Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
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Lagou, Vasiliki | Mägi, Reedik | Hottenga, Jouke- Jan | Grallert, Harald | Perry, John | Bouatia-Naji, Nabila | Marullo, Letizia | Rybin, Denis | Jansen, Rick | Min, Josine | Dimas, Antigone | Ulrich, Anna | Zudina, Liudmila | Gådin, Jesper | Jiang, Longda | Faggian, Alessia | Bonnefond, Amélie | Fadista, Joao | Stathopoulou, Maria | Isaacs, Aaron | Willems, Sara | Navarro, Pau | Tanaka, Toshiko | Jackson, Anne | Montasser, May | O’connell, Jeff | Bielak, Lawrence | Webster, Rebecca | Saxena, Richa | Stafford, Jeanette | Pourcain, Beate St | Timpson, Nicholas | Salo, Perttu | Shin, So-Youn | Amin, Najaf | Smith, Albert | Li, Guo | Verweij, Niek | Goel, Anuj | Ford, Ian | Johnson, Paul | Johnson, Toby | Kapur, Karen | Thorleifsson, Gudmar | Strawbridge, Rona | Rasmussen-Torvik, Laura | Esko, Tõnu | Mihailov, Evelin | Fall, Tove | Fraser, Ross | Mahajan, Anubha | Kanoni, Stavroula | Giedraitis, Vilmantas | Kleber, Marcus | 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 | Zemunik, Tatijana | Iperen, Erik Van | Kovacs, Peter | Hastie, Nicholas | Wild, Sarah | Mclachlan, Stela | Campbell, Susan | Polasek, Ozren | Carlson, Olga | Egan, Josephine | Kiess, Wieland | Willemsen, Gonneke | Kuusisto, Johanna | Laakso, Markku | Dimitriou, Maria | Hicks, Andrew | Rauramaa, Rainer | Bandinelli, Stefania | Thorand, Barbara | Liu, Yongmei | Miljkovic, Iva | Lind, Lars | Doney, Alex | Perola, Markus | Hingorani, Aroon | Kivimaki, Mika | Kumari, Meena | Bennett, Amanda | Groves, Christopher | Herder, Christian | Koistinen, Heikki | Kinnunen, Leena | Faire, Ulf De | Bakker, Stephan | Uusitupa, Matti | Palmer, Colin | Jukema, J. Wouter | Sattar, Naveed | Pouta, Anneli | Snieder, Harold | Boerwinkle, Eric | Pankow, James | Magnusson, Patrik | Krus, Ulrika | Scapoli, Chiara | de Geus, Eco | Blüher, Matthias | Wolffenbuttel, Bruce | Province, Michael | Abecasis, Goncalo | Meigs, James | Hovingh, G. Kees | Lindström, Jaana | Wilson, James | Wright, Alan | Dedoussis, George | Bornstein, Stefan | Schwarz, Peter | Tönjes, Anke | Winkelmann, Bernhard | Boehm, Bernhard | März, Winfried | Metspalu, Andres | Price, Jackie | Deloukas, Panos | Körner, Antje | Lakka, Timo | Keinanen-Kiukaanniemi, Sirkka | Saaristo, Timo | Bergman, Richard | Tuomilehto, Jaakko | Wareham, Nicholas | Langenberg, Claudia | Männistö, Satu | Franks, Paul | Hayward, Caroline | Vitart, Veronique | Kaprio, Jaakko | Visvikis-Siest, Sophie | Balkau, Beverley | Altshuler, David | Rudan, Igor | Stumvoll, Michael | Campbell, Harry | van Duijn, Cornelia | Gieger, Christian | Illig, Thomas | Ferrucci, Luigi | Pedersen, Nancy | Pramstaller, Peter | Boehnke, Michael | Frayling, Timothy | Shuldiner, Alan | Peyser, Patricia | Kardia, Sharon | Palmer, Lyle | Penninx, Brenda | Meneton, Pierre | Harris, Tamara | Navis, Gerjan | Harst, Pim van Der | Smith, George Davey | Forouhi, Nita | Loos, Ruth | Salomaa, Veikko | Soranzo, Nicole | Boomsma, Dorret | Groop, Leif | Tuomi, Tiinamaija | Hofman, Albert | Munroe, Patricia | Gudnason, Vilmundur | Siscovick, David | Watkins, Hugh | Lecoeur, Cecile | Vollenweider, Peter | Franco-Cereceda, Anders | Eriksson, Per | Jarvelin, Marjo-Riitta | Stefansson, Kari | Hamsten, Anders | Nicholson, George | Karpe, Fredrik | Dermitzakis, Emmanouil | Lindgren, Cecilia | Mccarthy, Mark | Froguel, Philippe | Kaakinen, Marika | Lyssenko, Valeriya | Watanabe, Richard | Ingelsson, Erik | Florez, Jose | Dupuis, Josée | Barroso, Inês | Morris, Andrew | Prokopenko, Inga
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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 menand impaired glucose tolerance in women, however, the genetic component underlyingthis phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individualsof European descent without diabetes. Here we report sex dimorphism in allelic effects onfasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in wholeblood in women compared to men. We also observe sex-homogeneous effects on fastingglucose at seven novel loci. Fasting insulin in women shows stronger genetic correlationsthan in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio iscausally related to insulin resistance in women, but not in men. These results positiondissection of metabolic and glycemic health sex dimorphism as a steppingstone for under-standing differences in genetic effects between women and men in related phenotypes.
