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

AK Manning; MF Hivert; RA Scott; JL Grimsby; N Bouatia-Naji; H Chen; D Rybin; CT Liu; LF Bielak; I Prokopenko; Najaf Amin; D Barnes; G Cadby; JJ (Jouke Jan) Hottenga; E Ingelsson; AU Jackson; T Johnson; S Kanoni; C Ladenvall; V Lagou; J Lahti; C Lecoeur; YM Liu; MT Martinez-Larrad; ME Montasser; P Navarro; JRB Perry; LJ Rasmussen-Torvik; P Salo; N Sattar; D Shungin; RJ Strawbridge; T Tanaka; Cornelia Duijn; P An; M de Andrade; JS Andrews; T Aspelund; M Atalay; Yuriy Aulchenko; B Balkau; S Bandinelli; JS Beckmann; JP Beilby; C Bellis; RN Bergman; J Blangero; M Boban; M Boehnke; E Boerwinkle; LL Bonnycastle; DI Boomsma; IB Borecki; Y Boettcher; C Bouchard; E Brunner; D Budimir; H Campbell; O Carlson; PS Chines; R Clarke; FS Collins; A Corbaton-Anchuelo; D Couper; U de Faire; GV Dedoussis; P Deloukas; M Dimitriou; JM Egan; G Eiriksdottir; MR Erdos; JG Eriksson; E Eury; L Ferrucci; I Ford; NG Forouhi; CS Fox; MG Franzosi; PW Franks; TM Frayling; P Froguel; P Galan; ED de Geus; B Gigante; NL Glazer; A Goel; L Groop; V Gudnason; G Hallmans; A Hamsten; O Hansson; TB Harris; C Hayward; S Heath; S Hercberg; AA Hicks; A Hingorani; Bert Hofman; J Hui; J Hung; MR Jarvelin; MA Jhun; PCD Johnson; JW Jukema; A Jula; WH Kao; J Kaprio; SLR Kardia; S Keinanen-Kiukaanniemi; M Kivimaki; I Kolcic; P Kovacs; M Kumari; J Kuusisto; KO Kyvik; M Laakso; T Lakka; L Lannfelt; GM Lathrop; LJ (Lenore) Launer; K Leander; G (Guo) Li; L Lind; J Lindstrom; S Lobbens; RJF Loos; JA Luan; V Lyssenko; R Magi; PKE Magnusson; M Marmot; P Meneton; KL Mohlke; V Mooser; MA Morken; I Miljkovic; N Narisu; J O'Connell; KK Ong; Ben Oostra; LJ Palmer; A Palotie; JS Pankow; JF Peden; NL Pedersen; M Pehlic; L Peltonen; B Penninx; M Pericic; M Perola; L Perusse; PA Peyser; O Polasek; PP Pramstaller; MA Province; K Raikkonen; R Rauramaa; E Rehnberg; K Rice; JI Rotter; I Rudan; A Ruokonen; T Saaristo; M Sabater-Lleal; V Salomaa; DB Savage; R Saxena; P Schwarz; U Seedorf; B Sennblad; M Serrano-Rios; AR Shuldiner; E.J.G. Sijbrands; DS Siscovick; JH Smit; KS Small; NL Smith; AV Smith; A Stancakova; K Stirrups; M Stumvoll; YV Sun; AJ Swift; A Toenjes; J Tuomilehto; S Trompet; André Uitterlinden; M Uusitupa; M Vikstrom; V Vitart; MC Vohl; BF Voight; P Vollenweider; G Waeber; DM Waterworth; H Watkins; E Wheeler; E Widen; SH Wild; SM Willems; G Willemsen; JF Wilson; JCM Witteman; AF Wright; H Yaghootkar; D Zelenika; T Zemunik; L Zgaga; NJ Wareham; MI McCarthy; I Barroso; RM Watanabe; JC Florez; J Dupuis; JB Meigs; C Langenberg

