Genome-wide association study of the modified stumvoll insulin sensitivity index identifies BCL2 and FAM19A2 as novel insulin sensitivity loci

Geoffrey A. Walford, Stefan Gustafsson, Denis Rybin, Alena Stancáková, Han Chen, Ching Ti Liu, Jaeyoung Hong, Richard A. Jensen, Ken Rice, Andrew P. Morris, Reedik Mägi, Anke Tönjes, Inga Prokopenko, Marcus E. Kleber, Graciela Delgado, Günther Silbernagel, Anne U. Jackson, Emil V. Appel, Niels Grarup, Joshua P. LewisMay E. Montasser, Claes Landenvall, Harald Staiger, Jian'An Luan, Timothy M. Frayling, Michael N. Weedon, Weijia Xie, Sonsoles Morcillo, María Teresa Martínez-Larrad, Mary L. Biggs, Yii Der Ida Chen, Arturo Corbaton-Anchuelo, Kristine Færch, Juan Miguel Gómez-Zumaquero, Mark O. Goodarzi, Jorge Kizer, Heikki A. Koistinen, Aaron Leong, Lars Lind, Cecilia Lindgren, Fausto Machicao, Alisa K. Manning, Gracia María Martín-Núñez, Gemma Rojo-Martínez, Jerome I. Rotter, David S. Siscovick, Joseph M. Zmuda, Zhongyang Zhang, Manuel Serrano-Rios, Ulf Smith, Federico Soriguer, Torben Hansen, Torben J. JØrgensen, Allan Linnenberg, Oluf Pedersen, Mark Walker, Claudia Langenberg, Robert A. Scott, Nicholas J. Wareham, Andreas Fritsche, Hans Ulrich Häring, Norbert Stefan, Leif Groop, Jeff R. O'Connell, Michael Boehnke, Richard N. Bergman, Francis S. Collins, Karen L. Mohlke, Jaakko Tuomilehto, Winfried März, Peter Kovacs, Michael Stumvoll, Bruce M. Psaty, Johanna Kuusisto, Markku Laakso, James B. Meigs, Josée Dupuis, Erik Ingelsson, Jose C. Florez

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: Rs13422522 (NYAP2; P = 8.87 × 10-11), rs12454712 (BCL2; P = 2.7 × 10-8), and rs10506418 (FAM19A2; P = 1.9 × 10-8). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

Original languageEnglish (US)
Pages (from-to)3200-3211
Number of pages12
JournalDiabetes
Volume65
Issue number10
DOIs
StatePublished - Oct 1 2016

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Genome-Wide Association Study
Insulin Resistance
Fasting
Genotype
Meta-Analysis
Genome
Insulin
Glucose

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Walford, G. A., Gustafsson, S., Rybin, D., Stancáková, A., Chen, H., Liu, C. T., ... Florez, J. C. (2016). Genome-wide association study of the modified stumvoll insulin sensitivity index identifies BCL2 and FAM19A2 as novel insulin sensitivity loci. Diabetes, 65(10), 3200-3211. https://doi.org/10.2337/db16-0199

Genome-wide association study of the modified stumvoll insulin sensitivity index identifies BCL2 and FAM19A2 as novel insulin sensitivity loci. / Walford, Geoffrey A.; Gustafsson, Stefan; Rybin, Denis; Stancáková, Alena; Chen, Han; Liu, Ching Ti; Hong, Jaeyoung; Jensen, Richard A.; Rice, Ken; Morris, Andrew P.; Mägi, Reedik; Tönjes, Anke; Prokopenko, Inga; Kleber, Marcus E.; Delgado, Graciela; Silbernagel, Günther; Jackson, Anne U.; Appel, Emil V.; Grarup, Niels; Lewis, Joshua P.; Montasser, May E.; Landenvall, Claes; Staiger, Harald; Luan, Jian'An; Frayling, Timothy M.; Weedon, Michael N.; Xie, Weijia; Morcillo, Sonsoles; Martínez-Larrad, María Teresa; Biggs, Mary L.; Chen, Yii Der Ida; Corbaton-Anchuelo, Arturo; Færch, Kristine; Gómez-Zumaquero, Juan Miguel; Goodarzi, Mark O.; Kizer, Jorge; Koistinen, Heikki A.; Leong, Aaron; Lind, Lars; Lindgren, Cecilia; Machicao, Fausto; Manning, Alisa K.; Martín-Núñez, Gracia María; Rojo-Martínez, Gemma; Rotter, Jerome I.; Siscovick, David S.; Zmuda, Joseph M.; Zhang, Zhongyang; Serrano-Rios, Manuel; Smith, Ulf; Soriguer, Federico; Hansen, Torben; JØrgensen, Torben J.; Linnenberg, Allan; Pedersen, Oluf; Walker, Mark; Langenberg, Claudia; Scott, Robert A.; Wareham, Nicholas J.; Fritsche, Andreas; Häring, Hans Ulrich; Stefan, Norbert; Groop, Leif; O'Connell, Jeff R.; Boehnke, Michael; Bergman, Richard N.; Collins, Francis S.; Mohlke, Karen L.; Tuomilehto, Jaakko; März, Winfried; Kovacs, Peter; Stumvoll, Michael; Psaty, Bruce M.; Kuusisto, Johanna; Laakso, Markku; Meigs, James B.; Dupuis, Josée; Ingelsson, Erik; Florez, Jose C.

