Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability.
Lagou V., Mägi R., Hottenga J-J., Grallert H., Perry JRB., Bouatia-Naji N., Marullo L., Rybin D., Jansen R., Min JL., Dimas AS., Ulrich A., Zudina L., Gådin JR., Jiang L., Faggian A., Bonnefond A., Fadista J., Stathopoulou MG., Isaacs A., Willems SM., Navarro P., Tanaka T., Jackson AU., Montasser ME., O'Connell JR., Bielak LF., Webster RJ., Saxena R., Stafford JM., Pourcain BS., Timpson NJ., Salo P., Shin S-Y., Amin N., Smith AV., Li G., Verweij N., Goel A., Ford I., Johnson PCD., Johnson T., Kapur K., Thorleifsson G., Strawbridge RJ., Rasmussen-Torvik LJ., Esko T., Mihailov E., Fall T., Fraser RM., Mahajan A., Kanoni S., Giedraitis V., Kleber ME., Silbernagel G., Meyer J., Müller-Nurasyid M., Ganna A., Sarin A-P., Yengo L., Shungin D., Luan J., Horikoshi M., An P., Sanna S., Boettcher Y., Rayner NW., Nolte IM., Zemunik T., Iperen EV., Kovacs P., Hastie ND., Wild SH., McLachlan S., Campbell S., Polasek O., Carlson O., Egan J., Kiess W., Willemsen G., Kuusisto J., Laakso M., Dimitriou M., Hicks AA., Rauramaa R., Bandinelli S., Thorand B., Liu Y., Miljkovic I., Lind L., Doney A., Perola M., Hingorani A., Kivimaki M., Kumari M., Bennett AJ., Groves CJ., Herder C., Koistinen HA., Kinnunen L., Faire UD., Bakker SJL., Uusitupa M., Palmer CNA., Jukema JW., Sattar N., Pouta A., Snieder H., Boerwinkle E., Pankow JS., Magnusson PK., Krus U., Scapoli C., de Geus EJCN., Blüher M., Wolffenbuttel BHR., Province MA., Abecasis GR., Meigs JB., Hovingh GK., Lindström J., Wilson JF., Wright AF., Dedoussis GV., Bornstein SR., Schwarz PEH., Tönjes A., Winkelmann BR., Boehm BO., März W., Metspalu A., Price JF., Deloukas P., Körner A., Lakka TA., Keinanen-Kiukaanniemi SM., Saaristo TE., Bergman RN., Tuomilehto J., Wareham NJ., Langenberg C., Männistö S., Franks PW., Hayward C., Vitart V., Kaprio J., Visvikis-Siest S., Balkau B., Altshuler D., Rudan I., Stumvoll M., Campbell H., van Duijn CM., Gieger C., Illig T., Ferrucci L., Pedersen NL., Pramstaller PP., Boehnke M., Frayling TM., Shuldiner AR., Peyser PA., Kardia SLR., Palmer LJ., Penninx BW., Meneton P., Harris TB., Navis G., Harst PVD., Smith GD., Forouhi NG., Loos RJF., Salomaa V., Soranzo N., Boomsma DI., Groop L., Tuomi T., Hofman A., Munroe PB., Gudnason V., Siscovick DS., Watkins H., Lecoeur C., Vollenweider P., Franco-Cereceda A., Eriksson P., Jarvelin M-R., Stefansson K., Hamsten A., Nicholson G., Karpe F., Dermitzakis ET., Lindgren CM., McCarthy MI., Froguel P., Kaakinen MA., Lyssenko V., Watanabe RM., Ingelsson E., Florez JC., Dupuis J., Barroso I., Morris AP., Prokopenko I., Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) None.
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.