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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 and Morris, Andrew P., et al. (2016) In Diabetes 65(10). p.3200-3211
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... (More)

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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published
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Diabetes
volume
65
issue
10
pages
12 pages
publisher
American Diabetes Association Inc.
external identifiers
  • scopus:84989162879
  • wos:000388372900037
ISSN
0012-1797
DOI
10.2337/db16-0199
language
English
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yes
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a1089904-0acf-4b54-b9aa-99471a04695c
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2016-10-18 13:09:48
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2017-11-14 09:51:04
@article{a1089904-0acf-4b54-b9aa-99471a04695c,
  abstract     = {<p>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<sup>-11</sup>), rs12454712 (BCL2; P = 2.7 × 10<sup>-8</sup>), and rs10506418 (FAM19A2; P = 1.9 × 10<sup>-8</sup>). 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.</p>},
  author       = {Walford, Geoffrey A. and Gustafsson, Stefan and Rybin, Denis and Stancáková, Alena and Chen, Han and Liu, Ching Ti and Hong, Jaeyoung and Jensen, Richard A. and Rice, Ken and Morris, Andrew P. and Mägi, Reedik and Tönjes, Anke and Prokopenko, Inga and Kleber, Marcus E. and Delgado, Graciela and Silbernagel, Günther and Jackson, Anne U. and Appel, Emil V. and Grarup, Niels and Lewis, Joshua P. and Montasser, May E. and Landenvall, Claes and Staiger, Harald and Luan, Jian'An and Frayling, Timothy M. and Weedon, Michael N. and Xie, Weijia and Morcillo, Sonsoles and Martínez-Larrad, María Teresa and Biggs, Mary L. and Chen, Yii Der Ida and Corbaton-Anchuelo, Arturo and Færch, Kristine and Gómez-Zumaquero, Juan Miguel and Goodarzi, Mark O. and Kizer, Jorge R. and Koistinen, Heikki A. and Leong, Aaron and Lind, Lars and Lindgren, Cecilia and Machicao, Fausto and Manning, Alisa K. and Martín-Núñez, Gracia María and Rojo-Martínez, Gemma and Rotter, Jerome I. and Siscovick, David S. and Zmuda, Joseph M. and Zhang, Zhongyang and Serrano-Rios, Manuel and Smith, Ulf and Soriguer, Federico and Hansen, Torben and JØrgensen, Torben J. and Linnenberg, Allan and Pedersen, Oluf and Walker, Mark and Langenberg, Claudia and Scott, Robert A. and Wareham, Nicholas J. and Fritsche, Andreas and Häring, Hans Ulrich and Stefan, Norbert and Groop, Leif and O'Connell, Jeff R. and Boehnke, Michael and Bergman, Richard N. and Collins, Francis S. and Mohlke, Karen L. and Tuomilehto, Jaakko and März, Winfried and Kovacs, Peter and Stumvoll, Michael and Psaty, Bruce M. and Kuusisto, Johanna and Laakso, Markku and Meigs, James B. and Dupuis, Josée and Ingelsson, Erik and Florez, Jose C.},
  issn         = {0012-1797},
  language     = {eng},
  month        = {10},
  number       = {10},
  pages        = {3200--3211},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Genome-wide association study of the modified stumvoll insulin sensitivity index identifies BCL2 and FAM19A2 as novel insulin sensitivity loci},
  url          = {http://dx.doi.org/10.2337/db16-0199},
  volume       = {65},
  year         = {2016},
}