Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
Authors: Lagou Vasiliki , Mägi Reedik , Hottenga Jouke- Jan , Grallert Harald , Perry John R. B. , Bouatia-Naji Nabila , Marullo Letizia , Rybin Denis , Jansen Rick , Min Josine L. , Dimas Antigone S. , Ulrich Anna , Zudina Liudmila , Gådin Jesper R. , Jiang Longda , Faggian Alessia , Bonnefond Amélie , Fadista Joao , Stathopoulou Maria G. , Isaacs Aaron , Willems Sara M. , Navarro Pau , Tanaka Toshiko , Jackson Anne U. , Montasser May E. , O’Connell Jeff R. , Bielak Lawrence F. , Webster Rebecca J. , Saxena Richa , Stafford Jeanette M. , Pourcain Beate St , Timpson Nicholas J. , Salo Perttu , Shin So-Youn , Amin Najaf , Smith Albert V. , Li Guo , Verweij Niek , Goel Anuj , Ford Ian , Johnson Paul C. D. , Johnson Toby , Kapur Karen , Thorleifsson Gudmar , Strawbridge Rona J. , Rasmussen-Torvik Laura J. , Esko Tõnu , Mihailov Evelin , Fall Tove , Fraser Ross M. , Mahajan Anubha , Kanoni Stavroula , Giedraitis Vilmantas , Kleber Marcus E. , Silbernagel Günther , Meyer Julia , Müller-Nurasyid Martina , Ganna Andrea , Sarin Antti-Pekka , Yengo Loic , Shungin Dmitry , Luan Jian’an , Horikoshi Momoko , An Ping , Sanna Serena , Boettcher Yvonne , Rayner N. William , Nolte Ilja M. , Zemunik Tatijana , Iperen Erik van , Kovacs Peter , Hastie Nicholas D. , Wild Sarah H. , McLachlan Stela , Campbell Susan , Polasek Ozren , Carlson Olga , Egan Josephine , Kiess Wieland , Willemsen Gonneke , Kuusisto Johanna , Laakso Markku , Dimitriou Maria , Hicks Andrew A. , Rauramaa Rainer , Bandinelli Stefania , Thorand Barbara , Liu Yongmei , Miljkovic Iva , Lind Lars , Doney Alex , Perola Markus , Hingorani Aroon , Kivimaki Mika , Kumari Meena , Bennett Amanda J. , Groves Christopher J. , Herder Christian , Koistinen Heikki A. , Kinnunen Leena , Faire Ulf de , Bakker Stephan J. L. , Uusitupa Matti , Palmer Colin N. A. , Jukema J. Wouter , Sattar Naveed , Pouta Anneli , Snieder Harold , Boerwinkle Eric , Pankow James S. , Magnusson Patrik K. , Krus Ulrika , Scapoli Chiara , de Geus Eco J. C. N. , Blüher Matthias , Wolffenbuttel Bruce H. R. , Province Michael A. , Abecasis Goncalo R. , Meigs James B. , Hovingh G. Kees , Lindström Jaana , Wilson James F. , Wright Alan F. , Dedoussis George V. , Bornstein Stefan R. , Schwarz Peter E. H. , Tönjes Anke , Winkelmann Bernhard R. , Boehm Bernhard O. , März Winfried , Metspalu Andres , Price Jackie F. , Deloukas Panos , Körner Antje , Lakka Timo A. , Keinanen-Kiukaanniemi Sirkka M. , Saaristo Timo E. , Bergman Richard N. , Tuomilehto Jaakko , Wareham Nicholas J. , Langenberg Claudia , Männistö Satu , Franks Paul W. , Hayward Caroline , Vitart Veronique , Kaprio Jaakko , Visvikis-Siest Sophie , Balkau Beverley , Altshuler David , Rudan Igor , Stumvoll Michael , Campbell Harry , van Duijn Cornelia M. , Gieger Christian , Illig Thomas , Ferrucci Luigi , Pedersen Nancy L. , Pramstaller Peter P. , Boehnke Michael , Frayling Timothy M. , Shuldiner Alan R. , Peyser Patricia A. , Kardia Sharon L. R. , Palmer Lyle J. , Penninx Brenda W. , Meneton Pierre , Harris Tamara B. , Navis Gerjan , Harst Pim van der , Smith George Davey , Forouhi Nita G. , Loos Ruth J. F. , Salomaa Veikko , Soranzo Nicole , Boomsma Dorret I. , Groop Leif , Tuomi Tiinamaija , Hofman Albert , Munroe Patricia B. , Gudnason Vilmundur , Siscovick David S. , Watkins Hugh , Lecoeur Cecile , Vollenweider Peter , Franco-Cereceda Anders , Eriksson Per , Jarvelin Marjo-Riitta , Stefansson Kari , Hamsten Anders , Nicholson George , Karpe Fredrik , Dermitzakis Emmanouil T. , Lindgren Cecilia M. , McCarthy Mark I. , Froguel Philippe , Kaakinen Marika A. , Lyssenko Valeriya , Watanabe Richard M. , Ingelsson Erik , Florez Jose C. , Dupuis Josée , Barroso Inês , Morris Andrew P. , Prokopenko Inga ,   Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)
Published: January 2021

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 atIRS1andZNF12loci, 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.