IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-020-19366-9.html
   My bibliography  Save this article

Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author

Listed:
  • Vasiliki Lagou

    (University of Oxford
    Laboratory of Adaptive Immunity
    VIB-KU Leuven Center for Brain and Disease Research)

  • Reedik Mägi

    (University of Tartu)

  • Jouke- Jan Hottenga

    (Vrije Universiteit
    VU University medical center)

  • Harald Grallert

    (Helmholtz Zentrum München Research Center for Environmental Health
    German Center for Diabetes Research (DZD)

  • John R. B. Perry

    (University of Cambridge School of Clinical Medicine)

  • Nabila Bouatia-Naji

    (University of Lille Nord de France
    CNRS UMR8199, Institut Pasteur de Lille
    INSERM U970, Paris Cardiovascular Research Center PARCC)

  • Letizia Marullo

    (University of Ferrara)

  • Denis Rybin

    (Boston University Data Coordinating Center)

  • Rick Jansen

    (VU University Medical Center)

  • Josine L. Min

    (University of Bristol
    University of Bristol)

  • Antigone S. Dimas

    (Biomedical Sciences Research Center Al. Fleming)

  • Anna Ulrich

    (Imperial College London)

  • Liudmila Zudina

    (Imperial College London)

  • Jesper R. Gådin

    (Karolinska University Hospital)

  • Longda Jiang

    (Imperial College London
    The University of Queensland)

  • Alessia Faggian

    (Imperial College London)

  • Amélie Bonnefond

    (University of Lille Nord de France
    CNRS UMR8199, Institut Pasteur de Lille
    Imperial College London)

  • Joao Fadista

    (Statens Serum Institut)

  • Maria G. Stathopoulou

    (Université de Lorraine, IGE-PCV)

  • Aaron Isaacs

    (Erasmus Medical Center
    Maastricht University
    Maastricht University)

  • Sara M. Willems

    (Erasmus Medical Center)

  • Pau Navarro

    (University of Edinburgh, Western General Hospital)

  • Toshiko Tanaka

    (National Institute on Aging)

  • Anne U. Jackson

    (University of Michigan)

  • May E. Montasser

    (University of Maryland, School of Medicine)

  • Jeff R. O’Connell

    (University of Maryland, School of Medicine)

  • Lawrence F. Bielak

    (University of Michigan)

  • Rebecca J. Webster

    (University of Western Australia Centre for Medical Research)

  • Richa Saxena

    (Broad Institute of Harvard and Massachusetts Institute of Technology (MIT)
    Center for Human Genetic Research, Massachusetts General Hospital
    Harvard Medical School
    Critical Care and Pain Medicine, MGH)

  • Jeanette M. Stafford

    (Wake Forest University School of Medicine)

  • Beate St Pourcain

    (University of Bristol
    University of Bristol)

  • Nicholas J. Timpson

    (University of Bristol
    University of Bristol)

  • Perttu Salo

    (Finnish Institute for Health and Welfare)

  • So-Youn Shin

    (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • Najaf Amin

    (Department of Epidemiology Erasmus MC)

  • Albert V. Smith

    (University of Michigan
    Icelandic Heart Association
    University of Iceland)

  • Guo Li

    (University of Washington
    University of Washington)

  • Niek Verweij

    (University of Groningen, University Medical Center Groningen)

  • Anuj Goel

    (University of Oxford
    University of Oxford)

  • Ian Ford

    (University of Glasgow)

  • Paul C. D. Johnson

    (University of Glasgow
    University of Glasgow)

  • Toby Johnson

    (Queen Mary University of London
    Queen Mary University of London)

  • Karen Kapur

    (University of Lausanne)

  • Gudmar Thorleifsson

    (deCODE Genetics)

  • Rona J. Strawbridge

    (Karolinska Institutet
    Karolinska University Hospital Solna
    University of Glasgow)

  • Laura J. Rasmussen-Torvik

    (Northwestern University Feinberg School of Medicine)

  • Tõnu Esko

    (University of Tartu)

  • Evelin Mihailov

    (University of Tartu)

  • Tove Fall

    (Uppsala University)

