Males and females present differences in complex traits and in the risk of a wide array of diseases. Genotype by sex (GxS) interactions are thought to account for some of these differences. However, the extent and basis of GxS are poorly understood. In the present study, we provide insights into both the scope and the mechanism of GxS across the genome of about 450,000 individuals of European ancestry and 530 complex traits in the UK Biobank. We found small yet widespread differences in genetic architecture across traits. We also found that, in some cases, sex-agnostic analyses may be missing trait-associated loci and looked into possible improvements in the prediction of high-level phenotypes. Finally, we studied the potential functional role of the differences observed through sex-biased gene expression and gene-level analyses. Our results suggest the need to consider sex-aware analyses for future studies to shed light onto possible sex-specific molecular mechanisms.

男性和女性在复杂的特征和多种疾病的风险方面存在差异。性别基因型 (GxS) 相互作用被认为是其中一些差异的原因。然而，人们对 GxS 的范围和基础知之甚少。在本研究中，我们深入了解了英国生物库中约 450,000 名欧洲血统个体和 530 种复杂性状的基因组中 GxS 的范围和机制。我们发现不同性状的遗传结构存在微小但广泛的差异。我们还发现，在某些情况下，与性别无关的分析可能会丢失与性状相关的基因座，并研究了高水平表型预测的可能改进。最后，我们研究了通过性别偏见基因表达和基因水平分析观察到的差异的潜在功能作用。我们的结果表明，未来的研究需要考虑性别意识分析，以揭示可能的性别特异性分子机制。