LAUSR

OBJECTIVES We aim to clarify the genetic overlaps underlying obesity-related traits, serum urate, and gout. METHODS We conducted a comprehensive genome-wide cross-trait analysis to identify genetic correlation, pleiotropic loci and causal relationship between obesity (exposures), gout (primary outcome) and serum urate (secondary outcome). Summary statistics were collected from the hitherto largest genome-wide association studies conducted for body mass index (BMI; N = 806 834), waist-to-hip ratio (WHR; N = 697 734), WHR adjusted for BMI (WHRadjBMI; N = 694 649), serum urate (N = 288 649), and gout (Ncase = 13 179 and Ncontrol = 750 634). RESULTS Positive overall genetic correlations were observed for BMI (rg =0.27, P = 6.62 × 1 0 -7), WHR (rg =0.22, P = 6.26 × 1 0 -7), and WHRadjBMI (rg =0.07, P = 6.08 × 1 0 -3) with gout. Partitioning the whole genome into 1,703 LD-independent regions, a significant local signal at 4q22 was identified for BMI and gout. The global and local shared genetic basis was further strengthened by the multiple pleiotropic loci identified in the cross-phenotype association study, multiple shared gene-tissue pairs observed by Transcriptome-wide association studies as well as causal relationships demonstrated by Mendelian randomization (BMI-gout: OR = 1.66, 95%CI = 1.45-1.88; WHR-gout: OR = 1.57, 95%CI = 1.37-1.81). Replacing the binary disease status of gout with its latent pathological measure serum urate, a similar pattern of correlation, pleiotropy, and causality was observed with even more pronounced magnitude and significance. CONCLUSION Our comprehensive genome-wide cross-trait analysis demonstrates a shared genetic basis, pleiotropic loci, as well as a causal relationship between obesity, serum urate, and gout, highlighting an intrinsic link underlying these complex traits.