  • Ross M. Fraser

    (University of Edinburgh
    Synpromics Ltd, Roslin Innovation Centre, Easter Bush Campus)

  • Anubha Mahajan

    (University of Oxford
    Genentech)

  • Stavroula Kanoni

    (Queen Mary University of London
    Wellcome Trust Sanger Institute)

  • Vilmantas Giedraitis

    (Uppsala Universitet)

  • Marcus E. Kleber

    (Heidelberg University)

  • Günther Silbernagel

    (Medical University of Graz)

  • Julia Meyer

    (German Research Center for Environmental Health)

  • Martina Müller-Nurasyid

    (German Research Center for Environmental Health
    Ludwig-Maximilians-Universität
    University Hospital Grosshadern, Ludwig-Maximilians-University
    Johannes Gutenberg University)

  • Andrea Ganna

    (Massachusetts General Hospital
    Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard)

  • Antti-Pekka Sarin

    (University of Helsinki
    Finnish Institute for Health and Welfare)

  • Loic Yengo

    (University of Lille Nord de France
    CNRS UMR8199, Institut Pasteur de Lille
    The University of Queensland)

  • Dmitry Shungin

    (Umeå University
    Skåne University Hospital Malmö
    Umeå University)

  • Jian’an Luan

    (University of Cambridge School of Clinical Medicine)

  • Momoko Horikoshi

    (University of Oxford
    University of Oxford
    RIKEN, Center for Integrative Medical Sciences, Laboratory for Endocrinology, Metabolism and Kidney Disease)

  • Ping An

    (Washington University School of Medicine)

  • Serena Sanna

    (Istituto di Ricerca Genetica e Biomedica, CNR
    University of Groningen)

  • Yvonne Boettcher

    (University of Leipzig
    University of Leipzig)

  • N. William Rayner

    (University of Oxford
    Wellcome Trust Sanger Institute
    University of Oxford)

  • Ilja M. Nolte

    (University of Groningen, University Medical Center Groningen)

  • Tatijana Zemunik

    (University of Split)

  • Erik van Iperen

    (University of Amsterdam)

  • Peter Kovacs

    (University of Leipzig)

  • Nicholas D. Hastie

    (University of Edinburgh, Western General Hospital)

  • Sarah H. Wild

    (University of Edinburgh)

  • Stela McLachlan

    (University of Edinburgh)

  • Susan Campbell

    (University of Edinburgh, Western General Hospital)

  • Ozren Polasek

    (University of Split)

  • Olga Carlson

    (National Institute of Aging)

  • Josephine Egan

    (National Institute of Aging)

  • Wieland Kiess

    (University of Leipzig
    University of Leipzig)

  • Gonneke Willemsen

    (Vrije Universiteit)

  • Johanna Kuusisto

    (University of Eastern Finland and Kuopio University Hospital)

  • Markku Laakso

    (University of Eastern Finland and Kuopio University Hospital)

  • Maria Dimitriou

    (Harokopio University)

  • Andrew A. Hicks

    (European Academy Bozen/Bolzano (EURAC) (Affiliated Institute of the University of LübeckLübeckGermany))

  • Rainer Rauramaa

    (Kuopio Research Institute of Exercise Medicine
    Kuopio University Hospital)

  • Stefania Bandinelli

    (Geriatric Unit, Azienda Sanitaria Firenze (ASF))

  • Barbara Thorand

    (German Center for Diabetes Research (DZD
    German Research Center for Environmental Health)

  • Yongmei Liu

    (Wake Forest University School of Medicine)

  • Iva Miljkovic

    (University of Pittsburgh)

  • Lars Lind

    (Uppsala University)

  • Alex Doney

    (University of Dundee)

  • Markus Perola

    (Finnish Institute for Health and Welfare
    University of Helsinki
    University of Tartu)

  • Aroon Hingorani

    (University College London)

  • Mika Kivimaki

    (University College London)

  • Meena Kumari

    (University College London
    University of Essex)

  • Amanda J. Bennett

    (University of Oxford)

  • Christopher J. Groves

    (University of Oxford)

