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 Stančáková; 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 Lewis; May 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 Faerch; Juan Miguel 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 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

doi:10.2337/db16-0199

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 Stančáková, 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 Faerch, Juan Miguel 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 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

Department of Public Health

34 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 language	English
Journal	Diabetes
Volume	65
Issue number	10
Pages (from-to)	3200-3211
Number of pages	12
ISSN	0012-1797
DOIs	https://doi.org/10.2337/db16-0199
Publication status	Published - 1 Oct 2016

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Walford, G. A., Gustafsson, S., Rybin, D., Stančáková, A., Chen, H., Liu, C-T., Hong, J., Jensen, R. A., Rice, K., Morris, A. P., Mägi, R., Tönjes, A., Prokopenko, I., Kleber, M. E., Delgado, G., Silbernagel, G., Jackson, A. U., Appel, E. V., Grarup, N., ... 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

Walford, GA, Gustafsson, S, Rybin, D, Stančáková, A, Chen, H, Liu, C-T, 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, J, Frayling, TM, Weedon, MN, Xie, W, Morcillo, S, Martínez-Larrad, MT, Biggs, ML, Ida Chen, Y-D, Corbaton-Anchuelo, A, Faerch, K, 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, T, Linnenberg, A, Pedersen, O, Walker, M, Langenberg, C, Scott, RA, Wareham, NJ, Fritsche, A, Häring, H-U, 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

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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.",

author = "Walford, {Geoffrey A} and Stefan Gustafsson and Denis Rybin and Alena Stan{\v c}{\'a}kov{\'a} and Han Chen and Ching-Ti Liu and Jaeyoung Hong and Jensen, {Richard A} and Ken Rice and Morris, {Andrew P} and Reedik M{\"a}gi and Anke T{\"o}njes and Inga Prokopenko and Kleber, {Marcus E} and Graciela Delgado and G{\"u}nther Silbernagel and Jackson, {Anne U} and Appel, {Emil V} and Niels Grarup and Lewis, {Joshua P} and Montasser, {May E} and Claes Landenvall and Harald Staiger and Jian'an Luan and Frayling, {Timothy M} and Weedon, {Michael N} and Weijia Xie and Sonsoles Morcillo and Mart{\'i}nez-Larrad, {Mar{\'i}a Teresa} and Biggs, {Mary L} and {Ida Chen}, Yii-Der and Arturo Corbaton-Anchuelo and Kristine Faerch and Zumaquero, {Juan Miguel} and Goodarzi, {Mark O} and Jorge Kizer and Koistinen, {Heikki A} and Aaron Leong and Lars Lind and Cecilia Lindgren and Fausto Machicao and Manning, {Alisa K} and Mart{\'i}n-N{\'u}{\~n}ez, {Gracia Mar{\'i}a} and Gemma Rojo-Mart{\'i}nez and Rotter, {Jerome I} and Siscovick, {David S} and Zmuda, {Joseph M} and Zhongyang Zhang and Manuel Serrano-Rios and Ulf Smith and Federico Soriguer and Torben Hansen and Torben J{\o}rgensen and Allan Linnenberg and Oluf Pedersen and Mark Walker and Claudia Langenberg and Scott, {Robert A} and Wareham, {Nicholas J} and Andreas Fritsche and Hans-Ulrich H{\"a}ring and Norbert Stefan and Leif Groop and O'Connell, {Jeff R} and Michael Boehnke and Bergman, {Richard N} and Collins, {Francis S} and Mohlke, {Karen L} and Jaakko Tuomilehto and Winfried M{\"a}rz and Peter Kovacs and Michael Stumvoll and Psaty, {Bruce M} and Johanna Kuusisto and Markku Laakso and Meigs, {James B} and Jos{\'e}e Dupuis and Erik Ingelsson and Florez, {Jose C}",

note = "{\textcopyright} 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.",

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doi = "10.2337/db16-0199",

language = "English",

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journal = "Diabetes",

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TY - JOUR

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 - Stančáková, 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 - Ida Chen, Yii-Der

AU - Corbaton-Anchuelo, Arturo

AU - Faerch, Kristine

AU - 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

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.

U2 - 10.2337/db16-0199

DO - 10.2337/db16-0199

M3 - Journal article

C2 - 27416945

SN - 0012-1797

VL - 65

SP - 3200

EP - 3211

JO - Diabetes

JF - Diabetes

IS - 10

ER -

Genome-wide association study of the modified Stumvoll Insulin Sensitivity Index identifies BCL2 and FAM19A2 as novel insulin sensitivity loci

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