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

Research output: Contribution to journalArticle

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

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    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