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

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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 & 59 others 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

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 GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-related traits Consortium. Discovery 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, body mass index (BMI) and in a model ("Model 3") analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI. 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 cardio-metabolic 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
JournalDiabetes
Volume65
Issue number10
Pages (from-to)3200-3211
Number of pages12
ISSN0012-1797
DOIs
Publication statusPublished - Oct 2016

ID: 165810385