  • Christian Herder

    (German Center for Diabetes Research (DZD
    Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf
    Heinrich Heine University Düsseldorf)

  • Heikki A. Koistinen

    (Finnish Institute for Health and Welfare
    University of Helsinki and Helsinki University Central Hospital
    Minerva Foundation Institute for Medical Research, Biomedicum 2U)

  • Leena Kinnunen

    (Finnish Institute for Health and Welfare)

  • Ulf de Faire

    (Karolinska Institutet)

  • Stephan J. L. Bakker

    (University of Groningen, University Medical Center Groningen)

  • Matti Uusitupa

    (University of Eastern Finland)

  • Colin N. A. Palmer

    (University of Dundee)

  • J. Wouter Jukema

    (Leiden University Medical Center
    Netherlands Heart Institute)

  • Naveed Sattar

    (University of Glasgow)

  • Anneli Pouta

    (Finnish Institute for Health and Welfare
    Oulu University Hospital and University of Oulu)

  • Harold Snieder

    (University of Groningen, University Medical Center Groningen)

  • Eric Boerwinkle

    (IMM Center for Human Genetics, University of Texas Health Science Center at Houston
    University of Texas Health Science Center at Houston)

  • James S. Pankow

    (University of Minnesota)

  • Patrik K. Magnusson

    (Karolinska Institutet)

  • Ulrika Krus

    (University Hospital Malmö, Lund University)

  • Chiara Scapoli

    (University of Ferrara)

  • Eco J. C. N. Geus

    (Vrije Universiteit
    VU University medical center)

  • Matthias Blüher

    (University of Leipzig
    Keck School of Medicine of USC)

  • Bruce H. R. Wolffenbuttel

    (University of Groningen, University Medical Center Groningen)

  • Michael A. Province

    (Washington University School of Medicine)

  • Goncalo R. Abecasis

    (University of Michigan)

  • James B. Meigs

    (Broad Institute of MIT and Harvard
    General Medicine Division, Massachusetts General Hospital
    Harvard Medical School)

  • G. Kees Hovingh

    (Amsterdam UMC
    Novo Nordisk A/S)

  • Jaana Lindström

    (Diabetes Prevention Unit)

  • James F. Wilson

    (University of Edinburgh, Western General Hospital
    University of Edinburgh)

  • Alan F. Wright

    (University of Edinburgh, Western General Hospital)

  • George V. Dedoussis

    (Harokopio University)

  • Stefan R. Bornstein

    (Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden)

  • Peter E. H. Schwarz

    (Technische Universität Dresden
    Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, TU Dresden
    German Center for Diabetes Research (DZD e.V.))

  • Anke Tönjes

    (University of Leipzig
    University of Leipzig)

  • Bernhard R. Winkelmann

    (Cardiology Group)

  • Bernhard O. Boehm

    (Nanyang Technological University Singapore and Imperial College London)

  • Winfried März

    (Heidelberg University
    Synlab Academy, Synlab Holding Deutschland GmbH)

  • Andres Metspalu

    (University of Tartu)

  • Jackie F. Price

    (University of Edinburgh)

  • Panos Deloukas

    (Queen Mary University of London
    Wellcome Trust Sanger Institute
    King Abdulaziz University)

  • Antje Körner

    (University of Leipzig
    Massachusetts General Hospital)

  • Timo A. Lakka

    (Kuopio Research Institute of Exercise Medicine
    University of Eastern Finland, Kuopio Campus)

  • Sirkka M. Keinanen-Kiukaanniemi

    (University of Oulu
    Oulu University Hospital)

  • Timo E. Saaristo

    (Finnish Diabetes Association
    Pirkanmaa Hospital District)

  • Richard N. Bergman

    (Cedars-Sinai Medical Center)

  • Jaakko Tuomilehto

    (Finnish Institute for Health and Welfare
    University of Helsinki
    Danube-University Krems
    King Abdulaziz University)

  • Nicholas J. Wareham

    (University of Cambridge School of Clinical Medicine)

  • Claudia Langenberg

    (University of Cambridge School of Clinical Medicine)

  • Satu Männistö

    (Finnish Institute for Health and Welfare)

