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Article Dans Une Revue Nature Communications Année : 2021

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

Vasiliki Lagou (1, 2) , Reedik Mägi (3) , Jouke- Jan Hottenga (4, 5) , Harald Grallert (6) , John Perry (7) , Nabila Bouatia-Naji (8, 9) , Letizia Marullo (10) , Denis Rybin (11) , Rick Jansen (12) , Josine Min (13) , Antigone Dimas (14) , Anna Ulrich (15) , Liudmila Zudina (15) , Jesper Gådin (16) , Longda Jiang (15, 17) , Alessia Faggian (15) , Amélie Bonnefond (8, 15) , Joao Fadista (18) , Maria Stathopoulou (19) , Aaron Isaacs (20, 21, 22) , Sara Willems (20) , Pau Navarro (23) , Toshiko Tanaka (24) , Anne Jackson (25) , May Montasser (26) , Jeff O’connell (26) , Lawrence Bielak (25) , Rebecca Webster (27) , Richa Saxena (28, 29, 30) , Jeanette Stafford (31) , Beate St Pourcain (13) , Nicholas Timpson (13) , Perttu Salo (32) , So-Youn Shin (33) , Najaf Amin (20) , Albert Smith (25, 34) , Guo Li (35) , Niek Verweij (36) , Anuj Goel (1) , Ian Ford (37) , Paul Johnson (37) , Toby Johnson (38) , Karen Kapur (39) , Gudmar Thorleifsson (40) , Rona Strawbridge (16, 37) , Laura Rasmussen-Torvik (41) , Tõnu Esko (3) , Evelin Mihailov (3) , Tove Fall (42) , Ross Fraser (43) , Anubha Mahajan (1) , Stavroula Kanoni (38, 33) , Vilmantas Giedraitis (42) , Marcus Kleber (44) , Günther Silbernagel (45) , Julia Meyer (6) , Martina Müller-Nurasyid (6, 46, 47) , Andrea Ganna (29, 28) , Antti-Pekka Sarin (48, 32) , Loic Yengo (8, 17) , Dmitry Shungin (49, 50) , Jian’an Luan (7) , Momoko Horikoshi (1, 51) , Ping An (52) , Serena Sanna (53, 54) , Yvonne Boettcher (55) , N. William Rayner (1, 33, 56) , Ilja Nolte (54) , Tatijana Zemunik (57) , Erik Van Iperen (58) , Peter Kovacs (55) , Nicholas Hastie (23) , Sarah Wild (43) , Stela Mclachlan (43) , Susan Campbell (23) , Ozren Polasek (57) , Olga Carlson (24) , Josephine Egan (24) , Wieland Kiess (55) , Gonneke Willemsen (4) , Johanna Kuusisto (59) , Markku Laakso (59) , Maria Dimitriou (60) , Andrew Hicks (61) , Rainer Rauramaa (62) , Stefania Bandinelli , Barbara Thorand (63, 6) , Yongmei Liu (31) , Iva Miljkovic (64) , Lars Lind (42) , Alex Doney (65) , Markus Perola (32, 48, 66) , Aroon Hingorani (67) , Mika Kivimaki (67) , Meena Kumari (67, 68) , Amanda Bennett (56) , Christopher Groves (56) , Christian Herder (63, 69) , Heikki Koistinen (32, 70) , Leena Kinnunen (32) , Ulf De Faire (16) , Stephan Bakker (54) , Matti Uusitupa (59) , Colin Palmer (65) , J. Wouter Jukema (71) , Naveed Sattar (72) , Anneli Pouta (32, 73) , Harold Snieder (54) , Eric Boerwinkle (74) , James Pankow (75) , Patrik Magnusson (16) , Ulrika Krus (50) , Chiara Scapoli (10) , Eco de Geus (4, 12) , Matthias Blüher (55, 76) , Bruce Wolffenbuttel (54) , Michael Province (52) , Goncalo Abecasis (25) , James Meigs (28, 29, 30) , G. Kees Hovingh (77) , Jaana Lindström (32) , James Wilson (23) , Alan Wright (23) , George Dedoussis (60) , Stefan Bornstein (78) , Peter Schwarz (78, 63) , Anke Tönjes (55) , Bernhard Winkelmann , Bernhard Boehm (79) , Winfried März (80) , Andres Metspalu (66) , Jackie Price (43) , Panos Deloukas (38, 33, 81) , Antje Körner (55, 29) , Timo Lakka (59) , Sirkka Keinanen-Kiukaanniemi (73) , Timo Saaristo (82) , Richard Bergman (83) , Jaakko Tuomilehto (32, 70, 84, 81) , Nicholas Wareham (7) , Claudia Langenberg (7) , Satu Männistö (32) , Paul Franks (50, 85, 49) , Caroline Hayward (23) , Veronique Vitart (23) , Jaakko Kaprio (48) , Sophie Visvikis-Siest (19) , Beverley Balkau (86) , David Altshuler (28, 29, 30) , Igor Rudan (43) , Michael Stumvoll (55) , Harry Campbell (43) , Cornelia van Duijn (20) , Christian Gieger (63, 87) , Thomas Illig (6, 88) , Luigi Ferrucci (24) , Nancy Pedersen (16) , Peter Pramstaller (61, 89) , Michael Boehnke (25) , Timothy Frayling (90) , Alan Shuldiner (26, 91) , Patricia Peyser (25) , Sharon Kardia (25) , Lyle Palmer (92) , Brenda Penninx (12) , Pierre Meneton (93) , Tamara Harris (24) , Gerjan Navis (54) , Pim van Der Harst (54) , George Davey Smith (13) , Nita Forouhi (7) , Ruth Loos (7, 94) , Veikko Salomaa (32) , Nicole Soranzo (33) , Dorret Boomsma (4) , Leif Groop (48, 50) , Tiinamaija Tuomi (48, 50) , Albert Hofman (20, 95) , Patricia Munroe (38) , Vilmundur Gudnason (34) , David Siscovick (35) , Hugh Watkins (1, 96) , Cecile Lecoeur (8) , Peter Vollenweider (97) , Anders Franco-Cereceda (16) , Per Eriksson (16) , Marjo-Riitta Jarvelin (15, 73) , Kari Stefansson (40, 34) , Anders Hamsten (16) , George Nicholson (98) , Fredrik Karpe (56) , Emmanouil Dermitzakis (99) , Cecilia Lindgren (1, 28, 56, 100) , Mark Mccarthy (1, 56) , Philippe Froguel (8, 15) , Marika Kaakinen (15, 101) , Valeriya Lyssenko (50, 102) , Richard Watanabe (76) , Erik Ingelsson (42, 103, 104) , Jose Florez (29) , Josée Dupuis (11) , Inês Barroso (33) , Andrew Morris (1, 66, 105, 106) , Inga Prokopenko (1, 15, 56, 101, 107)
1 The Wellcome Trust Centre for Human Genetics [Oxford]
2 KU Leuven - Catholic University of Leuven = Katholieke Universiteit Leuven
3 Institute of Genomics [Tartu, Estonia]
4 VU - Vrije Universiteit Amsterdam [Amsterdam]
5 VUMC - Vrije Universiteit Medical Centre
6 Helmholtz Zentrum München = German Research Center for Environmental Health
7 CAM - University of Cambridge [UK]
8 EGENODIA (GI3M) - Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283
9 PARCC (UMR_S 970/ U970) - Paris-Centre de Recherche Cardiovasculaire
10 UniFE - Università degli Studi di Ferrara = University of Ferrara
11 BU - Boston University [Boston]
12 VU University Medical Center [Amsterdam]
13 University of Bristol [Bristol]
14 BSRC - Biomedical Sciences Research Centre Alexander Fleming [Vari, Greece]
15 Imperial College London
16 Karolinska Institutet [Stockholm]
17 Institute for Molecular Bioscience
18 Statens Serum Institut [Copenhagen]
19 IGE-PCV - Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire
20 Erasmus MC - Erasmus University Medical Center [Rotterdam]
21 CARIM - Cardiovascular Research Institute Maastricht
22 Maastricht University [Maastricht]
23 IGMM - MRC Institute of Genetics and Molecular Medicine [Edinburgh]
24 NIA - National Institute on Aging [Bethesda, USA]
25 University of Michigan [Ann Arbor]
26 University of Maryland School of Medicine
27 UWA - The University of Western Australia
28 BROAD INSTITUTE - Broad Institute of MIT and Harvard
29 Massachusetts General Hospital [Boston]
30 HMS - Harvard Medical School [Boston]
31 Wake Forest University
32 National Institute for Health and Welfare [Helsinki]
33 The Wellcome Trust Sanger Institute [Cambridge]
34 University of Iceland [Reykjavik]
35 University of Washington [Seattle]
36 University of Groningen [Groningen]
37 University of Glasgow
38 William Harvey Research Institute, Barts and the London Medical School
39 UNIL - Université de Lausanne = University of Lausanne
40 deCODE genetics [Reykjavik]
41 Northwestern University Feinberg School of Medicine
42 Uppsala Universitet [Uppsala]
43 Edin. - University of Edinburgh
44 University Hospital Mannheim | Universitätsmedizin Mannheim
45 Karl-Franzens-Universität Graz
46 LMU - Ludwig Maximilian University [Munich] = Ludwig Maximilians Universität München
47 JGU - Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University
