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

• Published in: Nature communications Vol. 12; no. 1; pp. 24 - 18
• Main Authors: Lagou, Vasiliki, Mägi, Reedik, Grallert, Harald, Jansen, Rick, Dimas, Antigone S., Ulrich, Anna, Zudina, Liudmila, Gådin, Jesper R., Faggian, Alessia, Tanaka, Toshiko, Webster, Rebecca J., Saxena, Richa, Salo, Perttu, Shin, So-Youn, Amin, Najaf, Li, Guo, Verweij, Niek, Johnson, Paul C. D., Johnson, Toby, Rasmussen-Torvik, Laura J., Esko, Tõnu, Fall, Tove, Fraser, Ross M., Kanoni, Stavroula, Giedraitis, Vilmantas, Kleber, Marcus E., Sanna, Serena, Boettcher, Yvonne, Rayner, N. William, Nolte, Ilja M., Iperen, Erik van, Kovacs, Peter, Campbell, Susan, Polasek, Ozren, Egan, Josephine, Kiess, Wieland, Willemsen, Gonneke, Kuusisto, Johanna, Laakso, Markku, Thorand, Barbara, Miljkovic, Iva, Lind, Lars, Doney, Alex, Perola, Markus, Kivimaki, Mika, Kumari, Meena, Bennett, Amanda J., Groves, Christopher J., Koistinen, Heikki A., Bakker, Stephan J. L., Uusitupa, Matti, Palmer, Colin N. A., Pouta, Anneli, Krus, Ulrika, de Geus, Eco J. C. N., Wolffenbuttel, Bruce H. R., Abecasis, Goncalo R., Wright, Alan F., Dedoussis, George V., Schwarz, Peter E. H., Winkelmann, Bernhard R., Boehm, Bernhard O., März, Winfried, Metspalu, Andres, Price, Jackie F., Keinanen-Kiukaanniemi, Sirkka M., Saaristo, Timo E., Bergman, Richard N., Tuomilehto, Jaakko, Langenberg, Claudia, Vitart, Veronique, Visvikis-Siest, Sophie, Altshuler, David, Illig, Thomas, Ferrucci, Luigi, Pramstaller, Peter P., Peyser, Patricia A., Palmer, Lyle J., Penninx, Brenda W., Harst, Pim van der, Forouhi, Nita G., Loos, Ruth J. F., Boomsma, Dorret I., Hofman, Albert, Munroe, Patricia B., Gudnason, Vilmundur, Stefansson, Kari, Hamsten, Anders, Nicholson, George, Dermitzakis, Emmanouil T., Lindgren, Cecilia M., Froguel, Philippe, Kaakinen, Marika A., Lyssenko, Valeriya, Watanabe, Richard M., Ingelsson, Erik, Florez, Jose C., Barroso, Inês, Morris, Andrew P., Prokopenko, Inga
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 2021; Nature Publishing Group; Nature Portfolio
• Subjects: 45/43; 631/208/205/2138; 631/208/480; 692/163/2743/137/773; 692/53/2421; 692/699/2743/2815; Adult; Anorexia; Anorexia Nervosa - blood; Anorexia Nervosa - ethnology; Anorexia Nervosa - genetics; Anorexia Nervosa - physiopathology; Basic Medicine; Blood Glucose - metabolism; Clinical Medicine; Diabetes mellitus; Dimorphism; Eating disorders; Endocrinology and Diabetes; Endokrinologi och diabetes; Epidemiology; Fasting; Fasting - blood; Female; Gender aspects; Gender differences; Gene Expression; Gene loci; Genetic effects; Genetic Loci; Genome-wide association studies; Genome-Wide Association Study; Genomes; Glucose; Glucose Intolerance - blood; Glucose Intolerance - ethnology; Glucose Intolerance - genetics; Glucose Intolerance - physiopathology; Glucose tolerance; Hip; Humanities and Social Sciences; Humans; Insulin; Insulin - blood; Insulin Receptor Substrate Proteins - blood; Insulin Receptor Substrate Proteins - genetics; Insulin resistance; Insulin Resistance - genetics; Klinisk medicin; Kruppel-Like Transcription Factors - blood; Kruppel-Like Transcription Factors - genetics; Laboratory testing; Life Sciences; Male; Medical and Health Sciences; Medical Genetics; Medicin och hälsovetenskap; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Men; Middle Aged; multidisciplinary; Phenotype; Phenotypes; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Sex; Sex Characteristics; Sex differences; Sex Factors; Sexual dimorphism; Waist-Hip Ratio; White People; Women
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-19366-9

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. Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.