2615-P: Identification of Pleiotropic Loci Underlying Obesity and MASLD Using Multivariate GWAS

Introduction and Objective: Obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) are highly comorbid, but shared genetic mechanisms are unclear. We quantified genetic overlap and prioritized shared loci and regulatory genes. Methods: European-ancestry GWAS summary data were used for body mass index (BMI), BMI-adjusted waist circumference (WCadjBMI), waist-to-hip ratio (WHRadjBMI), hip circumference (HIPadjBMI), and MASLD. We applied linkage disequilibrium (LD) score regression, conditional/conjunctional false discovery rate (condFDR/conjFDR), multi-trait analysis of GWAS (MTAG), and summary-based Mendelian randomization (SMR) integrating liver, subcutaneous adipose, and visceral adipose eQTLs. Results: MASLD was positively correlated with BMI (rg=0.687; p=1.30×10−6), WCadjBMI (rg=0.260; p=2.09×10−2), and WHRadjBMI (rg=0.522; p=3.00×10−4), and negatively correlated with HIPadjBMI (rg=−0.273; p=9.90×10−3). condFDR identified 31 MASLD loci and 184 obesity-trait loci; conjFDR revealed 23 shared loci. MTAG detected 174 MASLD-related and 482 obesity-related risk loci. SMR highlighted both shared and tissue-specific expression effects across liver and adipose tissues. Conclusion: Multi-method analyses demonstrate substantial genetic sharing between obesity traits and MASLD, identify pleiotropic loci, and nominate tissue-specific regulatory genes that may inform risk stratification and therapeutic target discovery. Disclosure S. Wang: None.