Abstract
BACKGROUND: The association between adult height and coronary artery disease (CAD) was established a decade ago. Accumulating evidence has since linked adult height to a variety of cardiometabolic diseases (CMD). As waist-hip ratio (WHR) has become an increasingly important independent risk factor in addition to body mass index, we aim to assess whether leg-height ratio (LHR) could also be a risk factor independent of overall height. METHODS: LHR was defined as the ratio of leg length to standing height and further adjusted for overall height by regression. Using data from UK Biobank, we first performed genome-wide association study (GWAS) of LHR and height, then assessed their associations with 15 major CMD at phenotypic and genetic levels. Mediation and colocalization analyses were conducted to identify mediators and shared variants. RESULTS: We identified 747 genome-wide significant variants of LHR after stepwise conditional and joint analysis. SNP-based heritability was estimated at 24% for LHR, versus 47% for height. A low LHR (bottom 20%) was associated with a substantially higher risk of CAD than a medium (middle 60%) or high (top 20%) LHR, regardless of the height category. This pattern is pronounced for type 2 diabetes (T2D), where tall individuals with low LHR exhibit higher risk (HR = 1.39 [1.29−1.49], P = 2.7 × 10(–20)) than individuals of short or medium height with higher LHR. Lipids (especially high-density lipoprotein cholesterol) primarily mediated the protective effect of LHR on CMD, whereas inflammatory markers (especially neutrophils) mainly mediated the effect of height on CMD. Colocalization analyses revealed LHR-specific variants shared with CMD, including notable colocalization with T2D at the JAZF1 locus. CONCLUSIONS: LHR has independent and differential effects on a suite of CMD traits. The protective association between LHR and CMD is mainly mediated by lipids, and genes shared between LHR and these outcomes are predominantly enriched in development and differentiation of skeletal and embryonic tissues. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12933-025-03074-z.