A Phenome-wide Mendelian Randomisation study on genetically determined serum urate levels in UK Biobank cohort

ABSTRACT Introduction The role of serum urate level has been extensively investigated in observational studies. However, the extent of any causal effect remains unclear, making it difficult to evaluate its clinical relevance. Objectives To explore any causal or pleiotropic association between serum urate level and a broad spectrum of disease outcomes. Methods Phenome-wide association study (PheWAS) together with a Bayesian analysis of tree-structured phenotypic models (TreeWAS) was performed to examine disease outcomes related to genetically determined serum urate levels in 339,256 UK Biobank participants. Mendelian Randomisation (MR) analyses were performed to replicate significant findings using various GWAS consortia data. Sensitivity analyses were conducted to examine possible pleiotropic effects on metabolic traits of the genetic variants used as instruments for serum urate. Results PheWAS analysis, examining the association with 1,431 disease outcomes, identified a multitude of disease outcomes including gout, hypertension, hypercholesterolemia, and heart diseases (e.g., coronary atherosclerosis, myocardial infarction, and ischaemic heart disease) that were associated (p<3.35e-04) with genetically determined serum urate levels. TreeWAS analysis, examining 10,750 ICD-10 diagnostic terms, identified more sub-phenotypes of cardiovascular and cerebrovascular diseases (e.g., angina pectoris, heart failure, cerebral infarction). MR analysis successfully replicated the association with gout, hypertension, heart diseases and blood lipid levels, but indicated the existence of genetic pleiotropy. Sensitivity analyses support an inference that pleiotropic effects of genetic variants on urate and metabolic traits contribute to the observational associations with cardiovascular diseases. Conclusions High serum urate levels are associated with different types of cardiac events. The finding of genetic pleiotropy indicates the existence of common upstream pathological elements influencing both urate and metabolic traits, and this may suggest new opportunities and challenges for developing drugs targeting a more distal mediator that would be beneficial for both the treatment of gout and the prevention of cardiovascular comorbidities.