Quantifying the phenome-wide disease burden of obesity using electronic health records and genomics

Objective High BMI is associated with many comorbidities and mortality. This study aimed to elucidate the overall clinical risk of obesity using a genome- and phenome-wide approach. Methods This study performed a phenome-wide association study of BMI using a clinical cohort of 736,726 adults. This was followed by genetic association studies using two separate cohorts: one consisting of 65,174 adults in the Electronic Medical Records and Genomics (eMERGE) Network and another with 405,432 participants in the UK Biobank. Results Class 3 obesity was associated with 433 phenotypes, representing 59.3% of all billing codes in individuals with severe obesity. A genome-wide polygenic risk score for BMI, accounting for 7.5% of variance in BMI, was associated with 296 clinical diseases, including strong associations with type 2 diabetes, sleep apnea, hypertension, and chronic liver disease. In all three cohorts, 199 phenotypes were associated with class 3 obesity and polygenic risk for obesity, including novel associations such as increased risk of renal failure, venous insufficiency, and gastroesophageal reflux. Conclusions This combined genomic and phenomic systematic approach demonstrated that obesity has a strong genetic predisposition and is associated with a considerable burden of disease across all disease classes.