PD04-08 POLYGENIC RISK SCORE ASSOCIATES WITH URINARY TRACT STONE DIAGNOSIS IN MULTIETHNIC COHORT

Abstract

INTRODUCTION AND OBJECTIVE: Urinary tract stones have high heritability indicating a strong genetic component. However, genome wide association studies (GWAS) have uncovered only a few genome wide significant single nucleotide polymorphisms (SNPs). Polygenic scores sum the cumulative effect of many SNPs and shed light on underlying genetic architecture. METHODS: Using LDPred adjusted GWAS summary statistics from the UK Biobank (n=361,141), we generated a polygenic risk score (PRS) for urinary tract stone diagnosis which was ascertained using diagnostic codes. We then associated the PRS with stone diagnosis in a biobanked cohort using imputed genotyping data (BioMe Biobank, n=28,877) in a logistic regression model adjusted for ten genetic principal components (PCs), sex, age, body mass index (BMI), and history of gout, hypertension, and type 2 diabetes. Analyses were performed separately in racial groups and a meta-analysis was performed using the inverse-weighting method. A low risk cohort was defined as individuals with BMI <25 and no history of gout, hypertension, or type 2 diabetes. RESULTS: In our cohort (1,071 cases, 27,828 controls), for every standard deviation (SD) increase in PRS, we observed an increment in adjusted odds ratio (OR) of 1.2 (95% confidence interval 1.13-1.26; p<0.001). Individuals in the top PRS decile had adjusted OR of 2.6 (95% confidence interval 1.9 -3.6; p<0.001) for diagnosis compared to the lowest decile. Upon stratifying by clinical risk factors, we observed an increment in adjusted OR of 1.3 (95% confidence interval 1.12 - 1.58; p = 0.001) in the low-risk and 1.2 (95% confidence interval 1.1 - 1.2; p = 1.1 x 10-6) in the high-risk group for every SD increment in PRS. CONCLUSIONS: This study shows that a genome wide polygenic score is associated with urinary tract stones overall and in the absence of known clinical risk factors and provides insight into the complex genetic architecture of stones. This score may allow for early stratification of urinary tract stone risk in individuals without a history of stone formation or other clinical risk factors. (Figure Presented).