  • Paul W. Franks

    (Skåne University Hospital Malmö
    Harvard School of Public Health
    Umeå University)

  • Caroline Hayward

    (University of Edinburgh, Western General Hospital)

  • Veronique Vitart

    (University of Edinburgh, Western General Hospital)

  • Jaakko Kaprio

    (University of Helsinki
    University of Helsinki)

  • Sophie Visvikis-Siest

    (Université de Lorraine, IGE-PCV)

  • Beverley Balkau

    (Inserm, CESP Center for Research in Epidemiology and Public Health
    Univ Paris-Saclay, Univ Paris Sud, UVSQ, UMRS 1018, UMRS 1018)

  • David Altshuler

    (Broad Institute of Harvard and Massachusetts Institute of Technology (MIT)
    Center for Human Genetic Research, Massachusetts General Hospital
    Harvard Medical School)

  • Igor Rudan

    (University of Edinburgh)

  • Michael Stumvoll

    (University of Leipzig
    University of Leipzig)

  • Harry Campbell

    (University of Edinburgh)

  • Cornelia M. Duijn

    (Erasmus Medical Center
    Centre for Medical Systems Biology)

  • Christian Gieger

    (Helmholtz Zentrum München Research Center for Environmental Health
    German Center for Diabetes Research (DZD
    German Research Center for Environmental Health)

  • Thomas Illig

    (Helmholtz Zentrum München Research Center for Environmental Health
    Hannover Medical School
    Hannover Medical School)

  • Luigi Ferrucci

    (National Institute on Aging)

  • Nancy L. Pedersen

    (Karolinska Institutet)

  • Peter P. Pramstaller

    (European Academy Bozen/Bolzano (EURAC) (Affiliated Institute of the University of LübeckLübeckGermany)
    General Central Hospital
    University of Lübeck)

  • Michael Boehnke

    (University of Michigan)

  • Timothy M. Frayling

    (University of Exeter)

  • Alan R. Shuldiner

    (University of Maryland, School of Medicine
    Regeneron Pharmaceuticals)

  • Patricia A. Peyser

    (University of Michigan)

  • Sharon L. R. Kardia

    (University of Michigan)

  • Lyle J. Palmer

    (University of Adelaide)

  • Brenda W. Penninx

    (VU University Medical Center)

  • Pierre Meneton

    (Centre de Recherche des Cordeliers)

  • Tamara B. Harris

    (National Institute on Aging)

  • Gerjan Navis

    (University of Groningen, University Medical Center Groningen)

  • Pim van der Harst

    (University of Groningen, University Medical Center Groningen
    University Medical Center Groningen, University of Groningen)

  • George Davey Smith

    (University of Bristol)

  • Nita G. Forouhi

    (University of Cambridge School of Clinical Medicine)

  • Ruth J. F. Loos

    (University of Cambridge School of Clinical Medicine
    Icahn School of Medicine at Mount Sinai)

  • Veikko Salomaa

    (Finnish Institute for Health and Welfare)

  • Nicole Soranzo

    (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus)

  • Dorret I. Boomsma

    (Vrije Universiteit)

  • Leif Groop

    (University of Helsinki
    University Hospital Malmö, Lund University)

  • Tiinamaija Tuomi

    (University of Helsinki
    University Hospital Malmö, Lund University
    University of Helsinki and Helsinki University Hospital
    University of Helsinki and Folkhälsan Research Center)

  • Albert Hofman

    (Department of Epidemiology Erasmus MC
    Netherlands Consortium for healthy ageing
    Harvard T.H. Chan School of Public Health)

  • Patricia B. Munroe

    (Queen Mary University of London
    Queen Mary University of London)

  • Vilmundur Gudnason

    (Icelandic Heart Association
    Faculty of Medicine University of Iceland)

  • David S. Siscovick

    (University of Washington
    University of Washington
    University of Washington)

  • Hugh Watkins

    (University of Oxford
    University of Oxford)

  • Cecile Lecoeur

    (University of Lille Nord de France
    CNRS UMR8199, Institut Pasteur de Lille)

  • Peter Vollenweider

    (University Hospital Lausanne)

