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. 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 Færch; Juan Miguel Gómez-Zumaquero; Mark O. Goodarzi; Jorge R. 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

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 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 R. 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

Medicine

Research output: Contribution to journal › Article › peer-review

54 Scopus citations

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 (US)
Pages (from-to)	3200-3211
Number of pages	12
Journal	Diabetes
Volume	65
Issue number	10
DOIs	https://doi.org/10.2337/db16-0199
State	Published - Oct 1 2016

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism

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10.2337/db16-0199

Cite this

Walford, G. A., Gustafsson, S., Rybin, D., Stancáková, 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, 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, JR, 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

@article{94f64214ca9946d8af182efb8dfa6423,

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 Stanc{\'a}kov{\'a} and Han Chen and Liu, {Ching Ti} 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 Chen, {Yii Der Ida} and Arturo Corbaton-Anchuelo and Kristine F{\ae}rch and G{\'o}mez-Zumaquero, {Juan Miguel} and Goodarzi, {Mark O.} and Kizer, {Jorge R.} 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 J{\O}rgensen, {Torben J.} and Allan Linnenberg and Oluf Pedersen and Mark Walker and Claudia Langenberg and Scott, {Robert A.} and Wareham, {Nicholas J.} and Andreas Fritsche and H{\"a}ring, {Hans Ulrich} 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 = "Funding Information: This work was supported by National Institutes of Health grant DK099249 (to G.A.W.). Grant support was provided to cohorts. For METSIM, the study was funded by the Academy of Finland (grants 77299 and 124243). For Sorbs, the work was supported by grants from the German Research Council (DFG-SFB 1052, {"}Obesity mechanisms,{"} A01, C01, B03, and SPP 1629 TO 718/2-1), the German Diabetes Association, and the Diabetes Hilfs- und Forschungsfonds Deutschland (DHFD). This work was further supported by the Federal Ministry of Education and Research (BMBF), Germany, FKZ (01EO1501, AD2-060E to P.K.), and by the Boehringer Ingelheim Foundation. For FHS, the study was supported by the National Heart, Lung, and Blood Institute (contract nos. N02- HL-6-4278 [supporting its contract with Affymetrix, Inc., for genotyping services], N01-HC-25195, HL084756, and HHSN268201500001I) and the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK078616 to J.D., U01- DK085526 to H.C. and J.D., 2R01 DK078616 and K24 DK080140 to J.M.). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. A.K.M. was supported by American Diabetes Association Research Foundation (grant 7-12-MN-02). For CHS, research was supported by National Heart, Lung, and Blood Institute contract nos. HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and grant nos. U01HL080295, HL105756, and HL120393, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). For ULSAM, the project was supported by the Knut and Alice Wallenberg Foundation (Wallenberg Academy Fellow), the European Research Council (ERC Starting Grant), the Swedish Diabetes Foundation (grant 2013-024), the Swedish Research Council (grant 2012-1397), and the Swedish Heart-Lung Foundation (20120197). A.P.M. is a Wellcome Trust Senior Fellow in Basic Biomedical Science (grant WT098017 from the Nordic Center of Excellence in Disease Genetics). For LURIC, the study was supported by the 7th Framework Program (AtheroRemo, grant agreement no. 201668, and RiskyCAD, grant agreement no. 