Li Haochang, Hui Shirong, Cai Xuehong, He Ran, Yu Meijie, Li Yihao, Yu Rongbin, Huang Peng
Department of Epidemiology, Center for Global Health, School of Public Health, Key Laboratory of Public Health Safety and Emergency Prevention and Control Technology of Higher Education Institutions in Jiangsu Province, National Vaccine Innovation Platform, Nanjing Medical University, Nanjing 211166, China.
Genes (Basel). 2025 Jun 16;16(6):711. doi: 10.3390/genes16060711.
Obesity significantly impacts disease burden, with waist-to-hip ratio (WHR) as a key obesity indicator, but the genetic and biological pathways underlying WHR, particularly its sex-specific differences, remain poorly understood. This study explored WHR's sexual dimorphism and its links to complex traits using cross-sectional surveys and genetic data from Giant and UK Biobank (UKB). We analyzed WHR heritability, performed tissue-specific transcriptome-wide association studies (TWAS) using FUSION, and conducted genetic correlation analyses with linkage disequilibrium score regression (LDSC) and Local Analysis of [co]Variant Association (LAVA). Polygenic scores (PGS) for WHR were constructed using the clumping and thresholding method (CT), and associations with complex traits were assessed via logistic or linear models. The genetic analysis showed sex-specific heritability for WHR, with TWAS identifying female-specific (e.g., ) and male-specific (e.g., ) genes. Global genetic correlation analysis revealed sex-specific associations between WHR and 23 traits, while local analysis identified eight sex-specific loci across five diseases. Regression analysis highlighted sex-specific associations for 70 traits with WHR and 45 traits with WHR PGS, with stronger effects in females. Predictive models also performed better in females. This study underscores WHR's sexual dimorphism and its distinct associations with complex traits, offering insights into sex-specific biological differences, health management, and clinical advancements.
肥胖显著影响疾病负担，腰臀比（WHR）是关键的肥胖指标，但WHR背后的遗传和生物学途径，尤其是其性别特异性差异，仍知之甚少。本研究利用来自“巨人”（Giant）和英国生物银行（UKB）的横断面调查和遗传数据，探讨了WHR的性别二态性及其与复杂性状的联系。我们分析了WHR的遗传力，使用FUSION进行了组织特异性全转录组关联研究（TWAS），并通过连锁不平衡评分回归（LDSC）和[共]变体关联局部分析（LAVA）进行了遗传相关性分析。使用聚类和阈值法（CT）构建了WHR的多基因评分（PGS），并通过逻辑或线性模型评估其与复杂性状的关联。遗传分析显示WHR具有性别特异性遗传力，TWAS鉴定出了女性特异性（如……）和男性特异性（如……）基因。全球遗传相关性分析揭示了WHR与23个性状之间的性别特异性关联，而局部分析在五种疾病中鉴定出了八个性别特异性位点。回归分析突出了WHR与70个性状以及WHR PGS与45个性状之间的性别特异性关联，女性中的效应更强。预测模型在女性中也表现得更好。本研究强调了WHR的性别二态性及其与复杂性状的独特关联，为性别特异性生物学差异、健康管理和临床进展提供了见解。
