Rios and Shuldiner, {Alan R.} and Sijbrands, {Eric J G} and Siscovick, {David S.} and Smit, {Johannes H.} and Small, {Kerrin S.} and Smith, {Nicholas L.} and Smith, {Albert Vernon} and Alena Stanč{\'a}kov{\'a} and Kathleen Stirrups and Michael Stumvoll and Sun, {Yan V.} and Swift, {Amy J.} and Anke T{\"o}njes and Jaakko Tuomilehto and Stella Trompet and Uitterlinden, {Andre G.} and Matti Uusitupa and Max Vikstr{\"o}m and Veronique Vitart and Vohl, {Marie Claude} and Voight, {Benjamin F.} and Peter Vollenweider and Gerard Waeber and Waterworth, {Dawn M.} and Hugh Watkins and Eleanor Wheeler and Elisabeth Widen and Wild, {Sarah H.} and Willems, {Sara M.} and Gonneke Willemsen and Wilson, {James F.} and Witteman, {Jacqueline C M} and Wright, {Alan F.} and Hanieh Yaghootkar and Diana Zelenika and Tatijana Zemunik and Lina Zgaga and Wareham, {Nicholas J.} and McCarthy, {Mark I.} and Ines Barroso and Watanabe, {Richard M.} and Florez, {Jose C.} and Jos{\'e} Dupuis and Meigs, {James B.} and Claudia Langenberg",
year = "2012",
month = "6",
doi = "10.1038/ng.2274",
language = "English",
volume = "44",
pages = "659--669",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "6",

}

TY - JOUR

T1 - A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance

AU - Manning, Alisa K.

AU - Hivert, Marie France

AU - Scott, Robert A.

AU - Grimsby, Jonna L.

AU - Bouatia-Naji, Nabila

AU - Chen, Han

AU - Rybin, Denis

AU - Liu, Ching Ti

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PY - 2012/6

Y1 - 2012/6

N2 - Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-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.

AB - Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-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.

UR - http://www.scopus.com/inward/record.url?scp=84861614905&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861614905&partnerID=8YFLogxK

U2 - 10.1038/ng.2274

DO - 10.1038/ng.2274

M3 - Article

C2 - 22581228

AN - SCOPUS:84861614905

VL - 44

SP - 659

EP - 669

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 6

ER -