305739) of the European Union and by the INTERREG-IV-Oberrhein-Program (Project A28, Genetic mechanisms of cardiovascular diseases) with support from the European Regional Development Fund (ERDF) and the Wissenschaftsoffensive. M.E.K. and W.M. are supported by the German Federal Ministry of Education and Research as part of the Competence Cluster of Nutrition and Cardiovascular Health (nutriCARD). For Inter99, the study was financially supported by research grants from the Danish Research Council, the Danish Centre for Health Technology Assessment, Novo Nordisk, the Research Foundation of Copenhagen County, Ministry of Internal Affairs and Health of Denmark, the Danish Heart Foundation, the Danish Pharmaceutical Association, the Augustinus Foundation, the Ib Henriksen Foundation, the Becket Foundation, and the Danish Diabetes Association. For FUSION, the study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (DK093757, DK072193, DK062370) and the National Human Genome Research Institute (ZIA-HG000024). H.A.K. has received funding from the Academy of Finland (support for clinical research careers, grant no. 258753). Work on the Amish Studies was supported by National Institutes of Health awards K23GM102678 (from National Institute of General Medical Sciences) to J.P.L. and HL084756 (from National Heart, Lung, and Blood Institute) to J.R.O. The Botnia study has been financially supported by grants from the Sigrid Juselius Foundation, the Folkh{\"a}lsan Research Foundation, the Nordic Center of Excellence in Disease Genetics, a European Union grant (EXGENESIS, GA FP6 2004-005272), the Signe and Ane Gyllenberg Foundation, the Swedish Cultural Foundation in Finland, the Finnish Diabetes Research Foundation, the Foundation for Life and Health in Finland, the Finnish Medical Society, the Paavo Nurmi Foundation, the Helsinki University Central Hospital Research Foundation, the Perkl{\'e}n Foundation, the Ollqvist Foundation, the N{\"a}rpes Health Care Foundation, and the Ahokas Foundation. The DGI study was further supported by a Swedish Research Council Linn{\'e} grant (2006-237) and by the Ministry of Education in Finland, the Municipal Health Care Center and Hospital in Jakobstad, and the Health Care Centers in Vasa, N{\"a}rpes, and Korsholm. The T{\"u}bingen study was supported in part by a grant from the German Federal Ministry of Education and Research to the German Center for Diabetes Research (DZD e.V.). For the Ely Study, J.L., C.Lang, R.A.S., and N.J.W. acknowledge support from the Medical Research Council (MC-UU-12015/1). The Ely Study was funded by the Medical Research Council (MC-U106179471) and Diabetes UK. Genotyping in the Ely and Fenland studies was supported in part by a Medical Research Council- GlaxoSmithKline pilot program grant (G0701863). For the Birth Cohort 1936 and Inter99 studies, work was support by the Novo Nordisk Foundation Center for Basic Metabolic Research, an independent research center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). Work on the Pizarra study was support by Instituto de Salud Carlos III PI11/00880 and Instituto de Salud Carlos III PS09/02117. For Segovia, this work was supported by the Fondo Europeo para el Desarrollo Regional, Red de Centros RCMN (C03/08) grants FEDER 2FD 1997/2309, the Instituto de Salud Carlos III-RETIC RD06/0015/0012, Madrid, Spain (FIS 03/1618); CIBER in Diabetes and Associated Metabolic Disorders (Instituto de Salud Carlos III, Ministerio de Ciencia e Innovaci{\'o}n); and the Madrid Autonomous Community (MOIR S2010/BMD-2423), and by educational grants from Eli Lilly Lab, Spain; Bayer Pharmaceutical Co., Spain; and the Fundaci{\'o}n Mutua Madrile{\~n}a 2008, Spain. Publisher Copyright: {\textcopyright} 2016 by the American Diabetes Association.",

