Walford Geoffrey A, Gustafsson Stefan, Rybin Denis, Stančáková Alena, Chen Han, Liu Ching-Ti, Hong Jaeyoung, Jensen Richard A, Rice Ken, Morris Andrew P, Mägi Reedik, Tönjes Anke, Prokopenko Inga, Kleber Marcus E, Delgado Graciela, Silbernagel Günther, Jackson Anne U, Appel Emil V, Grarup Niels, Lewis Joshua P, Montasser May E, Landenvall Claes, Staiger Harald, Luan Jian'an, Frayling Timothy M, Weedon Michael N, Xie Weijia, Morcillo Sonsoles, Martínez-Larrad María Teresa, Biggs Mary L, Chen Yii-Der Ida, Corbaton-Anchuelo Arturo, Færch Kristine, Gómez-Zumaquero Juan Miguel, Goodarzi Mark O, Kizer Jorge R, Koistinen Heikki A, Leong Aaron, Lind Lars, Lindgren Cecilia, Machicao Fausto, Manning Alisa K, Martín-Núñez Gracia María, Rojo-Martínez Gemma, Rotter Jerome I, Siscovick David S, Zmuda Joseph M, Zhang Zhongyang, Serrano-Rios Manuel, Smith Ulf, Soriguer Federico, Hansen Torben, Jørgensen Torben J, Linnenberg Allan, Pedersen Oluf, Walker Mark, Langenberg Claudia, Scott Robert A, Wareham Nicholas J, Fritsche Andreas, Häring Hans-Ulrich, Stefan Norbert, Groop Leif, O'Connell Jeff R, Boehnke Michael, Bergman Richard N, Collins Francis S, Mohlke Karen L, Tuomilehto Jaakko, März Winfried, Kovacs Peter, Stumvoll Michael, Psaty Bruce M, Kuusisto Johanna, Laakso Markku, Meigs James B, Dupuis Josée, Ingelsson Erik, Florez Jose C
Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston, MA Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA Department of Medicine, Harvard Medical School, Boston, MA
Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
Diabetes. 2016 Oct;65(10):3200-11. doi: 10.2337/db16-0199. Epub 2016 Jul 14.
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.
全基因组关联研究（GWAS）发现，影响胰岛素敏感性空腹指标的常见变异很少。我们推测，对空腹和动态胰岛素敏感性指标进行综合评估的GWAS将发现新的常见变异。我们在葡萄糖和胰岛素相关性状联盟的荟萃分析中，对改良的斯图姆沃尔胰岛素敏感性指数（ISI）进行了GWAS。在16753名个体中进行了遗传关联的发现，并在13354名独立个体中对23个最显著的新位点进行了重复验证。在调整了年龄、性别和BMI的模型中，以及在分析了调整BMI后的基因型效应和基因型与BMI对ISI的相互作用效应的联合影响的模型（模型3）中，测试了与ISI的关联。在模型3中，三个变异达到全基因组显著性：rs13422522（NYAP2；P = 8.87×10^(-11)）、rs12454712（BCL2；P = 2.7×10^(-8)）和rs10506418（FAM19A2；P = 1.9×10^(-8)）。通过对已知的IRS1胰岛素敏感性位点进行条件分析，消除了NYAP2的关联；BCL2和FAM19A2的关联独立于已知的心脏代谢位点。总之，我们鉴定出两个新位点，并重复验证了与胰岛素敏感性相关的已知变异。需要进一步研究来阐明BCL2和FAM19A2位点的因果变异和功能。
