1. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
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Tove Fall, Anubha Mahajan, Dmitry Shungin, B. Balkau, Gerjan Navis, A. Metspalu, Anneli Pouta, Andrew A. Hicks, Ilja M. Nolte, Ian Ford, Aroon D. Hingorani, Stefan R Bornstein, Anuj Goel, Rona J. Strawbridge, Niek Verweij, Sarah H. Wild, Patricia B. Munroe, T.B. Harris, Jaana Lindström, Johnson Pcd., Nita G. Forouhi, Pierre Meneton, Patricia A. Peyser, Sarin A-P., Andrea Ganna, Timothy M. Frayling, Patrik K. E. Magnusson, Joanne M. Meyer, Yongmei Liu, Jeanette M. Stafford, Christian Herder, L Zudina, Maria G. Stathopoulou, May E. Montasser, Nicholas D. Hastie, Inês Barroso, Schwarz Peh., James B. Meigs, Perttu Salo, George Davey Smith, Gonneke Willemsen, Christopher J. Groves, Erik P A Van Iperen, M. A. Province, Veikko Salomaa, Naveed Sattar, Serena Sanna, Maria Dimitriou, Joop Jukema, Ulrika Krus, Albert V. Smith, Markku Laakso, James F. Wilson, George Nicholson, Loic Yengo, Tatijana Zemunik, Per Eriksson, Harold Snieder, Peter P. Pramstaller, Claudia Langenberg, R. Rauramaa, Alan R. Shuldiner, Pau Navarro, Veronique Vitart, Ross M. Fraser, Aaron Isaacs, C. Lecoeur, Jesper R. Gådin, Jackie F. Price, Letizia Marullo, L.F. Bielak, Sirkka Keinänen-Kiukaanniemi, Amélie Bonnefond, Michael Stumvoll, Alessia Faggian, Anke Tönjes, Tomohiro Tanaka, Wieland Kiess, Harry Campbell, Josée Dupuis, David Altshuler, João Fadista, Winfried März, G K Hovingh, Thomas Illig, Toby Johnson, H Grallert, Kari Stefansson, Reedik Mägi, Palmer Cna., de Geus Ejcn., Martina Müller-Nurasyid, Karen Kapur, Philippe Froguel, Dorret I. Boomsma, Anders Franco-Cereceda, Marcus E. Kleber, Boehnke M, Olga D. Carlson, Ozren Polasek, Andrew P. Morris, Alex S. F. Doney, Najaf Amin, Sara M. Willems, Vilmundur Gudnason, Jose C. Florez, Jeffery R. O'Connell, Nancy L. Pedersen, T. Saaristo, Wolffenbuttel Bhr., M. I. J. Uusitupa, Longda Jiang, Iva Miljkovic, James S. Pankow, Caroline Hayward, Hugh Watkins, Vasiliki Lagou, Johanna Kuusisto, Jaakko Tuomilehto, Alan F. Wright, Josephine M. Egan, Perry Jrb., C M van Duijn, Valeriya Lyssenko, Leif Groop, Stefania Bandinelli, Nigel W. Rayner, Tõnu Esko, Stela McLachlan, Momoko Horikoshi, Eric Boerwinkle, Rick Jansen, Richard N. Bergman, Gudmar Thorleifsson, Lyle J. Palmer, Vilmantas Giedraitis, Peter Kovacs, Nicholas J. Wareham, Luigi Ferrucci, N J Timpson, D Rybin, Anne U. Jackson, Tiinamaija Tuomi, Gonçalo R. Abecasis, Harst Pvd., Meena Kumari, Albert Hofman, Chiara Scapoli, Evelin Mihailov, Josine L. Min, Anders Hamsten, Hottenga J-J., Loos Rjf., Lars Lind, Ulf de Faire, Jaakko Kaprio, Guo Li, Beate St Pourcain, C Gieger, Amanda J. Bennett, Anna Ulrich, Nabila Bouatia-Naji, Satu Männistö, Antigone S. Dimas, Jarvelin M-R., Günther Silbernagel, F Karpe, A. Körner, David S. Siscovick, M Blüher, Rebecca J. Webster, Erik Ingelsson, Susan Campbell, Mika Kivimäki, Laura J. Rasmussen-Torvik, Heikki A. Koistinen, Sophie Visvikis-Siest, Bernhard O. Boehm, Inga Prokopenko, Ping An, Emmanouil T. Dermitzakis, Cecilia M. Lindgren, Kardia Slr., Richa Saxena, Igor Rudan, Richard M. Watanabe, Jian'an Luan, Marika Kaakinen, Shin S-Y., George Dedoussis, Panagiotis Deloukas, Mark I. McCarthy, Barbara Thorand, B.W.J.H. Penninx, Peter Vollenweider, Paul W. Franks, Leena Kinnunen, Markus Perola, Yvonne Boettcher, Timo A. Lakka, Nicole Soranzo, Stavroula Kanoni, Bakker Sjl., Winkelmann Br, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institute of Genomics [Tartu, Estonia], University of Tartu, Vrije Universiteit Amsterdam [Amsterdam] (VU), Vrije Universiteit Medical Centre (VUMC), Helmholtz-Zentrum München (HZM), University of Cambridge [UK] (CAM), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - 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Universität Mainz (JGU), Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Umeå University, Skane University Hospital [Malmo], Lund University [Lund], RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche [Roma] (CNR), University Medical Center Groningen [Groningen] (UMCG), Universität Leipzig [Leipzig], Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Split, Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA), University of Eastern Finland, Harokopio University of Athens, European Academy Bozen/Bolzano (EURAC), University of Kuopio, German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Ninewells Hospital and Medical School [Dundee], University College of London [London] (UCL), University of Essex, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], University of Helsinki, Leiden University Medical Center (LUMC), Institute of Cardiovascular and Medical Sciences [Glasgow], University of Oulu, The University of Texas Health Science Center at Houston (UTHealth), University of Minnesota Medical School, University of Minnesota System, Keck School of Medicine [Los Angeles], University of Southern California (USC), Amsterdam UMC, University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Lee Kong Chian School of Medicine, Nanyang Technological University (NTU), Universität Heidelberg [Heidelberg], King Abdulaziz University, Pirkanmaa Hospital District, Tampere University Hospital, Cedars-Sinai Medical Center, Danube University Krems, Harvard School of Public Health, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - 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Chan School of Public Health, John Radcliffe Hospital [Oxford University Hospital], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Université de Genève (UNIGE), Big Data Institute, University of Surrey (UNIS), University of Bergen (UiB), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford Cardiovascular Institute, University of Liverpool, University of Manchester [Manchester], Institute of Biochemistry and Genetics of Ufa Scientific Centre, Russian Academy of Sciences [Moscow] (RAS), Experimental Vascular Medicine, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, SIEST, Sofia, PreciDIAB Institute, the holistic approach of personal diabets care - - PreciDIAB2018 - ANR-18-IBHU-0001 - IBHU - VALID, Understanding the dynamic determinants of glucose homeostasis and social capability to promote Healthy and active aging - DYNAHEALTH - - H20202015-04-01 - 2019-03-31 - 633595 - VALID, Beyond the Genetics of Addiction - ADDICTION - - EC:FP7:ERC2011-12-01 - 2017-05-31 - 284167 - VALID, Rise of scientific excellence and collaboration for implementing personalised medicine in Estonia - ePerMed - - H20202016-01-01 - 2018-12-31 - 692145 - VALID, University of Oxford, Helmholtz Zentrum München = German Research Center for Environmental Health, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Università degli Studi di Ferrara = University of Ferrara (UniFE), Université de Lausanne = University of Lausanne (UNIL), Karl-Franzens-Universität Graz, Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Amsterdam UMC - Amsterdam University Medical Center, Nanyang Technological University [Singapour], Universität zu Lübeck = University of Lübeck [Lübeck], Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé (LIMICS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Université de Genève = University of Geneva (UNIGE), ANR-18-IBHU-0001,PreciDIAB,PreciDIAB Institute, the holistic approach of personal diabets care(2018), European Project: 633595,H2020,H2020-PHC-2014-two-stage,DYNAHEALTH(2015), European Project: 284167,EC:FP7:ERC,ERC-2011-StG_20101124,ADDICTION(2011), European Project: 692145,H2020,H2020-TWINN-2015,ePerMed(2016), Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, Functional Genomics, APH - Mental Health, Sociology and Social Gerontology, APH - Methodology, Hottenga, Jouke- Jan [0000-0002-5668-2368], Bouatia-Naji, Nabila [0000-0001-5424-2134], Jansen, Rick [0000-0002-3333-6737], Min, Josine L. [0000-0003-4456-9824], Faggian, Alessia [0000-0002-3799-9722], Bonnefond, Amélie [0000-0001-9976-3005], Isaacs, Aaron [0000-0001-5037-4834], Willems, Sara M. [0000-0002-6803-3007], Navarro, Pau [0000-0001-5576-8584], Jackson, Anne U. [0000-0002-9672-2547], Bielak, Lawrence F. [0000-0002-3443-8030], Saxena, Richa [0000-0003-2233-1065], Smith, Albert V. [0000-0003-1942-5845], Verweij, Niek [0000-0002-4303-7685], Goel, Anuj [0000-0003-2307-4021], Johnson, Paul C. D. [0000-0001-6663-7520], Strawbridge, Rona J. [0000-0001-8506-3585], Fall, Tove [0000-0003-2071-5866], Fraser, Ross M. [0000-0003-0488-2592], Kanoni, Stavroula [0000-0002-1691-9615], Giedraitis, Vilmantas [0000-0003-3423-2021], Kleber, Marcus E. [0000-0003-0663-7275], Müller-Nurasyid, Martina [0000-0003-3793-5910], Luan, Jian’an [0000-0003-3137-6337], Sanna, Serena [0000-0002-3768-1749], Nolte, Ilja M. [0000-0001-5047-4077], Zemunik, Tatijana [0000-0001-8120-2891], Kovacs, Peter [0000-0002-0290-5423], Wild, Sarah H. 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[0000-0002-4176-2947], Gudnason, Vilmundur [0000-0001-5696-0084], Lecoeur, Cecile [0000-0003-0075-6417], Jarvelin, Marjo-Riitta [0000-0002-2149-0630], Stefansson, Kari [0000-0003-1676-864X], Dermitzakis, Emmanouil T. [0000-0002-9302-6490], Lindgren, Cecilia M. [0000-0002-4903-9374], Froguel, Philippe [0000-0003-2972-0784], Kaakinen, Marika A. [0000-0002-9228-0462], Watanabe, Richard M. [0000-0003-1015-0531], Ingelsson, Erik [0000-0003-2256-6972], Dupuis, Josée [0000-0003-2871-3603], Barroso, Inês [0000-0001-5800-4520], Apollo - University of Cambridge Repository, Epidemiology, University Hospital Mannheim | Universitätsmedizin Mannheim, National Research Council of Italy | Consiglio Nazionale delle Ricerche (CNR), Universität Leipzig, Universiteit Leiden, Universität Heidelberg [Heidelberg] = Heidelberg University, Karl-Franzens-Universität [Graz, Autriche], Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, General practice, APH - Digital Health, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Center for Liver, Digestive and Metabolic Diseases (CLDM), Value, Affordability and Sustainability (VALUE), Cardiovascular Centre (CVC), Hottenga, Jouke-Jan [0000-0002-5668-2368], Min, Josine L [0000-0003-4456-9824], Willems, Sara M [0000-0002-6803-3007], Jackson, Anne U [0000-0002-9672-2547], Bielak, Lawrence F [0000-0002-3443-8030], Smith, Albert V [0000-0003-1942-5845], Johnson, Paul CD [0000-0001-6663-7520], Strawbridge, Rona J [0000-0001-8506-3585], Fraser, Ross M [0000-0003-0488-2592], Kleber, Marcus E [0000-0003-0663-7275], Luan, Jian'an [0000-0003-3137-6337], Nolte, Ilja M [0000-0001-5047-4077], Wild, Sarah H [0000-0001-7824-2569], Hicks, Andrew A [0000-0001-6320-0411], Koistinen, Heikki A [0000-0001-7870-070X], Bakker, Stephan JL [0000-0003-3356-6791], Palmer, Colin NA [0000-0002-6415-6560], Jukema, J Wouter [0000-0002-3246-8359], Magnusson, Patrik K [0000-0002-7315-7899], Wolffenbuttel, Bruce HR [0000-0001-9262-6921], Abecasis, Goncalo R [0000-0003-1509-1825], Meigs, James B [0000-0002-2439-2657], Wilson, James F [0000-0001-5751-9178], Schwarz, Peter EH [0000-0001-6317-7880], Boehm, Bernhard O [0000-0002-2706-7710], Wareham, Nicholas J [0000-0003-1422-2993], Franks, Paul W [0000-0002-0520-7604], van Duijn, Cornelia M [0000-0002-2374-9204], Pramstaller, Peter P [0000-0002-9831-8302], Frayling, Timothy M [0000-0001-8362-2603], Peyser, Patricia A [0000-0002-9717-8459], Forouhi, Nita G [0000-0002-5041-248X], Loos, Ruth JF [0000-0002-8532-5087], Boomsma, Dorret I [0000-0002-7099-7972], Munroe, Patricia B [0000-0002-4176-2947], Dermitzakis, Emmanouil T [0000-0002-9302-6490], Lindgren, Cecilia M [0000-0002-4903-9374], Kaakinen, Marika A [0000-0002-9228-0462], Watanabe, Richard M [0000-0003-1015-0531], Tampere University, Tays Research Services, Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), Fysiologie, RS: FHML MaCSBio, and RS: Carim - B01 Blood proteins & engineering
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Male ,Anorexia Nervosa ,medicine.medical_treatment ,45/43 ,Insulin Resistance/genetics ,SUSCEPTIBILITY ,Quantitative trait ,Impaired glucose tolerance ,0302 clinical medicine ,Architecture ,LS2_1 ,IMPUTATION ,Insulin ,ComputingMilieux_MISCELLANEOUS ,Fasting ,Publisher Correction ,3. Good health ,[SDV] Life Sciences [q-bio] ,Kruppel-Like Transcription Factors/blood ,Endokrinologi och diabetes ,Science & Technology - Other Topics ,Adult ,Blood Glucose ,European Continental Ancestry Group ,Female ,Gene Expression ,Genetic Loci ,Genome-Wide Association Study ,Glucose Intolerance ,Humans ,Insulin Receptor Substrate Proteins ,Insulin Resistance ,Kruppel-Like Transcription Factors ,Middle Aged ,Phenotype ,Sex Characteristics ,Sex Factors ,Waist-Hip Ratio ,Sex characteristics ,medicine.medical_specialty ,Science ,631/208/205/2138 ,Endocrinology and Diabetes ,General Biochemistry, Genetics and Molecular Biology ,White People ,Gender-differences ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,692/53/2421 ,GLYCEMIC TRAITS ,GENOME-WIDE ASSOCIATION ,Glycemic ,GENDER-DIFFERENCES ,Science & Technology ,IDENTIFICATION ,692/699/2743/2815 ,Blood Glucose/metabolism ,Diagnostic markers ,medicine.disease ,Anorexia Nervosa/blood ,030104 developmental biology ,Endocrinology ,Glucose ,Insulin/blood ,Anorexia Nervosa/ethnology ,Anorexia Nervosa/genetics ,Anorexia Nervosa/physiopathology ,Fasting/blood ,Glucose Intolerance/blood ,Glucose Intolerance/ethnology ,Glucose Intolerance/genetics ,Glucose Intolerance/physiopathology ,Insulin Receptor Substrate Proteins/blood ,Insulin Receptor Substrate Proteins/genetics ,Kruppel-Like Transcription Factors/genetics ,0301 basic medicine ,Identification ,[SDV]Life Sciences [q-bio] ,General Physics and Astronomy ,Genome-wide association studies ,Waist–hip ratio ,LS4_5 ,RISK ,ARCHITECTURE ,Multidisciplinary ,article ,Type 2 diabetes ,Multidisciplinary Sciences ,MENDELIAN RANDOMIZATION ,Pre-diabetes ,Medical Genetics ,Risk ,PATHOPHYSIOLOGY ,030209 endocrinology & metabolism ,3121 Internal medicine ,692/163/2743/137/773 ,NO ,Insulin resistance ,Internal medicine ,Diabetes mellitus ,medicine ,Mendelian randomization ,631/208/480 ,Medicinsk genetik ,business.industry ,General Chemistry ,Impaired fasting glucose ,business - Abstract
Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes., Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.
- Published
- 2021
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