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 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, 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 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

Journal: Diabetes 2017;65(10):3200-11

PMID: 27416945

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.

© 2016 by the American Diabetes Association.

Address: 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 [email protected].; Department of Medical Sciences, Uppsala University, Uppsala, Sweden.; Data Coordinating Center, Boston University School of Public Health, Boston, MA.; University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.; Department of Biostatistics, Boston University School of Public Health, Boston, MA Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA.; Department of Biostatistics, Boston University School of Public Health, Boston, MA.; Cardiovascular Health Research Unit, University of Washington, Seattle, WA Department of Medicine, University of Washington, Seattle, WA.; Department of Biostatistics, University of Washington, Seattle, WA.; Department of Biostatistics, University of Liverpool, Liverpool, U.K. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.; Estonian Genome Center, University of Tartu, Tartu, Estonia.; Department of Medicine, University of Leipzig, Leipzig, Germany.; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K. Department of Genomics of Common Disease, Imperial College London, London, U.K. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K.; Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.; Division of Angiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.; Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI.; The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, MD Program for Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, MD.; Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.; Department of Internal Medicine, Division of Endocrinology and Diabetology, Angiology, Nephrology, and Clinical Chemistry, University Hospital Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD), Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Tübingen, Germany.; MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, U.K.; University of Exeter Medical School, Exeter, U.K.; CIBER Pathophysiology of Obesity and Nutrition, Madrid, Spain Department of Endocrinology and Nutrition, Hospital Regional Universitario de Málaga, Málaga, Spain.; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.; Cardiovascular Health Research Unit, University of Washington, Seattle, WA Department of Biostatistics, University of Washington, Seattle, WA.; Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, CA.; Steno Diabetes Center, Gentofte, Denmark.; Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain Sequencing and Genotyping Platform, Hospital Carlos Haya de Málaga, Málaga, Spain.; Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA.; Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY.; Department of Health, National Institute for Health and Welfare, Helsinki, Finland Minerva Foundation Institute for Medical Research, Biomedicum 2U, Helsinki, Finland Department of Medicine and Abdominal Center: Endocrinology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.; Department of Medicine, Harvard Medical School, Boston, MA Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA.; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K. Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA.; German Center for Diabetes Research (DZD), Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Tübingen, Germany.; Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA Department of Medicine, Harvard Medical School, Boston, MA Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA.; Department of Endocrinology and Nutrition, Hospitales Regional Universitario y Virgen de la Victoria de Málaga, Málaga, Spain.; Department of Endocrinology and Nutrition, Hospital Regional Universitario de Málaga, Málaga, Spain Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.; Cardiovascular Health Research Unit, University of Washington, Seattle, WA Department of Medicine, University of Washington, Seattle, WA Department of Epidemiology, University of Washington, Seattle, WA The New York Academy of Medicine, New York, NY.; Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY.; The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.; Department of Public Health, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark Faculty of Medicine, Aalborg University, Aalborg, Denmark Research Center for Prevention and Health, The Capital Region of Denmark, Copenhagen, Denmark.; Research Center for Prevention and Health, The Capital Region of Denmark, Copenhagen, Denmark Department of Clinical Experimental Research, Rigshospitalet, Glostrup, Denmark Department of Clinical Medicine, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.; Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, U.K.; Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.; Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.; Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.; Department of Genetics, University of North Carolina, Chapel Hill, NC.; Chronic Disease Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland Centre for Vascular Prevention, Danube-University Krems, Krems, Austria Diabetes Research Group, King Abdulaziz University, Jeddah, Saudi Arabia Dasman Diabetes Institute, Dasman, Kuwait.; Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria Synlab Academy, Synlab Services GmbH, Mannheim and Augsburg, Germany.; Integrated Research and Treatment (IFB) Center AdiposityDiseases, University of Leipzig, Leipzig, Germany.; Cardiovascular Health Research Unit, University of Washington, Seattle, WA Department of Medicine, University of Washington, Seattle, WA Epidemiology and Health Services, University of Washington, Seattle, WA Group Health Research Institute, Seattle, WA Group Health Cooperation, Seattle, WA.; Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.; Department of Medicine, Harvard Medical School, Boston, MA Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, MA.; Department of Biostatistics, Boston University School of Public Health, Boston, MA Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA.; Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA.; 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.
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