Independent association of leg-height ratio with 15 cardiometabolic diseases

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:

Supplementary Information: The online version contains supplementary material available at 10.1186/s12933-025-03074-z.

Keywords: Cardiometabolic diseases; GWAS; Genetic association; Height; Leg-height ratio; Phenotypic association.

Fig. 1

a Manhattan plots of genome-wide association studies for height and LHR. The p value was capped at 1 × 10⁻⁵⁰ to alleviate the impact of lead SNPs with extreme p values. Variants with capped p < 1 × 10⁻²⁰ that remained independent after COJO analysis were annotated by their nearest genes. Black and blue annotations denote height-specific and LHR-specific signals, respectively, while shared signals are annotated in purple. b Heatmap shows genetic correlations between height, LHR, and 15 cardiometabolic diseases. The r_g values range from −1 (perfect negative correlation) to 1 (perfect positive correlation). *FDR-adjusted P < 0.05, **P < 0.01, ***P < 0.001. c Comparison of effect sizes of significant SNPs on height from our GWAS and those reported by the GIANT consortium (2022). d Effect sizes of significant SNPs on both height and LHR from our GWAS. LHR leg-height ratio, AF atrial fibrillation, VTE venous thromboembolism, CM cardiomyopathy, AA aortic aneurysm, HF heart failure, CKD chronic kidney disease, HS hemorrhagic stroke, IS ischemic stroke, PAC peripheral artery calcification, AS all types of stroke, T2D type 2 diabetes, TIA transient ischemic attack, CAD coronary artery disease, HT hypertension, MI myocardial infarction, SNP single nucleotide polymorphism

Fig. 2

Phenotypic associations of height and LHR with 15 cardiometabolic diseases in 323,765 individuals from the UK Biobank. Associations with P < 0.05/120 = 4.17 × 10⁻⁴ were considered statistically significant after Bonferroni correction. LHR leg-height ratio, AF atrial fibrillation, VTE venous thromboembolism, CM cardiomyopathy, AA aortic aneurysm, HF heart failure, CKD chronic kidney disease, HS hemorrhagic stroke, IS ischemic stroke, PAD peripheral artery disease, AS all types of stroke, T2D type 2 diabetes, TIA transient ischemic attack, CAD coronary artery disease, HT hypertension, MI myocardial infarction

Fig. 3

Joint associations of height and LHR with cardiometabolic diseases. Individuals were stratified into three categories separately for each trait: height was grouped into short (bottom 20%), medium (middle 60%), and tall (top 20%), while LHR was grouped into low (bottom 20%), medium (middle 60%), and high (top 20%). The reference group comprised individuals with both height and LHR in the medium range. * Adjusted P < 0.05, **P < 0.01, ***P < 0.001. LHR leg-height ratio, AF atrial fibrillation, VTE venous thromboembolism, CM cardiomyopathy, AA aortic aneurysm, HF heart failure, CKD chronic kidney disease, HS hemorrhagic stroke, IS ischemic stroke, PAD peripheral artery disease, AS all types of stroke, T2D type 2 diabetes, TIA transient ischemic attack, CAD coronary artery disease, HT hypertension, MI myocardial infarction

Fig. 4

Mediation analysis results. The Sankey plot illustrates the mediation analysis results of Height and LHR on four cardiometabolic diseases: CAD, MI, T2D, and HT. The numbers represent the mediation proportion (%) of each path from left to right. All mediators shown are statistically significant (P < 0.0001) and have a mediation proportion ≥ 5%. LHR leg-height ratio, HDL-c high-density lipoprotein cholesterol, APOA apolipoprotein A, APOB apolipoprotein B, AST/ALT aspartate aminotransferase to alanine aminotransferase ratio, ALT alanine aminotransferase, TG triglycerides, UA uric acid, GLU fasting glucose, HbA1c glycated hemoglobin A1c, CYS cystatin C, TBIL total bilirubin, NEUT neutrophils, WBC white blood cell count, CRP C-reactive protein, CAD coronary artery disease, MI myocardial infarction, T2D type 2 diabetes, HT hypertension

Fig. 5

Colocalization analysis results. a Colocalization analysis identified shared genetic variants between height or LHR and cardiometabolic diseases with significant genetic correlations; a posterior probability hypothesis 4 of shared signal (PP.H4) > 0.9 was considered evidence of colocalization. b–f LocusZoom plots illustrate representative regions of colocalized loci. LHR leg-height ratio, AF atrial fibrillation, VTE venous thromboembolism, CM cardiomyopathy, AA aortic aneurysm, T2D type 2 diabetes, CAD coronary artery disease, HT hypertension, MI myocardial infarction

Fig. 6

Tissue and cell-type enrichment analyses results. a Bar plot shows top 15 significantly enriched tissues for height and LHR. b Chord plot shows tissue enrichment of trait pairs between height or LHR and cardiometabolic diseases. Only display the top 10 significantly enriched tissues for each trait. c Bar plot shows top 15 significantly enriched cells for height and LHR. d Bar plot shows cell-type enrichment of trait pairs between height or LHR and cardiometabolic diseases. Only display the top 10 significantly enriched cells for each trait. Line thickness in chord plots indicates statistical significance (−log₁₀ adjusted P-value). Tissue enrichment analysis conducted on FUMA and cell-type enrichment analysis conducted on WebCSEA. All analysis based on significant genes retained from gene-based analysis using MAGMA. LHR leg-height ratio, AF atrial fibrillation, VTE venous thromboembolism, AA aortic aneurysm, T2D type 2 diabetes, CAD coronary artery disease, HT hypertension, MI myocardial infarction

Fig. 7

GO and KEGG enrichment results. a Gene Ontology biological process enrichment for shared genes between height or LHR and cardiometabolic disease. b Kyoto Encyclopedia of Genes and Genomes pathway enrichment for the same gene sets. LHR leg-height ratio, AF atrial fibrillation, T2D type 2 diabetes, CAD coronary artery disease, HT hypertension, MI myocardial infarction