Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci
Year: 2020
Type: article
Study design: Observational Study
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.
Source: UNC Libraries
DOI: 10.17615/gc55-0r45
Authors: Grarup, Niels, Morcillo, Sonsoles, Wareham, Nicholas J., Jensen, Richard A., Linnenberg, Allan, Dupuis, Josée, Laakso, Markku, Montasser, May E., O'Connell, Jeff R., Jackson, Anne U., Staiger, Harald, Morris, Andrew P., Meigs, James B., Martínez-Larrad, María Teresa, Zhang, Zhongyang, Scott, Robert A., Walker, Mark, Smith, Ulf, Stancáková, Alena, Soriguer, Federico, Prokopenko, Inga, Gustafsson, Stefan, Kovacs, Peter, Rojo-Martínez, Gemma, Goodarzi, Mark O., Groop, Leif, Stefan, Norbert, Rice, Ken, Delgado, Graciela, Psaty, Bruce M., Machicao, Fausto, Langenberg, Claudia, Rotter, Jerome I., Tuomilehto, Jaakko, Hansen, Torben, Leong, Aaron, Lindgren, Cecilia, Biggs, Mary L., Ingelsson, Erik, Kuusisto, Johanna, JØrgensen, Torben J., Serrano-Rios, Manuel, Häring, Hans-Ulrich, Mohlke, Karen L., Kleber, Marcus E., Hong, Jaeyoung, Collins, Francis S., Florez, Jose C., Chen, Han, Appel, Emil V., Corbaton-Anchuelo, Arturo, Luan, Jian'An, Manning, Alisa K., Lewis, Joshua P., Mägi, Reedik, Koistinen, Heikki A., Weedon, Michael N., Zmuda, Joseph M., Rybin, Denis, Bergman, Richard N., Landenvall, Claes, Xie, Weijia, Pedersen, Oluf, Stumvoll, Michael, März, Winfried, Fritsche, Andreas, Lind, Lars, Walford, Geoffrey A., Tönjes, Anke, Gómez-Zumaquero, Juan Miguel, Martín-Núñez, Gracia María, Boehnke, Michael, Færch, Kristine, Silbernagel, Günther, Liu, Ching-Ti, Chen, Yii-Der Ida, Siscovick, David S., Frayling, Timothy M., Kizer, Jorge R.
Institution: University of North Carolina at Chapel Hill
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: American Diabetes Association, American Diabetes Association Research Foundation, Amgen, Eli Lilly and Company, Pfizer, AstraZeneca, GlaxoSmithKline, Sanofi, Massachusetts General Hospital, Yale University, School of Medicine, Boston University, Hjerteforeningen, Danone, Fundación Mutua Madrileña, Helsingin ja Uudenmaan Sairaanhoitopiiri, Finska Läkaresällskapet, Wellcome Trust, Comunidad de Madrid, Folkhälsanin Tutkimussäätiö, Diabetes UK, European Commission, Deutsche Forschungsgemeinschaft, Academy of Finland, Bundesministerium für Bildung und Forschung, Hjärt-Lungfonden, Knut och Alice Wallenbergs Stiftelse, Novo Nordisk, Signe ja Ane Gyllenbergin Säätiö, Vetenskapsrådet, Samfundet Folkhälsan, Ministerio de Ciencia e Innovación, Augustinus Fonden, Copenhagen Graduate School for Nanoscience and Nanotechnology, Svenska Kulturfonden, Boehringer Ingelheim Stiftung, Paavo Nurmen Säätiö, Novo Nordisk Fonden, Novo Nordisk Foundation Center for Basic Metabolic Research, Diabetestutkimussäätiö, Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas, Diabetesforeningen, National Institutes of Health, Abbott Diagnostics, Medical Research Council, Instituto de Salud Carlos III, European Regional Development Fund, Uppsala Multidisciplinary Center for Advanced Computational Science, National Institute on Aging, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, Interreg
Awards: G1010903078, G1017378214, G1023702118, G1053820806, Aetiology of type 2 diabetes and related metabolic disorders, G1097528416, G1118486281, G125972088, G1364237091, G1391975923, G1401438683, G1438302022, G1455670351, G1560275704, G1576437321, G1614110324, G1660689499, G1696540499, G1726490033, G2124545180, G2175624253, G2178492673, G2193588257, G2440692098, G247538147, G250621538, European Collaborative Project on Inflamation and Vascular Wall Remodelling in Atherosclerosis, G2511508072, G2539352280, G2563633029, G2620658983, G2708136985, G270907595, G278200998, G2800149121, G2830784186, G2867912622, G2892497062, G2918387404, G2962705247, G2992805304, G3007488127, G3021948349, G3042145041, G3137375862, G3205625555, G3220743633, G322252321, G3294437106, G34347772, G3572394825, G36937976, G3721894273, G3764669582, G3803392666, Personalized diagnostics and treatment of high risk coronary artery disease patients., G4219624527, G423252844, G4237658384, G4418243127, G4474400647, G453267231, G4577178459, G4597325556, G4599028518, G4622379297, G4649070740, G4663679897, G4685761485, G472208673, G4919155732, G4942589162, G5145575165, G5249188777, G5251985303, G5281659474, G5339631484, G5439707361, G544148272, G5453233289, G5479317095, G5531839745, G5540580309, G5632764457, G5778869478, G5794462373, Cardiomics: Integration of -omics methods for identification of novel drug targets and clinical biomarkers for coronary heart disease, CHS Events Follow-up Study, G6493395989, G6705035318, G6729440087, G6768971220, G7197155317, G7217924807, G734086296, G7392450389, G7410979, G7505613430, G764651519, G766700449, G766843672, G781069238, G7879620334, G80149192, G8044342499, G806768229, G8068269535, G8213835172, G8260701975, G8392411440, G8492131798, CHS-Transition Phase -268055222, G8683204365, G8698498007, G879471657, G8892155751, G9000019908, G9000024289, G9000027259, G9000046001, G9000069887, G9000071222, G9000077981, G9000079831, G9000104961, G9000124008, G9000124674, G9000139054, G9000155215, G9000175748, G9000230115, G9000239990, G9000277595, G9000354881, G905887895, Integriertes Forschungs- und Behandlungszentrum AdipositasErkrankungen
OpenAlex ID: W4298305127