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

Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), Vasiliki Lagou, Reedik Mägi, Jouke- Jan Hottenga, Harald Grallert, John R B Perry, Nabila Bouatia-Naji, Letizia Marullo, Denis Rybin, Rick Jansen, Josine L Min, Antigone S Dimas, Anna Ulrich, Liudmila Zudina, Jesper R Gådin, Longda Jiang, Alessia Faggian, Amélie Bonnefond, Joao Fadista, Maria G StathopoulouAaron Isaacs, Sara M Willems, Pau Navarro, Toshiko Tanaka, Anne U Jackson, May E Montasser, Jeff R O'Connell, Lawrence F Bielak, Rebecca J Webster, Richa Saxena, Jeanette M Stafford, Beate St Pourcain, Nicholas J Timpson, Perttu Salo, So-Youn Shin, Najaf Amin, Albert V Smith, Guo Li, Niek Verweij, Anuj Goel, Ian Ford, Julia Meyer, Serena Sanna, Ilja M Nolte, Meena Kumari, Stephan J L Bakker, Harold Snieder, Bruce H R Wolffenbuttel, Brenda W Penninx, Gerjan Navis, Pim van der Harst

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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 understanding differences in genetic effects between women and men in related phenotypes.

Original languageEnglish
Pages (from-to)24
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 5-Jan-2021

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