Genetic insights of waist-to-height ratio on the risk of steatotic and advanced liver diseases: genome-wide association study and polygenic risk score-based analyses

The waist-to-height ratio (WHtR) is a simple and effective indicator to measure central obesity. However, the genetic basis and clinical implications of WHtR in relation to steatotic and advanced liver diseases remain largely unexplored. We performed a genome-wide association study (GWAS) in European individuals from the UK Biobank to identify genetic variants associated with WHtR, followed by extensive post-GWAS assessments, including colocalization analysis, transcriptome-wide association studies (TWAS), and LD score regression. Logistic and Cox regression, and interaction analysis, were employed to evaluate the impact of WHtR PRS on alcoholic and non-alcoholic fatty liver disease (AFLD and NAFLD), metabolic dysfunction-associated steatotic liver disease (MASLD), liver fibrosis, end-stage liver disease (ESLD), and liver cancer. Our GWAS identified 2,280 significant single nucleotide polymorphisms (SNPs) that were independently associated with WHtR. Colocalization analyses revealed that 55 SNPs influenced both WHtR and gene expression (including VEGFB, EZH1, CCND2 and etc.) in the visceral fat tissue. TWAS confirmed the involvement of these SNPs in visceral fat gene regulation. LD score regression analysis demonstrated that WHtR had significant positive genetic correlations with AFLD (rg = 0.123, p = 4.29 × 10⁻²), NAFLD (rg = 0.178, p = 1.78 × 10⁻⁷), and liver fibrosis (rg = 0.171, p = 2.57 × 10⁻²), yet no significant association was found with hepatocellular carcinoma (rg = 0.015, p = 0.872). Furthermore, the WHtR PRS was associated with increased risk of AFLD (OR = 1.09 [95% CI 1.03–1.13], p = 0.002), NAFLD (OR = 1.10 [95% CI 1.07–1.12], p < 0.001), MASLD (OR = 1.13 [95% CI 1.12–1.14], p < 0.001) and liver fibrosis (OR = 1.11 [95% CI 1.08–1.14], p < 0.001), although there was no statistical significance in relation to ESLD (p = 0.104) and hepatocellular carcinoma (p = 0.108). These findings were further corroborated by Cox regression analysis using WHtR PRS as well as logistic and Cox regression analysis using WHtR measures. The restricted cubic spline regression suggested potential linear relationships of WHtR PRS on the risks of NAFLD, MASLD and liver fibrosis. Notably, Gene-environment interaction analysis indicated that metabolic status, diabetes, and healthy dietary patterns could modulate the genetic liability to a high WHtR to the risk of NAFLD, MASLD, and liver fibrosis. The study identified WHtR-related genetic variants and their roles in gene regulation in visceral adipose tissue. Individuals predisposed to high WHtR constituted a high-risk group in developing alcoholic liver disease, NAFLD, MASLD and liver fibrosis. Our study highlights the value of WHtR for the risk assessment and personalized disease surveillance in steatotic liver diseases.