In: Diabetes, Vol. 65, No. 10, 01.10.2016, p. 3200-3211.

Research output: Contribution to journalArticle

Walford, GA, Gustafsson, S, Rybin, D, Stancáková, A, Chen, H, Liu, CT, Hong, J, Jensen, RA, Rice, K, Morris, AP, Mägi, R, Tönjes, A, Prokopenko, I, Kleber, ME, Delgado, G, Silbernagel, G, Jackson, AU, Appel, EV, Grarup, N, Lewis, JP, Montasser, ME, Landenvall, C, Staiger, H, Luan, JA, Frayling, TM, Weedon, MN, Xie, W, Morcillo, S, Martínez-Larrad, MT, Biggs, ML, Chen, YDI, Corbaton-Anchuelo, A, Færch, K, Gómez-Zumaquero, JM, Goodarzi, MO, Kizer, J, Koistinen, HA, Leong, A, Lind, L, Lindgren, C, Machicao, F, Manning, AK, Martín-Núñez, GM, Rojo-Martínez, G, Rotter, JI, Siscovick, DS, Zmuda, JM, Zhang, Z, Serrano-Rios, M, Smith, U, Soriguer, F, Hansen, T, JØrgensen, TJ, Linnenberg, A, Pedersen, O, Walker, M, Langenberg, C, Scott, RA, Wareham, NJ, Fritsche, A, Häring, HU, Stefan, N, Groop, L, O'Connell, JR, Boehnke, M, Bergman, RN, Collins, FS, Mohlke, KL, Tuomilehto, J, März, W, Kovacs, P, Stumvoll, M, Psaty, BM, Kuusisto, J, Laakso, M, Meigs, JB, Dupuis, J, Ingelsson, E & Florez, JC 2016, 'Genome-wide association study of the modified stumvoll insulin sensitivity index identifies BCL2 and FAM19A2 as novel insulin sensitivity loci', Diabetes, vol. 65, no. 10, pp. 3200-3211. https://doi.org/10.2337/db16-0199
Walford, Geoffrey A. ; Gustafsson, Stefan ; Rybin, Denis ; Stancáková, Alena ; Chen, Han ; Liu, Ching Ti ; Hong, Jaeyoung ; Jensen, Richard A. ; Rice, Ken ; Morris, Andrew P. ; Mägi, Reedik ; Tönjes, Anke ; Prokopenko, Inga ; Kleber, Marcus E. ; Delgado, Graciela ; Silbernagel, Günther ; Jackson, Anne U. ; Appel, Emil V. ; Grarup, Niels ; Lewis, Joshua P. ; Montasser, May E. ; Landenvall, Claes ; Staiger, Harald ; Luan, Jian'An ; Frayling, Timothy M. ; Weedon, Michael N. ; Xie, Weijia ; Morcillo, Sonsoles ; Martínez-Larrad, María Teresa ; Biggs, Mary L. ; Chen, Yii Der Ida ; Corbaton-Anchuelo, Arturo ; Færch, Kristine ; Gómez-Zumaquero, Juan Miguel ; Goodarzi, Mark O. ; Kizer, Jorge ; Koistinen, Heikki A. ; Leong, Aaron ; Lind, Lars ; Lindgren, Cecilia ; Machicao, Fausto ; Manning, Alisa K. ; Martín-Núñez, Gracia María ; Rojo-Martínez, Gemma ; Rotter, Jerome I. ; Siscovick, David S. ; Zmuda, Joseph M. ; Zhang, Zhongyang ; Serrano-Rios, Manuel ; Smith, Ulf ; Soriguer, Federico ; Hansen, Torben ; JØrgensen, Torben J. ; Linnenberg, Allan ; Pedersen, Oluf ; Walker, Mark ; Langenberg, Claudia ; Scott, Robert A. ; Wareham, Nicholas J. ; Fritsche, Andreas ; Häring, Hans Ulrich ; Stefan, Norbert ; Groop, Leif ; O'Connell, Jeff R. ; Boehnke, Michael ; Bergman, Richard N. ; Collins, Francis S. ; Mohlke, Karen L. ; Tuomilehto, Jaakko ; März, Winfried ; Kovacs, Peter ; Stumvoll, Michael ; Psaty, Bruce M. ; Kuusisto, Johanna ; Laakso, Markku ; Meigs, James B. ; Dupuis, Josée ; Ingelsson, Erik ; Florez, Jose C. / Genome-wide association study of the modified stumvoll insulin sensitivity index identifies BCL2 and FAM19A2 as novel insulin sensitivity loci. In: Diabetes. 2016 ; Vol. 65, No. 10. pp. 3200-3211.
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title = "Genome-wide association study of the modified stumvoll insulin sensitivity index identifies BCL2 and FAM19A2 as novel insulin sensitivity loci",
abstract = "Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: Rs13422522 (NYAP2; P = 8.87 × 10-11), rs12454712 (BCL2; P = 2.7 × 10-8), and rs10506418 (FAM19A2; P = 1.9 × 10-8). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.",
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T1 - Genome-wide association study of the modified stumvoll insulin sensitivity index identifies BCL2 and FAM19A2 as novel insulin sensitivity loci

