Abstract
We conducted a comprehensive genetic investigation of obesity in a cohort of 93,673 Korean individuals, categorized by body mass index and waist circumference using Korean-specific and international criteria. To explore the genetic architecture of obesity and its related comorbidities, we performed genome-wide association studies and constructed polygenic risk scores (PRSs) using both conventional single-trait and advanced multiple-trait models, including the PRSsum approach. Our analyses identified genome-wide significant loci and demonstrated their higher heritability for general obesity than for abdominal obesity, and for moderate obesity than for severe obesity. East Asian populations showed stronger genetic correlations between abdominal obesity and obesity-related diseases. Both single-trait and multiple-trait PRSs stratified individuals by risk, with low-PRS individuals exhibiting reduced risk for obesity, hypertension, and type 2 diabetes, while high-PRS individuals displayed elevated risk, particularly under the multiple-trait model. Interaction and mediation analyses revealed distinct genetic pathways through which obesity contributes to disease development. Collectively, our findings revealed key loci and shared genetic mechanisms linking obesity and its comorbidities in the Korean population. These insights highlight the value of multiple-trait PRS models and underscore the importance of ancestry-specific genetic research for addressing the obesity epidemic.