Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
Department of Microbiology and Immunology, Laboratory of Adaptive Immunity, KU Leuven, Leuven, Belgium.
Nat Commun. 2021 Jan 5;12(1):24. 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.
性别差异导致空腹血糖和胰岛素水平的变化。流行病学研究表明，男性空腹血糖受损的患病率较高，女性葡萄糖耐量受损的患病率较高，但这一现象背后的遗传因素尚未确定。我们通过对无糖尿病的欧洲血统个体进行全基因组关联研究荟萃分析，评估了性别二态性（73089/50404 名女性和 67506/47806 名男性）和性别综合（151188/105056 人）的空腹血糖/空腹胰岛素遗传效应。在这里，我们报告了 IRS1 和 ZNF12 基因座上空腹胰岛素的等位基因效应的性别二态性，后者在女性全血中的 RNA 表达高于男性。我们还观察到七个新基因座上空腹葡萄糖的性别同质效应。与男性相比，女性的空腹胰岛素表现出更强的遗传相关性，与腰围臀围比和神经性厌食症的遗传相关性更强。此外，腰围臀围比与女性的胰岛素抵抗有关，但与男性无关。这些结果为理解女性和男性在相关表型中遗传效应的差异提供了代谢和血糖健康性别二态性的剖析作为一个切入点。