AU - Walford, Geoffrey A.

AU - Gustafsson, Stefan

AU - Rybin, Denis

AU - Stancáková, Alena

AU - Chen, Han

AU - Liu, Ching Ti

AU - Hong, Jaeyoung

AU - Jensen, Richard A.

AU - Rice, Ken

AU - Morris, Andrew P.

AU - Mägi, Reedik

AU - Tönjes, Anke

AU - Prokopenko, Inga

AU - Kleber, Marcus E.

AU - Delgado, Graciela

AU - Silbernagel, Günther

AU - Jackson, Anne U.

AU - Appel, Emil V.

AU - Grarup, Niels

AU - Lewis, Joshua P.

AU - Montasser, May E.

AU - Landenvall, Claes

AU - Staiger, Harald

AU - Luan, Jian'An

AU - Frayling, Timothy M.

AU - Weedon, Michael N.

AU - Xie, Weijia

AU - Morcillo, Sonsoles

AU - Martínez-Larrad, María Teresa

AU - Biggs, Mary L.

AU - Chen, Yii Der Ida

AU - Corbaton-Anchuelo, Arturo

AU - Færch, Kristine

AU - Gómez-Zumaquero, Juan Miguel

AU - Goodarzi, Mark O.

AU - Kizer, Jorge

AU - Koistinen, Heikki A.

AU - Leong, Aaron

AU - Lind, Lars

AU - Lindgren, Cecilia

AU - Machicao, Fausto

AU - Manning, Alisa K.

AU - Martín-Núñez, Gracia María

AU - Rojo-Martínez, Gemma

AU - Rotter, Jerome I.

AU - Siscovick, David S.

AU - Zmuda, Joseph M.

AU - Zhang, Zhongyang

AU - Serrano-Rios, Manuel

AU - Smith, Ulf

AU - Soriguer, Federico

AU - Hansen, Torben

AU - JØrgensen, Torben J.

AU - Linnenberg, Allan

AU - Pedersen, Oluf

AU - Walker, Mark

AU - Langenberg, Claudia

AU - Scott, Robert A.

AU - Wareham, Nicholas J.

AU - Fritsche, Andreas

AU - Häring, Hans Ulrich

AU - Stefan, Norbert

AU - Groop, Leif

AU - O'Connell, Jeff R.

AU - Boehnke, Michael

AU - Bergman, Richard N.

AU - Collins, Francis S.

AU - Mohlke, Karen L.

AU - Tuomilehto, Jaakko

AU - März, Winfried

AU - Kovacs, Peter

AU - Stumvoll, Michael

AU - Psaty, Bruce M.

AU - Kuusisto, Johanna

AU - Laakso, Markku

AU - Meigs, James B.

AU - Dupuis, Josée

AU - Ingelsson, Erik

AU - Florez, Jose C.

PY - 2016/10/1

Y1 - 2016/10/1

N2 - Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: Rs13422522 (NYAP2; P = 8.87 × 10-11), rs12454712 (BCL2; P = 2.7 × 10-8), and rs10506418 (FAM19A2; P = 1.9 × 10-8). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

AB - Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: Rs13422522 (NYAP2; P = 8.87 × 10-11), rs12454712 (BCL2; P = 2.7 × 10-8), and rs10506418 (FAM19A2; P = 1.9 × 10-8). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.

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