title: Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci.
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.
authors.affiliation: 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 gwalford@partners.org.
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Walford
authors.affiliation: Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gustafsson
authors.affiliation: Data Coordinating Center, Boston University School of Public Health, Boston, MA.
authors.forename: Denis
authors.initials: D
authors.lastname: Rybin
authors.affiliation: University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors.forename: Alena
authors.initials: A
authors.lastname: Stančáková
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA.
authors.forename: Han
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA.
authors.forename: Ching-Ti
authors.initials: CT
authors.lastname: Liu
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA.
authors.forename: Jaeyoung
authors.initials: J
authors.lastname: Hong
authors.affiliation: Cardiovascular Health Research Unit, University of Washington, Seattle, WA Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Jensen
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, WA.
authors.forename: Ken
authors.initials: K
authors.lastname: Rice
authors.affiliation: Department of Biostatistics, University of Liverpool, Liverpool, U.K. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Morris
authors.affiliation: Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors.forename: Reedik
authors.initials: R
authors.lastname: Mägi
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Tönjes
authors.affiliation: 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.
authors.forename: Inga
authors.initials: I
authors.lastname: Prokopenko
authors.affiliation: Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
authors.forename: Marcus E
authors.initials: ME
authors.lastname: Kleber
authors.affiliation: Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
authors.forename: Graciela
authors.initials: G
authors.lastname: Delgado
authors.affiliation: Division of Angiology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Günther
authors.initials: G
authors.lastname: Silbernagel
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI.
authors.forename: Anne U
authors.initials: AU
authors.lastname: Jackson
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Emil V
authors.initials: EV
authors.lastname: Appel
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Grarup
authors.affiliation: 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.
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Lewis
authors.affiliation: 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.
authors.forename: May E
authors.initials: ME
authors.lastname: Montasser
authors.affiliation: 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.
authors.forename: Claes
authors.initials: C
authors.lastname: Landenvall
authors.affiliation: 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.
authors.forename: Harald
authors.initials: H
authors.lastname: Staiger
authors.affiliation: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, U.K.
authors.forename: Jian'an
authors.initials: J
authors.lastname: Luan
authors.affiliation: University of Exeter Medical School, Exeter, U.K.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
authors.affiliation: University of Exeter Medical School, Exeter, U.K.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Weedon
authors.affiliation: University of Exeter Medical School, Exeter, U.K.
authors.forename: Weijia
authors.initials: W
authors.lastname: Xie
authors.affiliation: CIBER Pathophysiology of Obesity and Nutrition, Madrid, Spain Department of Endocrinology and Nutrition, Hospital Regional Universitario de Málaga, Málaga, Spain.
authors.forename: Sonsoles
authors.initials: S
authors.lastname: Morcillo
authors.affiliation: Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Martínez-Larrad
authors.affiliation: Cardiovascular Health Research Unit, University of Washington, Seattle, WA Department of Biostatistics, University of Washington, Seattle, WA.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Biggs
authors.affiliation: Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, CA.
authors.forename: Yii-Der Ida
authors.initials: YD
authors.lastname: Chen
authors.affiliation: Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
authors.forename: Arturo
authors.initials: A
authors.lastname: Corbaton-Anchuelo
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Kristine
authors.initials: K
authors.lastname: Færch
authors.affiliation: Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain Sequencing and Genotyping Platform, Hospital Carlos Haya de Málaga, Málaga, Spain.
authors.forename: Juan Miguel
authors.initials: JM
authors.lastname: Gómez-Zumaquero
authors.affiliation: Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Mark O
authors.initials: MO
authors.lastname: Goodarzi
authors.affiliation: 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.
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Kizer
authors.affiliation: 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.
authors.forename: Heikki A
authors.initials: HA
authors.lastname: Koistinen
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Leong
authors.affiliation: Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lind
authors.affiliation: 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.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lindgren
authors.affiliation: German Center for Diabetes Research (DZD), Tübingen, Germany Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Tübingen, Germany.
authors.forename: Fausto
authors.initials: F
authors.lastname: Machicao
authors.affiliation: 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.
authors.forename: Alisa K
authors.initials: AK
authors.lastname: Manning
authors.affiliation: Department of Endocrinology and Nutrition, Hospitales Regional Universitario y Virgen de la Victoria de Málaga, Málaga, Spain.
authors.forename: Gracia María
authors.initials: GM
authors.lastname: Martín-Núñez
authors.affiliation: 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.
authors.forename: Gemma
authors.initials: G
authors.lastname: Rojo-Martínez
authors.affiliation: Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, CA.
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.affiliation: 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.
authors.forename: David S
authors.initials: DS
authors.lastname: Siscovick
authors.affiliation: Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Zmuda
authors.affiliation: 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.
authors.forename: Zhongyang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Serrano-Rios
authors.affiliation: The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Smith
authors.affiliation: 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.
authors.forename: Federico
authors.initials: F
authors.lastname: Soriguer
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.affiliation: 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.
authors.forename: Torben J
authors.initials: TJ
authors.lastname: Jørgensen
authors.affiliation: 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.
authors.forename: Allan
authors.initials: A
authors.lastname: Linnenberg
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, U.K.
authors.forename: Mark
authors.initials: M
authors.lastname: Walker
authors.affiliation: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, U.K.
authors.forename: Claudia
authors.initials: C
authors.lastname: Langenberg
authors.affiliation: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, U.K.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Scott
authors.affiliation: MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, U.K.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.affiliation: 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.
authors.forename: Andreas
authors.initials: A
authors.lastname: Fritsche
authors.affiliation: 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.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.affiliation: 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.
authors.forename: Norbert
authors.initials: N
authors.lastname: Stefan
authors.affiliation: Department of Clinical Sciences, Diabetes and Endocrinology, Lund University Diabetes Centre, Malmö, Sweden Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.affiliation: 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.
authors.forename: Jeff R
authors.initials: JR
authors.lastname: O'Connell
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI.
authors.forename: Michael
authors.initials: M
authors.lastname: Boehnke
authors.affiliation: Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Bergman
authors.affiliation: Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mohlke
authors.affiliation: 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.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Tuomilehto
authors.affiliation: 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.
authors.forename: Winfried
authors.initials: W
authors.lastname: März
authors.affiliation: Integrated Research and Treatment (IFB) Center AdiposityDiseases, University of Leipzig, Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kovacs
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Stumvoll
authors.affiliation: 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.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.affiliation: Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Kuusisto
authors.affiliation: Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.affiliation: 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.
authors.forename: James B
authors.initials: JB
authors.lastname: Meigs
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA Framingham Heart Study, National Heart, Lung, and Blood Institute, Framingham, MA.
authors.forename: Josée
authors.initials: J
authors.lastname: Dupuis
authors.affiliation: 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.
authors.forename: Erik
authors.initials: E
authors.lastname: Ingelsson
authors.affiliation: 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.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
mesh_terms: D019742:Chemokines, CC / Q000235:genetics* / Q000502:physiology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000502:physiology; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000502:physiology
chemical_list: D019742:Chemokines, CC; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C000593457:TAFA2 protein, human