Local genetic covariance between serum urate and kidney function estimated with Bayesian multitrait models

Abstract

Hyperuricemia (serum urate >6.8 mg/dl) is associated with several cardiometabolic and renal diseases, such as gout and chronic kidney disease. Previous studies have examined the shared genetic basis of chronic kidney disease and hyperuricemia in humans either using single-variant tests or estimating whole-genome genetic correlations between the traits. Individual variants typically explain a small fraction of the genetic correlation between traits, thus the ability to map pleiotropic loci is lacking power for available sample sizes. Alternatively, whole-genome estimates of genetic correlation indicate a moderate correlation between these traits. While useful to explain the comorbidity of these traits, whole-genome genetic correlation estimates do not shed light on what regions may be implicated in the shared genetic basis of traits. Therefore, to fill the gap between these two approaches, we used local Bayesian multitrait models to estimate the genetic covariance between a marker for chronic kidney disease (estimated glomerular filtration rate) and serum urate in specific genomic regions. We identified 134 overlapping linkage disequilibrium windows with statistically significant covariance estimates, 49 of which had positive directionalities, and 85 negative directionalities, the latter being consistent with that of the overall genetic covariance. The 134 significant windows condensed to 64 genetically distinct shared loci which validate 17 previously identified shared loci with consistent directionality and revealed 22 novel pleiotropic genes. Finally, to examine potential biological mechanisms for these shared loci, we have identified a subset of the genomic windows that are associated with gene expression using colocalization analyses. The regions identified by our local Bayesian multitrait model approach may help explain the association between chronic kidney disease and hyperuricemia.

Keywords: UK Biobank; chronic kidney disease; eGFR; gout; hyperuricemia; local genetic covariance; multitrait; pleiotropy; serum creatinine; serum urate.