Introduction: Right ventricular (RV) enlargement has been associated with increased mortality, regardless of the etiology. Pathophysiologic determinants of RV structure, however, are under characterized. Examining genetic architecture underlying variation in RV size may identify etiologic risk factors contributing to RV enlargement. Therefore, we interrogated a polygenic predictor for RV size to identify etiologic drivers of RV structure. Methods: We studied 10,522 adult subjects of European ancestry in Vanderbilt University Medical Center’s de-identified DNA biobank (BioVU) who had undergone an echocardiogram including measurement of RV diameter. Bayesian Sparse Linear Mixed Modeling (GEMMA v0.95) was used to create a polygenic predictor of RV diameter. A PheWAS using logistic regression was then conducted to determine clinical diagnoses significantly associated with genetically-determined RV diameter. Further associations between identified clinical factors and RV diameter were examined using 2-sample bivariate and multivariable Mendelian randomization (MR). Results: PheWAS identified obesity-related clinical diagnoses as the most significantly associated with RV diameter (Figure 1). Univariate MR for body mass index (BMI), waist circumference, fat mass, and body impedance all demonstrated a causal and positive association with RV diameter. Multivariable MR demonstrated the association between measures of adiposity and RV diameter persisted even after accounting for the effect of pulmonary pressure. Conclusions: Genetic architecture is shared between adiposity and RV structure. Measures of adiposity are causally associated with genetically predicted larger RV diameter. Common pathophysiologic mechanisms may regulate adiposity and right heart structure, suggesting adiposity may represent an intervenable therapeutic target for RV failure.