  • Anders Franco-Cereceda

    (Karolinska Institutet)

  • Per Eriksson

    (Karolinska University Hospital)

  • Marjo-Riitta Jarvelin

    (Imperial College London
    University of Oulu)

  • Kari Stefansson

    (deCODE Genetics
    University of Iceland)

  • Anders Hamsten

    (Karolinska Institutet
    Karolinska University Hospital Solna
    Karolinska University Hospital Solna)

  • George Nicholson

    (University of Oxford)

  • Fredrik Karpe

    (University of Oxford
    Churchill Hospital)

  • Emmanouil T. Dermitzakis

    (University of Geneva Medical School)

  • Cecilia M. Lindgren

    (University of Oxford
    Broad Institute of Harvard and Massachusetts Institute of Technology (MIT)
    University of Oxford
    University of Oxford)

  • Mark I. McCarthy

    (University of Oxford
    University of Oxford
    Churchill Hospital
    Genentech)

  • Philippe Froguel

    (University of Lille Nord de France
    CNRS UMR8199, Institut Pasteur de Lille
    Imperial College London)

  • Marika A. Kaakinen

    (Imperial College London
    University of Surrey)

  • Valeriya Lyssenko

    (University Hospital Malmö, Lund University
    University of Bergen)

  • Richard M. Watanabe

    (Keck School of Medicine of USC
    Keck School of Medicine of USC
    USC Diabetes and Obesity Research Institute)

  • Erik Ingelsson

    (Uppsala University
    Stanford University School of Medicine
    Stanford University)

  • Jose C. Florez

    (Center for Human Genetic Research, Massachusetts General Hospital
    Massachusetts General Hospital)

  • Josée Dupuis

    (Boston University School of Public Health)

  • Inês Barroso

    (Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus
    Wellcome Trust-MRC Institute of Metabolic Science
    University of Exeter Medical School)

  • Andrew P. Morris

    (University of Oxford
    University of Tartu
    University of Liverpool
    The University of Manchester)

  • Inga Prokopenko

    (University of Oxford
    Imperial College London
    University of Oxford
    University of Surrey)

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.

Suggested Citation

  • Vasiliki Lagou & Reedik Mägi & Jouke- Jan Hottenga & Harald Grallert & John R. B. Perry & Nabila Bouatia-Naji & Letizia Marullo & Denis Rybin & Rick Jansen & Josine L. Min & Antigone S. Dimas & Anna U, 2021. "Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-19366-9
    DOI: 10.1038/s41467-020-19366-9
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-020-19366-9
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-020-19366-9?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Natalie DeForest & Yuqi Wang & Zhiyi Zhu & Jacqueline S. Dron & Ryan Koesterer & Pradeep Natarajan & Jason Flannick & Tiffany Amariuta & Gina M. Peloso & Amit R. Majithia, 2024. "Genome-wide discovery and integrative genomic characterization of insulin resistance loci using serum triglycerides to HDL-cholesterol ratio as a proxy," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Zipeng Liu & Yiming Qin & Tian Wu & Justin D. Tubbs & Larry Baum & Timothy Shin Heng Mak & Miaoxin Li & Yan Dora Zhang & Pak Chung Sham, 2023. "Reciprocal causation mixture model for robust Mendelian randomization analysis using genome-scale summary data," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Zhen Qiao & Julia Sidorenko & Joana A. Revez & Angli Xue & Xueling Lu & Katri Pärna & Harold Snieder & Peter M. Visscher & Naomi R. Wray & Loic Yengo, 2023. "Estimation and implications of the genetic architecture of fasting and non-fasting blood glucose," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    4. Ewelina Maculewicz & Agata Leońska-Duniec & Andrzej Mastalerz & Ewa Szarska & Aleksandra Garbacz & Tomasz Lepionka & Roman Łakomy & Anna Anyżewska & Jerzy Bertrandt, 2022. "The Influence of FTO, FABP2, LEP, LEPR, and MC4R Genes on Obesity Parameters in Physically Active Caucasian Men," IJERPH, MDPI, vol. 19(10), pages 1-11, May.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-19366-9. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.