doi:10.1038/ng.2274

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

AK Manning, MF Hivert, RA Scott, JL Grimsby, N Bouatia-Naji, H Chen, D Rybin, CT Liu, LF Bielak, I Prokopenko, Najaf Amin, D Barnes, G Cadby, JJ (Jouke Jan) Hottenga, E Ingelsson, AU Jackson, T Johnson, S Kanoni, C Ladenvall, V LagouJ Lahti, C Lecoeur, YM Liu, MT Martinez-Larrad, ME Montasser, P Navarro, JRB Perry, LJ Rasmussen-Torvik, P Salo, N Sattar, D Shungin, RJ Strawbridge, T Tanaka, Cornelia Duijn, P An, M de Andrade, JS Andrews, T Aspelund, M Atalay, Yuriy Aulchenko, B Balkau, S Bandinelli, JS Beckmann, JP Beilby, C Bellis, RN Bergman, J Blangero, M Boban, M Boehnke, E Boerwinkle, LL Bonnycastle, DI Boomsma, IB Borecki, Y Boettcher, C Bouchard, E Brunner, D Budimir, H Campbell, O Carlson, PS Chines, R Clarke, FS Collins, A Corbaton-Anchuelo, D Couper, U de Faire, GV Dedoussis, P Deloukas, M Dimitriou, JM Egan, G Eiriksdottir, MR Erdos, JG Eriksson, E Eury, L Ferrucci, I Ford, NG Forouhi, CS Fox, MG Franzosi, PW Franks, TM Frayling, P Froguel, P Galan, ED de Geus, B Gigante, NL Glazer, A Goel, L Groop, V Gudnason, G Hallmans, A Hamsten, O Hansson, TB Harris, C Hayward, S Heath, S Hercberg, AA Hicks, A Hingorani, Bert Hofman, J Hui, J Hung, MR Jarvelin, MA Jhun, PCD Johnson, JW Jukema, A Jula, WH Kao, J Kaprio, SLR Kardia, S Keinanen-Kiukaanniemi, M Kivimaki, I Kolcic, P Kovacs, M Kumari, J Kuusisto, KO Kyvik, M Laakso, T Lakka, L Lannfelt, GM Lathrop, LJ (Lenore) Launer, K Leander, G (Guo) Li, L Lind, J Lindstrom, S Lobbens, RJF Loos, JA Luan, V Lyssenko, R Magi, PKE Magnusson, M Marmot, P Meneton, KL Mohlke, V Mooser, MA Morken, I Miljkovic, N Narisu, J O'Connell, KK Ong, Ben Oostra, LJ Palmer, A Palotie, JS Pankow, JF Peden, NL Pedersen, M Pehlic, L Peltonen, B Penninx, M Pericic, M Perola, L Perusse, PA Peyser, O Polasek, PP Pramstaller, MA Province, K Raikkonen, R Rauramaa, E Rehnberg, K Rice, JI Rotter, I Rudan, A Ruokonen, T Saaristo, M Sabater-Lleal, V Salomaa, DB Savage, R Saxena, P Schwarz, U Seedorf, B Sennblad, M Serrano-Rios, AR Shuldiner, E.J.G. Sijbrands, DS Siscovick, JH Smit, KS Small, NL Smith, AV Smith, A Stancakova, K Stirrups, M Stumvoll, YV Sun, AJ Swift, A Toenjes, J Tuomilehto, S Trompet, André Uitterlinden, M Uusitupa, M Vikstrom, V Vitart, MC Vohl, BF Voight, P Vollenweider, G Waeber, DM Waterworth, H Watkins, E Wheeler, E Widen, SH Wild, SM Willems, G Willemsen, JF Wilson, JCM Witteman, AF Wright, H Yaghootkar, D Zelenika, T Zemunik, L Zgaga, NJ Wareham, MI McCarthy, I Barroso, RM Watanabe, JC Florez, J Dupuis, JB Meigs, C Langenberg

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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 x 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	Undefined/Unknown
Pages (from-to)	659-U81
Journal	Nature Genetics
Volume	44
Issue number	6
DOIs	https://doi.org/10.1038/ng.2274
Publication status	Published - 2012

