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 language | English |
|---|---|
| Pages (from-to) | 659-669 |
| Number of pages | 11 |
| Journal | Nature Genetics |
| Volume | 44 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 2012 |
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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 journal › Article › peer-review
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
AU - Bielak, Lawrence F.
AU - Prokopenko, Inga
AU - Amin, Najaf
AU - Barnes, Daniel
AU - Cadby, Gemma
AU - Hottenga, Jouke Jan
AU - Ingelsson, Erik
AU - Jackson, Anne U.
AU - Johnson, Toby
AU - Kanoni, Stavroula
AU - Ladenvall, Claes
AU - Lagou, Vasiliki
AU - Lahti, Jari
AU - Lecoeur, Cecile
AU - Liu, Yongmei
AU - Martinez-Larrad, Maria Teresa
AU - Montasser, May E.
AU - Navarro, Pau
AU - Perry, John R.B.
AU - Rasmussen-Torvik, Laura J.
AU - Salo, Perttu
AU - Sattar, Naveed
AU - Shungin, Dmitry
AU - Strawbridge, Rona J.
AU - Tanaka, Toshiko
AU - Van Duijn, Cornelia M.
AU - An, Ping
AU - De Andrade, Mariza
AU - Andrews, Jeanette S.
AU - Aspelund, Thor
AU - Atalay, Mustafa
AU - Aulchenko, Yurii
AU - Balkau, Beverley
AU - Bandinelli, Stefania
AU - Beckmann, Jacques S.
AU - Beilby, John P.
AU - Bellis, Claire
AU - Bergman, Richard N.
AU - Blangero, John
AU - Boban, Mladen
AU - Boehnke, Michael
AU - Boerwinkle, Eric
AU - Bonnycastle, Lori L.
AU - Boomsma, Dorret I.
AU - Borecki, Ingrid B.
AU - Böttcher, Yvonne
AU - Bouchard, Claude
AU - Brunner, Eric
AU - Budimir, Danijela
AU - Campbell, Harry
AU - Carlson, Olga
AU - Chines, Peter S.
AU - Clarke, Robert
AU - Collins, Francis S.
AU - Corbató-Anchuelo, Arturo
AU - Couper, David
AU - De Faire, Ulf
AU - Dedoussis, George V.
AU - Deloukas, Panos
AU - Dimitriou, Maria
AU - Egan, Josephine M.
AU - Eiriksdottir, Gudny
AU - Erdos, Michael R.
AU - Eriksson, Johan G.
AU - Eury, Elodie
AU - Ferrucci, Luigi
AU - Ford, Ian
AU - Forouhi, Nita G.
AU - Fox, Caroline S.
AU - Franzosi, Maria Grazia
AU - Franks, Paul W.
AU - Frayling, Timothy M.
AU - Froguel, Philippe
AU - Galan, Pilar
AU - De Geus, Eco
AU - Gigante, Bruna
AU - Glazer, Nicole L.
AU - Goel, Anuj
AU - Groop, Leif
AU - Gudnason, Vilmundur
AU - Hallmans, Göran
AU - Hamsten, Anders
AU - Hansson, Ola
AU - Harris, Tamara B.
AU - Hayward, Caroline
AU - Heath, Simon
AU - Hercberg, Serge
AU - Hicks, Andrew A.
AU - Hingorani, Aroon
AU - Hofman, Albert
AU - Hui, Jennie
AU - Hung, Joseph
AU - Jarvelin, Marjo Riitta
AU - Jhun, Min A.
AU - Johnson, Paul C.D.
AU - Jukema, J. Wouter
AU - Jula, Antti
AU - Kao, W. H.
AU - Kaprio, Jaakko
AU - Kardia, Sharon L.R.
AU - Keinanen-Kiukaanniemi, Sirkka
AU - Kivimaki, Mika
AU - Kolcic, Ivana
AU - Kovacs, Peter
AU - Kumari, Meena
AU - Kuusisto, Johanna
AU - Kyvik, Kirsten Ohm
AU - Laakso, Markku
AU - Lakka, Timo
AU - Lannfelt, Lars
AU - Mark Lathrop, G.
AU - Launer, Lenore J.
AU - Leander, Karin
AU - Li, Guo
AU - Lind, Lars
AU - Lindstrom, Jaana
AU - Lobbens, Stéphane
AU - Loos, Ruth J.F.
AU - Luan, Jian'An
AU - Lyssenko, Valeriya
AU - Mägi, Reedik
AU - Magnusson, Patrik K.E.
AU - Marmot, Michael
AU - Meneton, Pierre
AU - Mohlke, Karen L.
AU - Mooser, Vincent
AU - Morken, Mario A.
AU - Miljkovic, Iva
AU - Narisu, Narisu
AU - O'Connell, Jeff
AU - Ong, Ken K.
AU - Oostra, Ben A.
AU - Palmer, Lyle J.
AU - Palotie, Aarno
AU - Pankow, James S.
AU - Peden, John F.
AU - Pedersen, Nancy L.
AU - Pehlic, Marina
AU - Peltonen, Leena
AU - Penninx, Brenda
AU - Pericic, Marijana
AU - Perola, Markus
AU - Perusse, Louis
AU - Peyser, Patricia A.
AU - Polasek, Ozren
AU - Pramstaller, Peter P.
AU - Province, Michael A.
AU - Räikkönen, Katri
AU - Rauramaa, Rainer
AU - Rehnberg, Emil
AU - Rice, Ken
AU - Rotter, Jerome I.
AU - Rudan, Igor
AU - Ruokonen, Aimo
AU - Saaristo, Timo
AU - Sabater-Lleal, Maria
AU - Salomaa, Veikko
AU - Savage, David B.
AU - Saxena, Richa
AU - Schwarz, Peter
AU - Seedorf, Udo
AU - Sennblad, Bengt
AU - Serrano-Rios, Manuel
AU - Shuldiner, Alan R.
AU - Sijbrands, Eric J.G.
AU - Siscovick, David S.
AU - Smit, Johannes H.
AU - Small, Kerrin S.
AU - Smith, Nicholas L.
AU - Smith, Albert Vernon
AU - Stančáková, Alena
AU - Stirrups, Kathleen
AU - Stumvoll, Michael
AU - Sun, Yan V.
AU - Swift, Amy J.
AU - Tönjes, Anke
AU - Tuomilehto, Jaakko
AU - Trompet, Stella
AU - Uitterlinden, Andre G.
AU - Uusitupa, Matti
AU - Vikström, Max
AU - Vitart, Veronique
AU - Vohl, Marie Claude
AU - Voight, Benjamin F.
AU - Vollenweider, Peter
AU - Waeber, Gerard
AU - Waterworth, Dawn M.
AU - Watkins, Hugh
AU - Wheeler, Eleanor
AU - Widen, Elisabeth
AU - Wild, Sarah H.
AU - Willems, Sara M.
AU - Willemsen, Gonneke
AU - Wilson, James F.
AU - Witteman, Jacqueline C.M.
AU - Wright, Alan F.
AU - Yaghootkar, Hanieh
AU - Zelenika, Diana
AU - Zemunik, Tatijana
AU - Zgaga, Lina
AU - Wareham, Nicholas J.
AU - McCarthy, Mark I.
AU - Barroso, Ines
AU - Watanabe, Richard M.
AU - Florez, Jose C.
AU - Dupuis, José
AU - Meigs, James B.
AU - Langenberg, Claudia
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
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 -