year = "2016",

month = oct,

day = "1",

doi = "10.2337/db16-0199",

language = "English (US)",

volume = "65",

pages = "3200--3211",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association Inc.",

number = "10",

}

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 - 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 R.

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.

N1 - Funding Information: This work was supported by National Institutes of Health grant DK099249 (to G.A.W.). Grant support was provided to cohorts. For METSIM, the study was funded by the Academy of Finland (grants 77299 and 124243). For Sorbs, the work was supported by grants from the German Research Council (DFG-SFB 1052, "Obesity mechanisms," A01, C01, B03, and SPP 1629 TO 718/2-1), the German Diabetes Association, and the Diabetes Hilfs- und Forschungsfonds Deutschland (DHFD). This work was further supported by the Federal Ministry of Education and Research (BMBF), Germany, FKZ (01EO1501, AD2-060E to P.K.), and by the Boehringer Ingelheim Foundation. For FHS, the study was supported by the National Heart, Lung, and Blood Institute (contract nos. N02- HL-6-4278 [supporting its contract with Affymetrix, Inc., for genotyping services], N01-HC-25195, HL084756, and HHSN268201500001I) and the National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK078616 to J.D., U01- DK085526 to H.C. and J.D., 2R01 DK078616 and K24 DK080140 to J.M.). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. A.K.M. was supported by American Diabetes Association Research Foundation (grant 7-12-MN-02). For CHS, research was supported by National Heart, Lung, and Blood Institute contract nos. HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and grant nos. U01HL080295, HL105756, and HL120393, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). For ULSAM, the project was supported by the Knut and Alice Wallenberg Foundation (Wallenberg Academy Fellow), the European Research Council (ERC Starting Grant), the Swedish Diabetes Foundation (grant 2013-024), the Swedish Research Council (grant 2012-1397), and the Swedish Heart-Lung Foundation (20120197). A.P.M. is a Wellcome Trust Senior Fellow in Basic Biomedical Science (grant WT098017 from the Nordic Center of Excellence in Disease Genetics). For LURIC, the study was supported by the 7th Framework Program (AtheroRemo, grant agreement no. 201668, and RiskyCAD, grant agreement no. 305739) of the European Union and by the INTERREG-IV-Oberrhein-Program (Project A28, Genetic mechanisms of cardiovascular diseases) with support from the European Regional Development Fund (ERDF) and the Wissenschaftsoffensive. M.E.K. and W.M. are supported by the German Federal Ministry of Education and Research as part of the Competence Cluster of Nutrition and Cardiovascular Health (nutriCARD). For Inter99, the study was financially supported by research grants from the Danish Research Council, the Danish Centre for Health Technology Assessment, Novo Nordisk, the Research Foundation of Copenhagen County, Ministry of Internal Affairs and Health of Denmark, the Danish Heart Foundation, the Danish Pharmaceutical Association, the Augustinus Foundation, the Ib Henriksen Foundation, the Becket Foundation, and the Danish Diabetes Association. For FUSION, the study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (DK093757, DK072193, DK062370) and the National Human Genome Research Institute (ZIA-HG000024). H.A.K. has received funding from the Academy of Finland (support for clinical research careers, grant no. 258753). Work on the Amish Studies was supported by National Institutes of Health awards K23GM102678 (from National Institute of General Medical Sciences) to J.P.L. and HL084756 (from National Heart, Lung, and Blood Institute) to J.R.O. The Botnia study has been financially supported by grants from the Sigrid Juselius Foundation, the Folkhälsan Research Foundation, the Nordic Center of Excellence in Disease Genetics, a European Union grant (EXGENESIS, GA FP6 2004-005272), the Signe and Ane Gyllenberg Foundation, the Swedish Cultural Foundation in Finland, the Finnish Diabetes Research Foundation, the Foundation for Life and Health in Finland, the Finnish Medical Society, the Paavo Nurmi Foundation, the Helsinki University Central Hospital Research Foundation, the Perklén Foundation, the Ollqvist Foundation, the Närpes Health Care Foundation, and the Ahokas Foundation. The DGI study was further supported by a Swedish Research Council Linné grant (2006-237) and by the Ministry of Education in Finland, the Municipal Health Care Center and Hospital in Jakobstad, and the Health Care Centers in Vasa, Närpes, and Korsholm. The Tübingen study was supported in part by a grant from the German Federal Ministry of Education and Research to the German Center for Diabetes Research (DZD e.V.). For the Ely Study, J.L., C.Lang, R.A.S., and N.J.W. acknowledge support from the Medical Research Council (MC-UU-12015/1). The Ely Study was funded by the Medical Research Council (MC-U106179471) and Diabetes UK. Genotyping in the Ely and Fenland studies was supported in part by a Medical Research Council- GlaxoSmithKline pilot program grant (G0701863). For the Birth Cohort 1936 and Inter99 studies, work was support by the Novo Nordisk Foundation Center for Basic Metabolic Research, an independent research center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation (www.metabol.ku.dk). Work on the Pizarra study was support by Instituto de Salud Carlos III PI11/00880 and Instituto de Salud Carlos III PS09/02117. For Segovia, this work was supported by the Fondo Europeo para el Desarrollo Regional, Red de Centros RCMN (C03/08) grants FEDER 2FD 1997/2309, the Instituto de Salud Carlos III-RETIC RD06/0015/0012, Madrid, Spain (FIS 03/1618); CIBER in Diabetes and Associated Metabolic Disorders (Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación); and the Madrid Autonomous Community (MOIR S2010/BMD-2423), and by educational grants from Eli Lilly Lab, Spain; Bayer Pharmaceutical Co., Spain; and the Fundación Mutua Madrileña 2008, Spain. Publisher Copyright: © 2016 by the American Diabetes Association.

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.

UR - http://www.scopus.com/inward/record.url?scp=84989162879&partnerID=8YFLogxK

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U2 - 10.2337/db16-0199

DO - 10.2337/db16-0199

M3 - Article

C2 - 27416945

AN - SCOPUS:84989162879

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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