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Cite this

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., ... 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-U81. https://doi.org/10.1038/ng.2274

@article{2d4f5e0ed19641d394940a32f8dbe938,

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 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 x 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 = "AK Manning and MF Hivert and RA Scott and JL Grimsby and N Bouatia-Naji and H Chen and D Rybin and CT Liu and LF Bielak and I Prokopenko and Najaf Amin and D Barnes and G Cadby and Hottenga, {JJ (Jouke Jan)} and E Ingelsson and AU Jackson and T Johnson and S Kanoni and C Ladenvall and V Lagou and J Lahti and C Lecoeur and YM Liu and MT Martinez-Larrad and ME Montasser and P Navarro and JRB Perry and LJ Rasmussen-Torvik and P Salo and N Sattar and D Shungin and RJ Strawbridge and T Tanaka and Cornelia Duijn and P An and {de Andrade}, M and JS Andrews and T Aspelund and M Atalay and Yuriy Aulchenko and B Balkau and S Bandinelli and JS Beckmann and JP Beilby and C Bellis and RN Bergman and J Blangero and M Boban and M Boehnke and E Boerwinkle and LL Bonnycastle and DI Boomsma and IB Borecki and Y Boettcher and C Bouchard and E Brunner and D Budimir and H Campbell and O Carlson and PS Chines and R Clarke and FS Collins and A Corbaton-Anchuelo and D Couper and {de Faire}, U and GV Dedoussis and P Deloukas and M Dimitriou and JM Egan and G Eiriksdottir and MR Erdos and JG Eriksson and E Eury and L Ferrucci and I Ford and NG Forouhi and CS Fox and MG Franzosi and PW Franks and TM Frayling and P Froguel and P Galan and {de Geus}, ED and B Gigante and NL Glazer and A Goel and L Groop and V Gudnason and G Hallmans and A Hamsten and O Hansson and TB Harris and C Hayward and S Heath and S Hercberg and AA Hicks and A Hingorani and Bert Hofman and J Hui and J Hung and MR Jarvelin and MA Jhun and PCD Johnson and JW Jukema and A Jula and WH Kao and J Kaprio and SLR Kardia and S Keinanen-Kiukaanniemi and M Kivimaki and I Kolcic and P Kovacs and M Kumari and J Kuusisto and KO Kyvik and M Laakso and T Lakka and L Lannfelt and GM Lathrop and Launer, {LJ (Lenore)} and K Leander and Li, {G (Guo)} and L Lind and J Lindstrom and S Lobbens and RJF Loos and JA Luan and V Lyssenko and R Magi and PKE Magnusson and M Marmot and P Meneton and KL Mohlke and V Mooser and MA Morken and I Miljkovic and N Narisu and J O'Connell and KK Ong and Ben Oostra and LJ Palmer and A Palotie and JS Pankow and JF Peden and NL Pedersen and M Pehlic and L Peltonen and B Penninx and M Pericic and M Perola and L Perusse and PA Peyser and O Polasek and PP Pramstaller and MA Province and K Raikkonen and R Rauramaa and E Rehnberg and K Rice and JI Rotter and I Rudan and A Ruokonen and T Saaristo and M Sabater-Lleal and V Salomaa and DB Savage and R Saxena and P Schwarz and U Seedorf and B Sennblad and M Serrano-Rios and AR Shuldiner and E.J.G. Sijbrands and DS Siscovick and JH Smit and KS Small and NL Smith and AV Smith and A Stancakova and K Stirrups and M Stumvoll and YV Sun and AJ Swift and A Toenjes and J Tuomilehto and S Trompet and Andr{\'e} Uitterlinden and M Uusitupa and M Vikstrom and V Vitart and MC Vohl and BF Voight and P Vollenweider and G Waeber and DM Waterworth and H Watkins and E Wheeler and E Widen and SH Wild and SM Willems and G Willemsen and JF Wilson and JCM Witteman and AF Wright and H Yaghootkar and D Zelenika and T Zemunik and L Zgaga and NJ Wareham and MI McCarthy and I Barroso and RM Watanabe and JC Florez and J Dupuis and JB Meigs and C Langenberg",

