35 blood and urine biomarkers in Polycystic Kidney Disease: a bidirectional Mendelian randomization study

Abstract

Polycystic Kidney Disease (PKD), a highly prevalent hereditary condition, presents significant gaps in understanding its early-stage pathophysiology and lacks reliable biomarkers to capture these early mechanistic changes. In this investigation, we leveraged a bidirectional Mendelian randomization(MR) analysis, utilizing data from comprehensive genome-wide association studies (GWAS) to systematically explore the causal relationships between serum and urine biomarkers and PKD onset. Instrumental variable selection adhered to stringent criteria to ensure methodological rigor and robust causal inference. Our primary analytical method, inverse variance weighted (IVW), was complemented by MR-Egger, Weighted Median, and Weighted Mode sensitivity analyses to account for pleiotropy and other biases. Heterogeneity was tested using the Cochrane Q statistic, while horizontal pleiotropy was probed via the MR-Egger intercept test and MR-PRESSO global test. Sensitivity to instrument selection was evaluated with a Leave-one-out analysis. The MR analysis identified two serum biomarkers—Gamma-Glutamyl Transferase (GGT) and Sex Hormone-Binding Globulin (SHBG)—as exhibiting statistically significant causal associations with PKD risk. However, reverse MR analysis revealed no significant feedback effect of PKD genetic liability on these biomarker levels. These findings highlight GGT and SHBG as potential biomarkers for early PKD detection, offering novel insights into its pathobiological underpinnings and informing future therapeutic target development.