48 FIMM - Institute for Molecular Medicine Finland [Helsinki]
49 Umeå University
50 Skane University Hospital [Malmo]
51 RIKEN IMS - RIKEN Center for Integrative Medical Sciences [Yokohama]
52 Washington University School of Medicine in St. Louis
53 IRGB - Istituto di Ricerca Genetica e Biomedica
54 UMCG - University Medical Center Groningen [Groningen]
55 Leipzig University / Universität Leipzig
56 OCDEM - Oxford Centre for Diabetes, Endocrinology and Metabolism
57 University of Split
58 AMC - Academic Medical Center - Academisch Medisch Centrum [Amsterdam]
59 University of Eastern Finland
60 Harokopio University of Athens
61 EURAC - European Academy Bozen/Bolzano
62 University of Kuopio
63 DZD - German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg]
64 PITT - University of Pittsburgh
65 Ninewells Hospital and Medical School [Dundee]
66 University of Tartu
67 UCL - University College of London [London]
68 University of Essex
69 Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf]
70 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
71 LUMC - Leiden University Medical Center
72 Institute of Cardiovascular and Medical Sciences [Glasgow]
73 University of Oulu
74 UTHealth - The University of Texas Health Science Center at Houston
75 University of Minnesota Medical School
76 Keck School of Medicine [Los Angeles]
77 Amsterdam UMC - Amsterdam University Medical Center
78 University Hospital Carl Gustav Carus [Dresden, Germany]
79 Lee Kong Chian School of Medicine
80 Universität Heidelberg [Heidelberg] = Heidelberg University
81 King Abdulaziz University
82 Pirkanmaa Hospital District
83 Cedars-Sinai Medical Center
84 Danube University Krems
85 Harvard School of Public Health
86 CESP - Centre de recherche en épidémiologie et santé des populations
87 EPI - Institute of Epidemiology [Neuherberg]
88 MHH - Medizinische Hochschule Hannover = Hannover Medical School
89 Universität zu Lübeck = University of Lübeck [Lübeck]
90 University of Exeter
91 Regeneron Pharmaceuticals [Tarrytown, NY]
92 University of Adelaide
93 LIMICS - Laboratoire d'Informatique Médicale et Ingénierie des Connaissances en e-Santé
94 MSSM - Icahn School of Medicine at Mount Sinai [New York]
95 Harvard T.H. Chan School of Public Health
96 John Radcliffe Hospital [Oxford University Hospital]
97 CHUV - Centre Hospitalier Universitaire Vaudois = Lausanne University Hospital [Lausanne]
98 University of Oxford
99 UNIGE - Université de Genève = University of Geneva
100 Big Data Institute
101 UNIS - University of Surrey
102 UiB - University of Bergen
103 Stanford School of Medicine [Stanford]
104 Stanford Cardiovascular Institute
105 University of Liverpool
106 University of Manchester [Manchester]
107 Institute of Biochemistry and Genetics of Ufa Scientific Centre
Ian Ford
  • Fonction : Auteur
Paul Johnson
Stefania Bandinelli
  • Fonction : Auteur
Lars Lind
Goncalo Abecasis
  • Fonction : Auteur
  • PersonId : 948452
George Dedoussis
Bernhard Winkelmann
  • Fonction : Auteur

Résumé

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 under- standing differences in genetic effects between women and men in related phenotypes.
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hal-03105716 , version 1 (01-06-2022)

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Vasiliki Lagou, Reedik Mägi, Jouke- Jan Hottenga, Harald Grallert, John Perry, et al.. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability. Nature Communications, 2021, 12 (1), pp.24. ⟨10.1038/s41467-020-19366-9⟩. ⟨hal-03105716⟩
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