year = "2012",

doi = "10.1038/ng.2274",

language = "Undefined/Unknown",

volume = "44",

pages = "659--U81",

journal = "Nature Genetics",

issn = "1061-4036",

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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, YM, Martinez-Larrad, MT, Montasser, ME, Navarro, P, Perry, JRB, Rasmussen-Torvik, LJ, Salo, P, Sattar, N, Shungin, D, Strawbridge, RJ, Tanaka, T, Duijn, C, 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, Boettcher, Y, Bouchard, C, Brunner, E, Budimir, D, Campbell, H, Carlson, O, Chines, PS, Clarke, R, Collins, FS, Corbaton-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, ED, 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, B, 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, Lathrop, GM, Launer, LJ, Leander, K, Li, G, Lind, L, Lindstrom, J, Lobbens, S, Loos, RJF, Luan, JA, Lyssenko, V, Magi, R, Magnusson, PKE, Marmot, M, Meneton, P, Mohlke, KL, Mooser, V, Morken, MA, Miljkovic, I, Narisu, N, O'Connell, J, Ong, KK, Oostra, B, 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, Raikkonen, 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, Stancakova, A, Stirrups, K, Stumvoll, M, Sun, YV, Swift, AJ, Toenjes, A, Tuomilehto, J, Trompet, S, Uitterlinden, A, Uusitupa, M, Vikstrom, 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-U81. https://doi.org/10.1038/ng.2274

TY - JOUR

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

AU - Manning, AK

AU - Hivert, MF

AU - Scott, RA

AU - Grimsby, JL

AU - Bouatia-Naji, N

AU - Chen, H

AU - Rybin, D

AU - Liu, CT

AU - Bielak, LF

AU - Prokopenko, I

AU - Amin, Najaf

AU - Barnes, D

AU - Cadby, G

AU - Hottenga, JJ (Jouke Jan)

