TY - JOUR
T1 - Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
AU - Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)
AU - Lagou, Vasiliki
AU - Mägi, Reedik
AU - Hottenga, Jouke Jan
AU - Grallert, Harald
AU - Perry, John R.B.
AU - Bouatia-Naji, Nabila
AU - Marullo, Letizia
AU - Rybin, Denis
AU - Jansen, Rick
AU - Min, Josine L.
AU - Dimas, Antigone S.
AU - Ulrich, Anna
AU - Zudina, Liudmila
AU - Gådin, Jesper R.
AU - Jiang, Longda
AU - Faggian, Alessia
AU - Bonnefond, Amélie
AU - Fadista, Joao
AU - Stathopoulou, Maria G.
AU - Isaacs, Aaron
AU - Willems, Sara M.
AU - Navarro, Pau
AU - Tanaka, Toshiko
AU - Jackson, Anne U.
AU - Montasser, May E.
AU - O’Connell, Jeff R.
AU - Bielak, Lawrence F.
AU - Webster, Rebecca J.
AU - Saxena, Richa
AU - Stafford, Jeanette M.
AU - Pourcain, Beate St
AU - Timpson, Nicholas J.
AU - Salo, Perttu
AU - Shin, So Youn
AU - Amin, Najaf
AU - Smith, Albert V.
AU - Li, Guo
AU - Verweij, Niek
AU - Goel, Anuj
AU - Ford, Ian
AU - Johnson, Paul C.D.
AU - Johnson, Toby
AU - Kapur, Karen
AU - Thorleifsson, Gudmar
AU - Strawbridge, Rona J.
AU - Rasmussen-Torvik, Laura J.
AU - Esko, Tõnu
AU - Mihailov, Evelin
AU - Fall, Tove
AU - Fraser, Ross M.
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85099096262
U2 - 10.1038/s41467-020-19366-9
DO - 10.1038/s41467-020-19366-9
M3 - Article
C2 - 33402679
AN - SCOPUS:85099096262
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 24
ER -