Abstract
Background/Objectives: Diabetic kidney disease (DKD) is a common diabetic complication, driven by a multifactorial pathogenesis that includes various genetic components. However, the precise causative genes and their underlying biological pathways remain poorly understood. Methods: We performed a cross-tissue transcriptome-wide association study (TWAS) of DKD using expression quantitative trait loci (eQTL) data from 49 tissues in the Genotype-Tissue Expression (GTEx) version 8 (v8) resource. Five complementary analytical frameworks-sparse canonical correlation analysis (sCCA), functional summary-based imputation (FUSION), fine-mapping of causal gene sets (FOCUS), summary-data-based Mendelian randomization (SMR), and multi-marker analysis of genomic annotation (MAGMA)-were integrated to nominate candidate genes. Causal inference was refined using Mendelian randomization (MR), and biological significance was evaluated through pathway enrichment, protein interaction networks, and druggability profiling. Results: We identified 23 candidate genes associated with DKD risk, of which 13 were supported by MR analysis. Among these, 10 represent previously unreported susceptibility genes. Notably, four genes-HLA-DRB1, HLA-DRB5, NOTCH4, and CYP21A2-encode potentially druggable proteins, with HLA-DRB5 and CYP21A2 both qualifying as novel susceptibility genes and therapeutic targets. These genes converge on immune modulation, steroid biosynthesis, DNA repair, and transcriptional regulation-processes central to DKD pathogenesis. Conclusions: Our study represents the first systematic cross-tissue TWAS of DKD, revealing a prioritized set of genetically and functionally supported susceptibility genes. The identification of druggable targets among these genes provides critical insight into the mechanistic underpinnings of DKD and highlights their potential for future therapeutic development. These findings enhance our understanding of DKD pathophysiology and offer a foundation for precision medicine strategies in nephrology.