title: Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity.
abstract: Patients with established type 2 diabetes display both β-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.Alexander Fleming, Biomedical Sciences Research Center, Vari, Athens, Greece.
authors.forename: Antigone S
authors.initials: AS
authors.lastname: Dimas
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, U.K.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Lagou
authors.affiliation: Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.
authors.forename: Adam
authors.initials: A
authors.lastname: Barker
authors.affiliation: Department of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA.
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Knowles
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, U.K.Estonian Genome Center, University of Tartu, Tartu, Estonia.
authors.forename: Reedik
authors.initials: R
authors.lastname: Mägi
authors.affiliation: Department of Medicine, Université de Sherbrooke, Sherbrooke, Québec, CanadaGeneral Medicine Division, Massachusetts General Hospital, Boston, MA.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Hivert
authors.affiliation: Department of Biology and Evolution, University of Ferrara, Ferrara, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Benazzo
authors.affiliation: Boston University Data Coordinating Center, Boston, MA.
authors.forename: Denis
authors.initials: D
authors.lastname: Rybin
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI.
authors.forename: Anne U
authors.initials: AU
authors.lastname: Jackson
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Stringham
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, SwedenDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ci
authors.initials: C
authors.lastname: Song
authors.affiliation: Charité-Universitätsmedizin Berlin, Department of Endocrinology and Metabolism, Berlin, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Fischer-Rosinsky
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Trine Welløv
authors.initials: TW
authors.lastname: Boesgaard
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: Department of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA.
authors.forename: Fahim A
authors.initials: FA
authors.lastname: Abbasi
authors.affiliation: Department of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA.
authors.forename: Themistocles L
authors.initials: TL
authors.lastname: Assimes
authors.affiliation: Department of Genetics and Genomic Sciences, Institute of Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, NY.
authors.forename: Ke
authors.initials: K
authors.lastname: Hao
authors.affiliation: Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Xia
authors.initials: X
authors.lastname: Yang
authors.affiliation: CNRS UMR8199-Institute of Biology, Pasteur Institute, Lille 2-Droit et Santé University, Lille, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Lecoeur
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, U.K.University of Cambridge Metabolic Research Laboratories and National Institute for Health Research Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.
authors.forename: Inês
authors.initials: I
authors.lastname: Barroso
authors.affiliation: Genome Technology Branch, National Human Genome Research Institute, Bethesda, MD.
authors.forename: Lori L
authors.initials: LL
authors.lastname: Bonnycastle
authors.affiliation: IFB AdiposityDiseases, Leipzig University Medical Center, Leipzig, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Böttcher
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, U.K.
authors.forename: Suzannah
authors.initials: S
authors.lastname: Bumpstead
authors.affiliation: Genome Technology Branch, National Human Genome Research Institute, Bethesda, MD.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Chines
authors.affiliation: Genome Technology Branch, National Human Genome Research Institute, Bethesda, MD.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Erdos
authors.affiliation: Department of Medicine III, Division of Prevention and Care of Diabetes, University of Dresden, Dresden, Germany.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Graessler
authors.affiliation: Interdisciplinary Center for Clinical Research Leipzig, Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kovacs
authors.affiliation: Genome Technology Branch, National Human Genome Research Institute, Bethesda, MD.
authors.forename: Mario A
authors.initials: MA
authors.lastname: Morken
authors.affiliation: Genome Technology Branch, National Human Genome Research Institute, Bethesda, MD.
authors.forename: Narisu
authors.initials: N
authors.lastname: Narisu
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, U.K.
authors.forename: Felicity
authors.initials: F
authors.lastname: Payne
authors.affiliation: Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors.forename: Alena
authors.initials: A
authors.lastname: Stancakova
authors.affiliation: Genome Technology Branch, National Human Genome Research Institute, Bethesda, MD.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Swift
authors.affiliation: IFB AdiposityDiseases, Leipzig University Medical Center, Leipzig, GermanyDepartment of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Tönjes
authors.affiliation: Department of Medicine III, Division of Prevention and Care of Diabetes, University of Dresden, Dresden, Germany.
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Bornstein
authors.affiliation: CNRS UMR8199-Institute of Biology, Pasteur Institute, Lille 2-Droit et Santé University, Lille, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Cauchi
authors.affiliation: CNRS UMR8199-Institute of Biology, Pasteur Institute, Lille 2-Droit et Santé University, Lille, FranceDepartment of Genomics of Common Disease, Imperial College London, London, U.K.
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.affiliation: CNRS UMR8199-Institute of Biology, Pasteur Institute, Lille 2-Droit et Santé University, Lille, FranceDepartment of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Meyre
authors.affiliation: Department of Medicine III, Division of Prevention and Care of Diabetes, University of Dresden, Dresden, Germany.
authors.forename: Peter E H
authors.initials: PE
authors.lastname: Schwarz
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.affiliation: Lundberg Laboratory for Diabetes Research, Center of Excellence for Metabolic and Cardiovascular Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Smith
authors.affiliation: Department of Biostatistics and Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI.
authors.forename: Michael
authors.initials: M
authors.lastname: Boehnke
authors.affiliation: Department of Physiology & Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Bergman
authors.affiliation: Genome Technology Branch, National Human Genome Research Institute, Bethesda, MD.
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
authors.affiliation: Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mohlke
authors.affiliation: Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, FinlandCentre for Vascular Prevention, Danube University Krems, Krems, AustriaKing Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Jaakko
authors.initials: J
authors.lastname: Tuomilehto
authors.affiliation: Department of Medicine and Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertemous
authors.affiliation: Department of Medical Sciences, Akademiska Sjukhuset, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Lind
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkFaculty of Health Sciences, University of Southern Denmark, Odense, Denmark.
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkHagedorn Research Institute, Copenhagen, DenmarkInstitute of Biomedical Science, Faculty of Health Sciences, University of Copenhagen, Copenhagen, DenmarkFaculty of Health Sciences, University of Aarhus, Aarhus, 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: Charité-Universitätsmedizin Berlin, Department of Endocrinology and Metabolism, Berlin, GermanyDepartment of Clinical Nutrition, German Institute of Human Nutrition, Nuthetal, Germany.
authors.forename: Andreas F H
authors.initials: AF
authors.lastname: Pfeiffer
authors.affiliation: Charité-Universitätsmedizin Berlin, Department of Endocrinology and Metabolism, Berlin, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Spranger
authors.affiliation: IFB AdiposityDiseases, Leipzig University Medical Center, Leipzig, GermanyDepartment of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Stumvoll
authors.affiliation: General Medicine Division, Massachusetts General Hospital, Boston, MADepartment of Medicine, Harvard Medical School, Boston, MA.
authors.forename: James B
authors.initials: JB
authors.lastname: Meigs
authors.affiliation: Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
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: Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, U.K.
authors.forename: Claudia
authors.initials: C
authors.lastname: Langenberg
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MAThe National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA.
authors.forename: Josée
authors.initials: J
authors.lastname: Dupuis
authors.affiliation: Departments of Preventive Medicine and Physiology & Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, CA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Watanabe
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MACenter for Human Genetic Research and Diabetes Research Center (Diabetes Unit), Massachusetts General Hospital, Boston, MAProgram in Medical and Population Genetics, Broad Institute, Cambridge, MA.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Ingelsson
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, U.K.Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, U.K.
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, U.K.Department of Genomics of Common Disease, Imperial College London, London, U.K.
authors.forename: Inga
authors.initials: I
authors.lastname: Prokopenko
mesh_terms: D000483:Alleles; D016000:Cluster Analysis; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*; D012307:Risk Factors; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D007328:Insulin; D014157:Transcription Factors