Investigating the Sexual Dimorphism of Waist-to-Hip Ratio and Its Associations with Complex Traits.

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.