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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 
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 under- standing differences in genetic effects between women and men in related phenotypes.
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https://hal.univ-lorraine.fr/hal-03105716
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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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