AU - Ingelsson, E

AU - Jackson, AU

AU - Johnson, T

AU - Kanoni, S

AU - Ladenvall, C

AU - Lagou, V

AU - Lahti, J

AU - Lecoeur, C

AU - Liu, YM

AU - Martinez-Larrad, MT

AU - Montasser, ME

AU - Navarro, P

AU - Perry, JRB

AU - Rasmussen-Torvik, LJ

AU - Salo, P

AU - Sattar, N

AU - Shungin, D

AU - Strawbridge, RJ

AU - Tanaka, T

AU - Duijn, Cornelia

AU - An, P

AU - de Andrade, M

AU - Andrews, JS

AU - Aspelund, T

AU - Atalay, M

AU - Aulchenko, Yuriy

AU - Balkau, B

AU - Bandinelli, S

AU - Beckmann, JS

AU - Beilby, JP

AU - Bellis, C

AU - Bergman, RN

AU - Blangero, J

AU - Boban, M

AU - Boehnke, M

AU - Boerwinkle, E

AU - Bonnycastle, LL

AU - Boomsma, DI

AU - Borecki, IB

AU - Boettcher, Y

AU - Bouchard, C

AU - Brunner, E

AU - Budimir, D

AU - Campbell, H

AU - Carlson, O

AU - Chines, PS

AU - Clarke, R

AU - Collins, FS

AU - Corbaton-Anchuelo, A

AU - Couper, D

AU - de Faire, U

AU - Dedoussis, GV

AU - Deloukas, P

AU - Dimitriou, M

AU - Egan, JM

AU - Eiriksdottir, G

AU - Erdos, MR

AU - Eriksson, JG

AU - Eury, E

AU - Ferrucci, L

AU - Ford, I

AU - Forouhi, NG

AU - Fox, CS

AU - Franzosi, MG

AU - Franks, PW

AU - Frayling, TM

AU - Froguel, P

AU - Galan, P

AU - de Geus, ED

AU - Gigante, B

AU - Glazer, NL

AU - Goel, A

AU - Groop, L

AU - Gudnason, V

AU - Hallmans, G

AU - Hamsten, A

AU - Hansson, O

AU - Harris, TB

AU - Hayward, C

AU - Heath, S

AU - Hercberg, S

AU - Hicks, AA

AU - Hingorani, A

AU - Hofman, Bert

AU - Hui, J

AU - Hung, J

AU - Jarvelin, MR

AU - Jhun, MA

AU - Johnson, PCD

AU - Jukema, JW

AU - Jula, A

AU - Kao, WH

AU - Kaprio, J

AU - Kardia, SLR

AU - Keinanen-Kiukaanniemi, S

AU - Kivimaki, M

AU - Kolcic, I

AU - Kovacs, P

AU - Kumari, M

AU - Kuusisto, J

AU - Kyvik, KO

AU - Laakso, M

AU - Lakka, T

AU - Lannfelt, L

AU - Lathrop, GM

AU - Launer, LJ (Lenore)

AU - Leander, K

AU - Li, G (Guo)

AU - Lind, L

AU - Lindstrom, J

AU - Lobbens, S

AU - Loos, RJF

AU - Luan, JA

AU - Lyssenko, V

AU - Magi, R

AU - Magnusson, PKE

AU - Marmot, M

AU - Meneton, P

AU - Mohlke, KL

AU - Mooser, V

AU - Morken, MA

AU - Miljkovic, I

AU - Narisu, N

AU - O'Connell, J

AU - Ong, KK

AU - Oostra, Ben

AU - Palmer, LJ

AU - Palotie, A

AU - Pankow, JS

AU - Peden, JF

AU - Pedersen, NL

AU - Pehlic, M

AU - Peltonen, L

AU - Penninx, B

AU - Pericic, M

AU - Perola, M

AU - Perusse, L

AU - Peyser, PA

AU - Polasek, O

AU - Pramstaller, PP

AU - Province, MA

AU - Raikkonen, K

AU - Rauramaa, R

AU - Rehnberg, E

AU - Rice, K

AU - Rotter, JI

AU - Rudan, I

AU - Ruokonen, A

AU - Saaristo, T

AU - Sabater-Lleal, M

AU - Salomaa, V

AU - Savage, DB

AU - Saxena, R

AU - Schwarz, P

AU - Seedorf, U

AU - Sennblad, B

AU - Serrano-Rios, M

AU - Shuldiner, AR

AU - Sijbrands, E.J.G.

AU - Siscovick, DS

AU - Smit, JH

AU - Small, KS

AU - Smith, NL

AU - Smith, AV

AU - Stancakova, A

AU - Stirrups, K

AU - Stumvoll, M

AU - Sun, YV

AU - Swift, AJ

AU - Toenjes, A

AU - Tuomilehto, J

AU - Trompet, S

AU - Uitterlinden, André

AU - Uusitupa, M

AU - Vikstrom, M

AU - Vitart, V

AU - Vohl, MC

AU - Voight, BF

AU - Vollenweider, P

AU - Waeber, G

AU - Waterworth, DM

AU - Watkins, H

AU - Wheeler, E

AU - Widen, E

AU - Wild, SH

AU - Willems, SM

AU - Willemsen, G

AU - Wilson, JF

AU - Witteman, JCM

AU - Wright, AF

AU - Yaghootkar, H

AU - Zelenika, D

AU - Zemunik, T

AU - Zgaga, L

AU - Wareham, NJ

AU - McCarthy, MI

AU - Barroso, I

AU - Watanabe, RM

AU - Florez, JC

AU - Dupuis, J

AU - Meigs, JB

AU - Langenberg, C

PY - 2012

Y1 - 2012

N2 - 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 x 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 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 x 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.

U2 - 10.1038/ng.2274

DO - 10.1038/ng.2274

M3 - Article

SN - 1061-4036

VL - 44

SP - 659-U81

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -